Abstract: Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). In experimental investigations, lithium induces brain-derived neurotrophic factor (BDNF). Recent studies have found a decrease of BDNF in the serum and brains of AD patients with potentially consecutive lack of neurotrophic support. We assessed the influence of a lithium treatment on BDNF serum concentration in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. In AD patients treated with lithium, a significant increase of BDNF serum levels, and additionally a significant decrease of ADAS-Cog sum scores in comparison to placebo-treated patients, were found. Diminution of cognitive impairment was inversely correlated with lithium serum concentration. Upregulation of BDNF might be part of a neuroprotective effect of lithium in AD patients. The results of the present investigation encourage performing studies with longer treatment phases to observe potential positive long-term effects of lithium in AD patients.

Abstract: Mutations in the progranulin (PGRN) gene have recently been identified in families with frontotemporal lobar degeneration and ubiquitin-positive brain inclusions linked to chromosome 17q21. We have previously described a Swedish family displaying frontotemporal dementia with rapid progression and linkage to chromosome 17q21. In this study, we performed an extended clinical and neuropathological investigation of affected members of the family and a genetic analysis of the PGRN gene. There was a large variation of the initial presenting symptoms in this family, but common clinical features were non-fluent aphasia and loss of spontaneous speech as well as personality and behavioural changes. Mean age at onset was 54 years with disease duration of close to 4 years. Neuropathological examination revealed frontotemporal neurodegeneration with ubiquitin and TAR DNA binding protein-43 immunoreactive intraneuronal inclusions. Mutation screening of the PGRN gene identified a 1 bp deletion in exon 1 causing a frameshift of the coding sequence and introducing a premature termination codon in exon 2 (Gly35GlufsX19). Analysis of PGRN messenger RNA (mRNA) levels revealed a considerable decrease in lymphoblasts from mutation carriers and fragment size separation, and sequence analysis confirmed that the mutated mRNA allele was almost absent in these samples. In conclusion, the PGRN Gly35fs mutation causes frontotemporal dementia with variable clinical presentation in a large Swedish family, most likely through nonsense-mediated decay of mutant PGRN mRNA and resulting haploinsufficiency.

Abstract: OBJECTIVES: To study the effects of omega (Omega)-3 fatty acid (FA) supplements on weight and appetite in patients with mild to moderate Alzheimer's disease (AD) in relation to inflammatory biomarkers and apolipoprotein E epsilon4 (APOEepsilon4). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Specialist memory clinics in the Stockholm catchment area. PARTICIPANTS: Two hundred four patients (aged 73+/-9, 52% women) with mild to moderate AD. INTERVENTION: Patients with AD received 1.7 g of docosahexaenoic acid (DHA) and 0.6 g of eicosapentaenoic acid (EPA) (Omega-3/Omega-3 group; n=89, aged 73+/-9, 57% women) or placebo 0.6 g of linoleic acid per day (placebo/Omega-3 group; n=85, aged 73+/-9, 46% women) for 6 months. After 6 months, all patients received DHA and EPA for another 6 months. MEASUREMENTS: Anthropometry, biochemical nutritional and inflammatory markers, and appetite assessed by caregiver. RESULTS: Mean weight and body mass index (kg/m(2)) at baseline were 70.0+/-11.8 kg and 24.3+/-3.0 kg/m(2), respectively. At 6- and 12-month follow-up, weight had increased 0.7+/-2.5 kg (P=.02) and 1.4+/-2.9 kg (P<.001) in the Omega-3/Omega-3 group. In the placebo group, weight was unchanged at 6 months but had increased (P=.01) at 12 months follow-up after Omega-3 supplementation was initiated. Appetite improved in the Omega-3/Omega-3 group over the treatment period (P=.01). In logistic regression analyses, not carrying the APOEepsilon4 allele and high plasma DHA concentrations were independently related to weight gain in the combined group of patients at 6 months follow-up. CONCLUSION: A DHA-enriched Omega-3 FA supplement may positively affect weight and appetite in patients with mild to moderate AD. Not carrying the APOEepsilon4 allele and high DHA were independently associated with weight gain.

Abstract: BACKGROUND: Epidemiological and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids (omega3), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may have effects in psychiatric and behavioral symptoms in Alzheimer's disease (AD). An association with APOEomega4 carriers and neuropsychiatric symptoms in AD has also been suggested. OBJECTIVE: To determine effects of dietary omega3 supplementation to AD patients with mild to moderate disease on psychiatric and behavioral symptoms, daily functions and a possible relation to APOEgenotype. METHODS: Randomized, double-blind, placebo-controlled clinical trial where 204 AD patients (74+/-9 years) with acetylcholine esterase inhibitor treatment and a MMSE>15 points were randomized to daily intake of 1.7 g DHA and 0.6 g EPA (omega3 group) or placebo for 6 months. Then, all received the omega3 supplementation for 6 more months. Neuropsychiatric symptoms were measured with Neuropsychiatric Inventory (NPI) and Montgomery Asberg Depression Scale (MADRS). Caregivers burden and activities of daily living (Disability Assessment for Dementia, DAD) were also assessed. RESULTS: One hundred and seventy-four patients fulfilled the trial. 72% were APOEomega4 carriers. No significant overall treatment effects on neuropsychiatric symptoms, on activities of daily living or on caregiver's burden were found. However, significant positive treatment effects on the scores in the NPI agitation domain in APOEomega4 carriers (p=0.006) and in MADRS scores in non-APOEomega4 carriers (p=0.005) were found. CONCLUSIONS: Supplementation with omega3 in patients with mild to moderate AD did not result in marked effects on neuropsychiatric symptoms except for possible positive effects on depressive symptoms (assessed by MADRS) in non-APOEomega4 carriers and agitation symptoms (assessed by NPI) in APOEomega4 carriers. ClinicalTrials.gov identifier: NCT00211159

Abstract: BACKGROUND: Beta amyloid (Abeta) protein accumulates in the brains of individuals with Alzheimer disease (AD) and is detectable in cerebrospinal fluid and plasma. OBJECTIVE: To examine plasma levels of Abeta peptides Abeta(40) and Abeta(42) as predictors of incident AD and other types of dementia. DESIGN: Prospective, population-based cohort study. SETTING: The Uppsala Longitudinal Study of Adult Men. PARTICIPANTS: Plasma Abeta(40) and Abeta(42) levels were analyzed as predictors of incident AD in 1045 men at age 70 years and 680 men at age 77 years using Cox proportional hazards analyses. Alzheimer disease and other types of dementia were diagnosed by standardized screening, clinical evaluation, and medical record review. MAIN OUTCOME MEASURES: Hazard ratios of AD (primary outcome) and vascular dementia or other dementia (secondary outcomes) according to baseline levels of plasma Abeta(40) and Abeta(42). RESULTS: From the age of 77 years at baseline, 46 individuals developed AD at follow-up (median, 5.3 years). A low plasma Abeta(40) level at age 77 years was associated with higher incidence of AD. The multivariate-adjusted hazard ratio was 4.87 (95% confidence interval, 1.63-14.6) for the lowest Abeta(40) tertile compared with the highest tertile. On follow-up from age 70 years at baseline (median, 11.2 years), 82 individuals developed AD. Plasma Abeta(40) and Abeta(42) levels measured at age 70 years were not significantly associated with incident AD. CONCLUSIONS: Low plasma Abeta(40) levels predicted incident AD in elderly men independently of potential confounders. Plasma Abeta(42) levels were not significantly associated with AD incidence. The clinical value of Abeta measurement in plasma remains to be established in future studies.

Abstract: BACKGROUND: Dietary fish or fish oil rich in n-3 fatty acids (n-3 FAs), eg, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms. Whereas most studies have explored the effects of predominantly EPA-based n-3 FAs preparations, few have addressed the effects of n-3 FAs preparations with DHA as the main FA. OBJECTIVE: The objective was to determine the effects of 6 mo of dietary supplementation with an n-3 FAs preparation rich in DHA on release of cytokines and growth factors from peripheral blood mononuclear cells (PBMCs). DESIGN: In a randomized, double-blind, placebo-controlled trial, 174 Alzheimer disease (AD) patients received daily either 1.7 g DHA and 0.6 g EPA (n-3 FAs group) or placebo for 6 mo. In the present study blood samples were obtained from the 23 first randomized patients, and PBMCs were isolated before and after 6 mo of treatment. RESULTS: Plasma concentrations of DHA and EPA were significantly increased at 6 mo in the n-3 FAs group. This group also showed significant decreases of interleukin (IL)-6, IL-1beta, and granulocyte colony-stimulating factor secretion after stimulation of PBMCs with lipopolysaccharide. Changes in the DHA and EPA concentrations were negatively associated with changes in IL-1beta and IL-6 release for all subjects. Reductions of IL-1beta and IL-6 were also significantly correlated with each other. In contrast, this n-3 FA treatment for 6 mo did not decrease tumor necrosis factor-alpha, IotaL-8, IL-10, and granulocyte-macrophage colony-stimulating factor secretion. CONCLUSION: AD patients treated with DHA-rich n-3 FAs supplementation increased their plasma concentrations of DHA (and EPA), which were associated with reduced release of IL-1beta, IL-6, and granulocyte colony-stimulating factor from PBMCs. This trial was registered at clinicaltrials.gov as NCT00211159.

Abstract: BACKGROUND: A majority of mutations within the beta-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. OBJECTIVE: To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation. DESIGN, SETTING, AND PARTICIPANTS: Affected and nonaffected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. RESULTS: The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character. CONCLUSIONS: Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.

Abstract: BACKGROUND: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD). METHODS: Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects. RESULTS: On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-beta protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 micromol/L] vs highest [>1.30 micromol/L] tertile = 2.67, 95% CI 1.22-5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-mumol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03-1.63, p < 0.03). CONCLUSIONS: Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.

Abstract: Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau(181)) and the 42 amino acid isoform of beta-amyloid (Abeta42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (+/-S.D.) 76.1+/-7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4-6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p<0.0001), for all three markers. We conclude that T-tau, P-tau and Abeta42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Abeta immunotherapy and tau phosphorylation inhibitors.

Abstract:

Abstract: BACKGROUND: Memantine is a moderate affinity N-methyl-D-aspartate receptor antagonist approved for treatment of Alzheimer's disease (AD). In AD, tau is abnormally hyperphosphorylated. However, no significant changes of phosphorylated tau levels in CSF are found at follow-up in studies with AD patients. It has been shown in vitro that memantine reverse induced abnormal hyperphosphorylation of tau in hippocampal neurons of rats. METHODS: Eleven AD patients were examined with cognitive tests and interviews of relatives. CSF analyses were performed before starting treatment with memantine as well as after 1 year. RESULTS: A statistically significant reduction of CSF phosphorylated tau at the 1-year follow-up was seen, from median 126 (interquartile range 107-153) to 108 (88-133) ng/l (p = 0.018). No statistically significant differences of total tau or Abeta42 were found. CONCLUSION: The results may reflect effects of memantine on a key pathological feature in AD in line with previous in vitro findings.

Abstract: BACKGROUND: Epidemiologic and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids, for example, docosahexaenoic acid and eicosapentaenoic acid, may prevent Alzheimer disease (AD). OBJECTIVE: To determine effects of dietary omega-3 fatty acid supplementation on cognitive functions in patients with mild to moderate AD. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. PARTICIPANTS: Two hundred four patients with AD (age range [mean +/- SD], 74 +/- 9 years) whose conditions were stable while receiving acetylcholine esterase inhibitor treatment and who had a Mini-Mental State Examination (MMSE) score of 15 points or more were randomized to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic acid (omega-3 fatty acid-treated group) or placebo for 6 months, after which all received omega-3 fatty acid supplementation for 6 months more. MAIN OUTCOME MEASURES: The primary outcome was cognition measured with the MMSE and the cognitive portion of the Alzheimer Disease Assessment Scale. The secondary outcome was global function as assessed with the Clinical Dementia Rating Scale; safety and tolerability of omega-3 fatty acid supplementation; and blood pressure determinations. RESULTS: One hundred seventy-four patients fulfilled the trial. At baseline, mean values for the Clinical Dementia Rating Scale, MMSE, and cognitive portion of the Alzheimer Disease Assessment Scale in the 2 randomized groups were similar. At 6 months, the decline in cognitive functions as assessed by the latter 2 scales did not differ between the groups. However, in a subgroup (n = 32) with very mild cognitive dysfunction (MMSE >27 points), a significant (P<.05) reduction in MMSE decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group. A similar arrest in decline rate was observed between 6 and 12 months in this placebo subgroup when receiving omega-3 fatty acid supplementation. The omega-3 fatty acid treatment was safe and well tolerated. CONCLUSIONS: Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD (MMSE >27 points).

Abstract: BACKGROUND: Subjects with dementia are at risk for protein-energy malnutrition. OBJECTIVE: To study the nutritional status, the short-term effects of adapted nutritional routines and the long-term mortality in subjects admitted for evaluation of cognitive dysfunction. DESIGN: prospective observational study. SETTING: University Hospital. SUBJECTS: A total of 231 patients (80 +/- 7 years, 65% women). METHODS: Body mass index (BMI, kg/m2), serum concentrations of albumin, ferritin, vitamin B12, folic acid and haemoglobin as well as Mini-Mental State Examination (MMSE, 0-30 p) results and co-morbidity were recorded at hospital admittance and before discharge. Seven years later, mortality was registered. RESULTS: Mean BMI was in the normal range (23.3 +/- 4) as were the biochemical indices, and they did not vary among patients with Alzheimer's disease (AD), vascular dementia (VaD), mild cognitive impairment, mixed dementia and other diagnoses. A BMI of <23 was found in 108 (52%) subjects. Weight and MMSE score correlated weakly (r = 0.18, P < 0.01) at inclusion. During a median hospital stay of 3 weeks, an average weight gain of 0.5 +/- 1.8 kg (P < 0.001) and an increase in MMSE score of 0.9 +/- 3 (P < 0.001) was observed. However, these changes did not correlate. A BMI of <23 was associated with an increased risk for 7-year mortality (OR 3, 95% CI = 1.3-6.7), which was independent of age, male gender, dementia diagnosis and co-morbidity. CONCLUSIONS: Nutritional status did not vary in patients with various dementia diagnoses. A BMI of <23 was related to reduced 7-year survival, but this result was independent of co-morbidity, male gender and age.

Abstract: Hypoxemia is a powerful stimulus of glutamate release in the central nervous system (CNS) and a hallmark phenomenon in sleep disordered breathing (SDB). Glutamate effects that include neuronal damage and apoptosis following hypoxemia and apnea following microinjections in animal models are in part mediated via postjunctional N-methyl-D-aspartate (NMDA) receptors. This was a double blind, randomized, placebo-controlled single dose cross-over study of the NMDA receptor antagonist AR-R15896AR in 15 male patients with moderate to severe SDB. Seven patients received 120 mg and eight patients received 350 mg AR-R15896AR or corresponding placebo (given by 2 h infusion) starting half an hour before estimated sleep onset. AR-R15896AR concentrations were in line with the predicting kinetic model. A standard polysomnographic montage was applied. Repeated plasma samples were obtained in nine patients for analysis of plasma glutamate. Glutamate concentration in plasma did not change overnight and was unrelated to severity of SDB. Overall AHI (apnea-hypopnea index; primary efficacy variable) or investigated oxygen saturation variables were not significantly changed after AR-R15896AR at either dosage level. Side effects were mostly confined to the higher dose level and included vivid dreams, nightmares as well as in two cases mild hallucinations. The previously postulated role of glutamate in SDB could not be confirmed after AR-R15896AR induced NMDA-receptor blockade.

Abstract: OBJECTIVE: We investigated the nutritional, cognitive and functional status in residents of two service-flat (SF) complexes and the effects of a nutrition education programme for care staff. DESIGN: Controlled nonrandomised study. SETTING: Two SF complexes, that is community-assisted accommodation. SUBJECTS: Of 115 eligible SF residents, 80 subjects participated (age 83+/-7 y, 70% women). INTERVENTION: The nutritional status was assessed using body mass index (BMI, kg/m(2)), subjective global assessment (SGA), serum concentrations of albumin, insulin-like growth factor-I (IGF-I) and vitamin B(12). Cognitive and functional status were evaluated using the Mini Mental State Examination (MMSE, 0-30 points, <24 points indicates impaired cognition) and the Katz activities of daily living (ADL) index, respectively. Two assessments were made with a 5-month interval. At the start, a 12-h education programme was given to the staff at one of the SF complexes. RESULTS: At baseline, the means of BMI and the biochemical nutritional indices were normal, whereas one-third had BMI <22 kg/m(2) and one-fourth had lost > or =10% of previous weight. According to SGA, 30% demonstrated possible or serious malnutrition. The median MMSE was 23 points (19.5-26.5, 25-75th percentile). Nearly 70% were ADL-independent. At the 5-month follow-up there were no differences in the nutritional and cognitive status of the residents. The nutritional knowledge of the staff improved slightly (P<0.05) at both SF complexes (NS between groups). CONCLUSIONS: Around one-third of SF residents appeared to be at nutritional risk. Five months after a 12-h staff nutrition education programme, no objective changes were seen in the nutritional status of the SF residents.

Abstract: F2-isoprostanes are produced by the non-enzymatic peroxidation of arachidonic acid in membrane phospholipids. This paper describes a new method for the determination of all four classes of F2-isoprostanes in human cerebrospinal fluid (CSF) involving separation on a 1 mm x 150 mm porous graphitic carbon (PGC) column and detection by triple quadrupole mass spectrometry in negative-ion electrospray mode. The sample pre-treatment consisted of an ultrafiltration step, following which 300 microl of CSF sample could be injected directly onto a 1 mm x 10 mm PGC guard column functioning as a trap for the analytes. The loading solvent was Milli-Q water at 125 microl/min. After 3 min, the sample was switched into the separation column. The F2-isoprostanes were separated in 20 min using a linear solvent gradient comprising water, methanol, acetonitrile and ammonium hydroxide at a pH of 9.5 and a flow of 50 microl/min The limit of detection (calculated as 3S/N) was approximately 40 pM (14 pg/ml). The assay was linear within the examined range (18-450 pg/ml), using CSF spiked with iPF2alpha-III standard (r(2)>0.995). Repeatability data were calculated for CSF spiked to 90 pg/ml and the relative standard deviation (RSD) obtained was 3% (n=6).

Abstract: Brain aggregates of conformationally altered proteins are key features of neurodegeneration and are believed to directly cause or contribute to disease development. Mechanisms underlying the dysregulation of proteins in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other neurodegenerative disorders are now being characterized, due to the discovery of genes causing rare disease forms. As of today, only symptomatic pharmacotherapies are available, but new insights into the underlying molecular mechanisms are providing strategies to prevent or even cure these devastating disorders.

Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer's disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30-50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.

Abstract: Given the remarkable similarities between the genetics of tau diseases and the genetics of alpha-synuclein diseases, and given the fact that we have recently found a triplication of the alpha-synuclein locus in a family in which we had shown linkage to the alpha-synuclein locus, we determined to test whether some of the several families with autosomal dominant frontal temporal dementia which show genetic linkage to the tau locus but in which tau mutations have not been found could be caused by similar structural mutations. We did not find any such mutations.

Abstract: The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.

Abstract: Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant condition clinically characterized by behavioral, cognitive and motor disturbances. It was recently discovered that the majority of the FTDP-17 families carry missense or 5' splice mutations in the exons coding for the microtubule-binding domains of the tau protein. However, in at least five FTDP-17 families, no such mutations could be identified. In the present study, we aimed at further investigate abnormalities in the tau gene in a Swedish FTDP-17 family, where no mutations in the tau gene previously have been identified. Initially, we searched for larger deletions by Southern blot hybridization. Furthermore, possible abnormal splicing events was investigated by RT-PCR from brain tissue of affected individuals. In addition, we investigated the presence of mutations in other genes in the FTDP-17 candidate region on chromosome 17q21; Gamma-tubulin, Glial Fibrillary Acid Protein (GFAP), Human dual specificity phosphatase tyrosine/serine (VHR), Rap-interacting protein 8 (RPIP8), P35, and the recently identified FTDCG1. In conclusion, no pathological changes in the tau gene were observed, neither was any mutations segregating with the disease detected in the investigated candidate genes. Further investigation of extended intron sequences or promoter regions of the tau gene and additional candidate genes on chromosome 17q21, therefore seems to be necessary in order to identify the additional causes of FTDP-17.

Abstract: Individuals carrying a mutation associated with Alzheimer's disease (AD) may serve as a model of mild cognitive impairment (MCI). Nondemented individuals from these families can be subdivided into asymptomatic and symptomatic groups. Four families were studied. Two families are associated with APP mutations (KN670/671ML, E693G) and two with PS1 mutation (M146V, H163Y). Clinical symptoms, level of global cognitive functioning as evaluated by Mini-Mental State Examination, neuropsychological test results, neuroradiological examinations (magnetic resonance imaging (MRI) and single-photon emission tomography (SPECT)), as well as cerebrospinal fluid (CSF) measurements of tau and beta-amyloid are reported. Nondemented mutation carriers did not report any symptoms indicating cognitive decline. In addition, no clinical signs of dementia or marked cognitive impairment in neuropsychological tests were found. A reduction of temporal blood flow with SPECT was indicated in 5/13 nondemented mutation carriers. Two of these 13 individuals had moderate hyperintensities in deep white matter as observed on MRI. CSF measurements of A beta 42/43 were inconclusive because of large biological variation. A nonsignificant elevation of tau was detected in mutation carriers. In conclusion, clinical examinations of relatively young individuals carrying an AD mutation did not reveal any marked abnormalities before the clinical onset of dementia.

Abstract: F2-isoprostanes (F2-iPs) comprise four classes of isomers produced non-enzymatically by free radical attack on arachidonic acid, a component of the cell membrane. This paper describes a new method for the quantification of F2-isoprostanes in urine samples from thoroughly diagnosed Alzheimer's disease (AD) patients. The sample pretreatment consisted of liquid extraction of 900 microl urine with diethyl ether, its subsequent evaporation, and finally, reconstitution in 50 microl water. Of this, 20 microl was injected into a HPLC system with a 15 mm x 1 mm porous graphitic carbon column coupled to a triple quadrupole mass spectrometer running in negative electrospray ionization mode. The F2-isoprostanes were separated in 15 min using a linear solvent gradient comprising water, methanol, acetonitrile and ammonium hydroxide at a pH of 9.5. The average recovery obtained was approximately 75%. The limit of detection (3S/N) was calculated for iPF2alpha-III to be 0.7 pg injected on column, corresponding to 0.1 nM. The average level of iPF2alpha was 241 +/- 163 pg/mg creatinine in the urine samples from AD patients (average +/- standard deviation). The corresponding control values were 216 +/- 101 pg/mg creatinine, i.e. no statistically significant difference was noticed. No correlation pattern specific to Alzheimer's disease was revealed by principal component analysis of the isoprostane peaks obtained either. The results from this study support earlier findings that levels of peripheral isoprostanes are not increased in patients with Alzheimer's disease.

Abstract: BACKGROUND AND PURPOSE: A low-affinity, use-dependent N-Methyl-D-Aspartate (NMDA) antagonist AR-R15896AR has neuroprotective properties in animal models of ischaemic stroke. The aim of the present study was to examine the safety and tolerability of a new and higher dosage regimen that would enable acute stroke patients to achieve and maintain neuroprotective plasma concentrations. METHODS: A randomised, multi-centre, double-blind, placebo-controlled, parallel group study was carried out at 19 centres in France, Germany and the Netherlands in patients with a clinical diagnosis of acute ischaemic stroke, and onset of symptoms within 12 hours before start of study drug administration. Two loading doses of 3.5 mg/kg of AR-R15896AR over 60 minutes, followed by a 2.5 mg/kg infusion over the next 120 minutes were given. Eight hours after the start of the loading dose infusion, the first maintenance dose (120 mg) was administered over 60 minutes. Eight further maintenance infusions were administered at intervals of 8 hours over a total treatment period of 3 days. Main variables were safety, tolerability and pharmacokinetics. Follow-up assessments also included the Barthel Index (BI) and the NIH Stroke Scale (NIHSS) at 4-7 days after the end of the last infusion and at 30 days after the onset of stroke. RESULTS: 103 patients with acute ischaemic stroke were randomised to either treatment with AR-R15896AR (70 patients) or placebo (33 patients). Mortality was not significantly different in the AR-R15896AR group compared with the placebo group (10 % vs. 6 %). Serious adverse events during treatment due to psychiatric conditions were associated with AR-R15896AR (3 vs. 0). Other side effects were more common in the group treated with AR-R15896AR: vomiting (29 % vs. 9 %), nausea (23 % vs. 12 %), fever (17 % vs. 12 %), agitation (7 % vs. 3 %), dizziness (7 % vs. 0 %), and hallucinations (6 % vs. 0 %). No significant difference between the two groups (with respect to the proportions of patients with favourable outcome) was detected in either the analysis of the BI or the NIHSS. Pharmacokinetic data showed that plasma concentrations of AR-R15896AR were in the expected neuroprotective range. CONCLUSION: In most of the patients with acute stroke receiving AR-R15896AR the intended high plasma levels were reached within a short time period. However, active treatment produced more side effects than placebo, thus indicating safety concerns and tolerability issues for use in high doses in an acute stroke population.

Abstract: OBJECTIVES: We studied the nutritional status and the effects of nutritional intervention on body weight, cognition and activities of daily life (ADL)-function in demented individuals. DESIGN: Controlled non-randomised study. SETTING: Group-living for demented elderly (GLD), ie community assisted housing. SUBJECTS AND INTERVENTIONS: Twenty-two residents living in one of two units (GLD-I), received oral liquid supplements (1720 kJ/410 kcal/day) and the personnel of the GLD-I were given nutritional education. Fourteen residents in the other unit (GLD-C) served as controls. After 6 months 21 (83 (4) y, 81% women) and 12 (85 (4) y, 100% women) of the participants, respectively, were re-examined according to body mass index (BMI, kg/m2), cognitive function (Mini Mental State Examination (MMSE, 0-30 p) and Clinical Dementia Rating Scale (CDR) and the Katz' ADL index. RESULTS: Body mass index (BMI) < or =20 was found in 19% of the participants and 44% had BMI< or =23. BMI correlated with MMSE (r=0.43, P<0.01). The weight of the residents in the intervention group increased by 3.4 (3) kg (P=0.001) at follow-up, whereas the weight remained unchanged in the control group. The cognitive function was low at the start in both groups, ie MMSE approximately 9 and no apparent positive effect of the nutritional intervention was seen. In addition, the ADL functions appeared to deteriorate in both groups. CONCLUSIONS: Being underweight was common among demented elderly in group-living and was related to low cognitive capacity. Five months of oral supplementation, along with education of personnel, was followed by a weight gain. In this study the nutritional treatment did not affect the rate of decline in cognitive function or Katz' ADL index. SPONSORSHIP: Supported by grants from the Swedish National Board of Health and Social Welfare. Semper Foods AB provided the liquid supplements.

Abstract: Concentration of mercury (Hg) in whole blood in an elderly urban population with a mean age of 87 years was studied in relation to cognitive function, arterial blood pressure (arterial BP), age, gender, body mass index (BMI) and smoking habits. This population-based study consisted of 106 subjects both males and females. Clinical assessment of the subjects included medical and social history, physical and neurologic examination and assessment of cognitive functions with Mini-Mental State Examination (MMSE). Information on use of all potentially antihypertensive drugs was collected. Whole blood from 106 subjects were collected and analysed for mercury by Cold Vapour Atomic Absorption Spectrometry (Milton Ray ASS-CV) with Seronorm Trace Element as matrix matched quality control. Males and females did not differ in blood-mercury (B-Hg) concentrations or in any of the other studied variables. B-Hg concentrations did not differ between smokers and non-smokers. Females were treated more often than males with antihypertensive drugs. There was no relation found between B-Hg concentration and cognitive function, arterial BP, age, gender or BMI. In conclusion, no relations were found between B-Hg concentrations and the studied variables.

Abstract: White matter lesions (WMLs) in the brain is a common, unspecific finding on magnetic resonance imaging appearing both in the healthy elderly as well as in a number of different diseases including dementia disorders. However, the pathophysiological and clinical significance of WMLs in dementia disorders is still unknown. In this study, we investigated the possibility of their origin being inflammatory by studying the correlation between WMLs and cerebrospinal fluid (CSF) levels of the proinflammatory cytokine soluble interleukin-1 receptor type II (sIL-1RII). The sIL-1RII is a member of the IL-1 family, and has been found to be elevated in CSF from Alzheimer's disease (AD) patients. In the present study, two groups of patients complaining of memory disturbances with little or extensive WMLs respectively, were examined, as well as healthy subjects. In accordance with other reports, WML scores (total, periventricular as well as deep lesions) were positively correlated with age but not mini mental state examination (MMSE) scores, and were significantly higher in patients with a dementia diagnosis as compared to non-demented subjects. There were no differences in sIL-1RII levels in CSF regardless of amount of total, periventricular or deep WMLs, nor were there any differences between demented and non-demented subjects. In conclusion, sIL-1RII levels in CSF are not correlated to magnetic resonance imaging WMLs in patients with dementia disorders or in healthy subjects.

Abstract: The characterisation of the borderline syndrome between normal cognitive function and Alzheimer's disease (AD), often mentioned as Mild Cognitive Impairment (MCI) has been a goal for recent research. However, a variety of definitions of MCI-like syndromes and the uncertainty about the final diagnosis have hampered progress. To overcome these problems, the present study will describe cognitive function in two healthy mutation carriers and two matched non-carriers of the Swedish double mutation family, during the time period when carriers convert to a symptomatic stage, i.e., true preclinical AD, and finally into the stage when a clinical diagnosis of AD is first possible. The findings question the generality of common MCI concepts and the commonly held beliefs about cognitive features in late preclinical stage of AD.

Abstract: Deregulation of amyloid precursor protein (APP) processing with increased production of amyloid beta-peptide (Abeta) is considered to be a key pathogenic event in Alzheimer's disease (AD). It has been suggested that stimulation of the muscarinic M(1) receptor subtype affects APP processing and leads to a change in Abeta concentration. To test the hypothesis that treatment with a cholinesterase inhibitor could change the levels of Abeta in plasma, we measured Abeta42 and Abeta40 plasma levels in AD subjects before tacrine treatment and at weeks 2 and 6 of treatment. Treatment with tacrine had no statistically significant effect on plasma Abeta42 and Abeta40 either at 2 weeks or at 6 weeks of administration compared to baseline levels. Plasma Abeta42 and Abeta40 levels showed large subject-to-subject variation but small variation within the same patient over the 3-sample interval. After 2 weeks of treatment with tacrine, there was a strong negative correlation between tacrine concentration and levels of Abeta42 (r = -0.64; p = 0.01) and Abeta40 (r = -0.55; p = 0.04). However, after 6 weeks there was no correlation between plasma concentrations of tacrine and Abeta42 (r = 0.33; p = 0.34) or Abeta40 (r = -0.22; p = 0.54) levels in plasma. After 2 weeks of treatment with an acetylcholinesterase inhibitor, we found a correlation between higher drug concentrations and lower beta-amyloid levels. This might indicate an effect on APP metabolism with an increased alpha-cleavage. But after 6 weeks of drug treatment, there was no obvious drug effect on beta-amyloid concentrations. This finding may indicate that compensatory mechanisms have started at 6 weeks and that no long-term effect on key pathological features in AD is to be expected by an inhibition of acetylcholinesterase.

Abstract: Cerebrospinal fluid (CSF) tau is a promising biochemical ante-mortem marker for Alzheimer's disease (AD). Levels are increased in AD compared to other dementias, neurological diseases and healthy controls. An age-related decrease in both soluble tau and tau bound to paired helical filaments has been shown in brains from non-demented subjects. To study tau levels in normal ageing, we investigated CSF in 29 healthy individuals aged 45-80 years. A statistically significant increase in CSF tau with increasing age was found which might be caused by neuronal loss during normal ageing and redistribution of soluble tau from the brain into CSF. We could not demonstrate any influence by the APOE genotype, though larger populations have to be investigated to confirm this result. In conclusion, we found an age-dependent increase in CSF tau in healthy individuals. We emphasise the importance of establishing an age-dependent interval of CSF tau in non-demented subjects.

Abstract: The authors examined the impact of the apolipoprotein E (APOE)(*)epsilon4 allele on Alzheimer's disease incidence in relation to use of antihypertensive medication. A population-based (Kungsholmen Project) cohort of 985 nondemented Swedish subjects aged >/=75 years was followed for an average of 3 years (1990-1992); 164 dementia (122 Alzheimer's disease) cases were identified. Compared with (*)epsilon3/(*)epsilon3, the APOE(*)epsilon4 allele increased the risk of developing dementia (relative risk (RR) = 1.5, 95% confidence interval (CI): 1.1, 2.1) and Alzheimer's disease (RR = 1.7, 95% CI: 1.2, 2.5). Subjects using antihypertensive medication at baseline (n = 432, 80% used diuretics) had a decreased risk of dementia (RR = 0.6, 95% CI: 0.5, 0.9) and Alzheimer's disease (RR = 0.5, 95% CI: 0.3, 0.8) after adjustment for several variables, including APOE. The effect of antihypertensive medication use was more pronounced among (*)epsilon4 carriers. For those not using antihypertensive medication, the relative risks of dementia and Alzheimer's disease for carriers were 2.2 (95% CI: 1.4, 3.4) and 2.3 (95% CI: 1.4, 3.7), respectively. The corresponding relative risks for those using antihypertensive medication were 0.9 (95% CI: 0.5, 1.6) and 1.1 (95% CI: 0.6, 2.2). The APOE(*)epsilon4 allele is an important predictor of dementia and Alzheimer's disease incidence. Further studies are needed to clarify whether use of antihypertensive medication, especially diuretics, modifies the effect of the allele.

Abstract: Today, cognitive impairment can be successfully treated with acetylcholine esterase inhibitors (AChE-I) in many, but not all, patients with Alzheimer's disease (AD). To investigate the relation between tacrine treatment, inheritance of ApoE epsilon4 alleles, and rate of progression, the differences in MMSE and CIBIC scores (efficacy parameters) after 6 and 12 months of tacrine (an AChE-I) treatment were investigated in 145 AD patients. Of these, 84 were ApoE epsilon4-positive (ApoE4) and 61 were ApoE epsilon4-negative (ApoE2-3). No differences were found after 6 months of treatment, but after 12 months the CIBIC scores revealed that the ApoE4 patients had declined more than the ApoE2-3 patients (p < 0.05). No differences were found for the last 6 months of treatment. The results primarily suggest a faster rate of decline in the ApoE4 AD compared to the ApoE2-3, but may also reflect that ApoE epsilon4 genotype inheritance is a negative predictor of treatment effect of tacrine in AD patients.

Abstract: OBJECTIVE: To explore the associations of low serum levels of vitamin B(12) and folate with AD occurrence. METHODS: A population-based longitudinal study in Sweden, the Kungsholmen PROJECT: A random sample of 370 nondemented persons, aged 75 years and older and not treated with B(12) and folate, was followed for 3 years to detect incident AD cases. Two cut-off points were used to define low levels of vitamin B(12) (< or =150 and < or =250 pmol/L) and folate (< or =10 and < or =12 nmol/L), and all analyses were performed using both definitions. AD and other types of dementia were diagnosed by specialists according to DSM-III-R criteria. RESULTS: When using B(12) < or =150 pmol/L and folate < or =10 nmol/L to define low levels, compared with people with normal levels of both vitamins, subjects with low levels of B(12) or folate had twice higher risks of developing AD (relative risk [RR] = 2.1, 95% CI = 1.2 to 3.5). These associations were even stronger in subjects with good baseline cognition (RR = 3.1, 95% CI = 1.1 to 8.4). Similar relative risks of AD were found in subjects with low levels of B(12) or folate and among those with both vitamins at low levels. A comparable pattern was detected when low vitamin levels were defined as B(12) < or =250 pmol/L and folate < or =12 nmol/L. CONCLUSIONS: This study suggests that vitamin B(12) and folate may be involved in the development of AD. A clear association was detected only when both vitamins were taken into account, especially among the cognitively intact subjects. No interaction was found between the two vitamins. Monitoring serum B(12) and folate concentration in the elderly may be relevant for prevention of AD.

Abstract: Concentration of cadmium in blood in an elderly population with a mean age of 87 years was studied in relation to age, blood pressure, BMI, cognitive function, gender and smoking. This population-based study consisted of 804 subjects both men and women. Clinical examination included medical and social history, physical and neurologic examination, and assessment of cognitive functions with Mini-Mental State Examination (MMSE). Information on prescription and non-prescription drug use was collected. Anti-hypertensive drugs included all medicines potentially used for treating high blood pressure. Blood pressure was measured. Whole blood from 763 subjects was analysed for cadmium by atomic absorption spectrophotometry (GFAAS) with Zeeman background correction and with a graphite furnace using the L'vov platform technique including quality control. Differences in cadmium concentrations were related to non-smokers (3.9 nmol/l), previous smokers (4.4 nmol/l) and current smokers (7.5 nmol/l). There were no relations between cadmium and age, blood pressure or cognitive functions. In conclusion, increased cadmium levels were found in smokers. A possible contribution from previous occupational exposure needs to be further evaluated.

Abstract: BACKGROUND AND PURPOSE: Both stroke and the apolipoprotein E (APOE) epsilon4 allele increase the risk of dementia. However, the interaction between stroke and APOE on dementia is still unclear. We addressed this topic by using a longitudinal design. METHODS: We followed up a community cohort of 1301 subjects aged >/=75 years, who did not have dementia at baseline. Among them, 92 subjects had a history of stroke (from 3 months to 16 years before baseline interview). After the 3-year follow-up, 224 dementia cases had been diagnosed. During the period of follow-up, 91 subjects had a first occurrence of stroke (incident stroke). The APOE genotype was known for 985 subjects. Cox proportional hazards regression models were constructed to estimate the risk for dementia in terms of relative risks (RRs) for stroke and the APOE epsilon4 allele, with adjustment for age, sex, education, systolic blood pressure, antihypertensive medication use, and heart disease. RESULTS: In the entire study population, RRs for dementia related to history of stroke and incident stroke were 1.7 (95% CI, 1.1 to 2.6) and 2.4 (95% CI, 1.6 to 3.5), respectively, after adjustment for all potential confounders. Subjects with stroke that occurred within 3 years before baseline had RR of 2.4 (95% CI, 1.4 to 4.2), whereas those with stroke occurring >3 years before baseline had RR of dementia of 1.1 (95% CI, 0.6 to 2.3). Among those with APOE information, individuals with only history of stroke (that occurred within 3 years before baseline) had RR of 3.1 (95% CI, 1.4 to 6.6), individuals with only the APOE epsilon4 allele had RR of 1.7 (95% CI, 1.1 to 2.5), and individuals with both factors had RR of 5.3 (95% CI, 2.1 to 13.4). The corresponding figures when incident stroke was examined instead of history of stroke were 2.3 (95% CI, 1.3 to 4.1), 1.7 (95% CI, 1.1 to 2.4), and 4.6 (95% CI, 2.0 to 10.6), respectively. The RR of interaction term for history of stroke and APOE epsilon4 was 1.1 (95% CI, 0.3 to 3.8; P=0.8). The corresponding figure was 1.2 (95% CI, 0.4 to 4.4; P=0.7) for incident stroke and APOE epsilon4. Furthermore, the RRs of dementia without any stroke and dementia with stroke in relation to APOE epsilon4 were 1.6 (95% CI, 1.1 to 2.3) and 1.2 (95% CI, 0.6 to 2.4), respectively. In addition, the APOE epsilon4 allele was not significantly related to the occurrence of stroke (RR=0.8; 95% CI, 0.5 to 1.5). CONCLUSIONS: A relatively fresh stroke is a risk factor for dementia. APOE epsilon4 increases the risk of dementia without stroke but not dementia with stroke. Our data do not support a multiplicative effect of stroke and the APOE epsilon4 allele on the risk of dementia. However, both factors seem to have an additive effect on the risk of dementia. The APOE epsilon4 allele does not increase the risk of stroke in this Swedish elderly population.

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Abstract: BACKGROUND: The Kungsholmen project is a longitudinal study of ageing and dementia conducted in Stockholm in 1987. In a 1994-96 follow-up, 804 subjects had their blood samples analyzed for lead. METHODS: Lead concentration in blood in an elderly population aged 75+ (mean age of 88.4 years) was studied in relation to age, blood pressure (BP), body mass index (BMI), cognitive function measured with Mini-Mental State Examination (MMSE), gender, and smoking. RESULTS: The mean blood lead level (n = 762) was 3.7 microg/dL (0.18 micromol/L) whole blood with a standard deviation of 2.3, (0.11). There was a contribution of gender with men having higher blood lead levels than women (beta = -0.20; P = 0.000001) but not of smoking habits (beta = 0.07; P = 0.08) when these variables were entered into a multiple regression model with lead as the dependent variable (R = 0.22; P < 0.000001). Different multiple regression models were tested with lead as the dependent variable. No relation was found between lead concentrations and age, BMI, systolic BP, diastolic BP, or MMSE. Systolic and diastolic BP were correlated to BMI (R = 0.10; P = 0.01 and R = 0.22; P = 0.000 001, respectively). CONCLUSIONS: In this elderly population from a specified area of Stockholm it is unlikely that lead exposure affects BP or cognition. However, high lead levels in blood may reflect earlier occupational exposure or life style factors.

Abstract: All mutations known to cause familial Alzheimer's disease (AD) act by increasing the levels of soluble beta-amyloid peptide (A beta), especially the longer form, A beta42. However, in vivo elevation of soluble A beta in sporadic AD has so far not been shown. In the present study, we used enzyme-linked immunosorbent assays specific for A beta42 and A beta40 to investigate cerebrospinal fluid from sporadic AD at different stages of disease severity, to clarify the roles of A beta42 and A beta40 during disease progression. We also evaluated three other groups--one group of patients with mild cognitive impairment who were at risk of developing dementia, a cognitively intact, nondemented reference group diagnosed with depression, and a perfectly healthy control group. We found that A beta42 is strongly elevated in early and mid stages of AD, and thereafter it declines with disease progression. On the contrary, A beta40 levels were decreased in early and mid stages of AD. The group of cognitively impaired patients and the depression reference group had significantly higher levels of A beta42 than the healthy control group, implying that A beta42 is increased not only in AD, but in other central nervous system conditions as well. Our data also point out the importance of having thoroughly examined control material. The initial increase and subsequent decrease of A beta42 adds a new biochemical tool to follow the progression of AD and might be important in the monitoring of therapeutics.

Abstract: Evidence from epidemiological, clinical and experimental studies favour the hypothesis that inflammatory events are part of the neuropathology in Alzheimer's disease. Proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been found in activated microglia in the vicinity of amyloid plaques in Alzheimer's disease brain. In the present study, the levels of soluble IL-1 receptor type II (sIL-1R type II), IL-1 receptor antagonist (IL-1ra), IL-1beta, IL-6 and TNF-alpha were analyzed in cerebrospinal fluid (CSF) samples from Alzheimer's disease patients and control subjects. The levels of sIL-1R type II were significantly higher in CSF from Alzheimer's disease patients than in CSF samples from control subjects (38.5+/-8 pg/ml (mean+/-S.E.M.) vs. 7.9+/-4 pg/ml, p<0.05). Measurements of the proinflammatory cytokines IL-6 and TNF-alpha showed no significant difference between the two groups, and the levels of IL-1beta and IL-1ra in the present material were too low to permit detection. The increased levels of sIL-1R type II may reflect a compensatory mechanism to balance an increased release of IL-1 receptor agonists in the Alzheimer's disease brain.

Abstract: Apolipoprotein E (APOE) and alpha1-antichymotrypsin (ACT) genotype and allele frequency distribution were investigated in 113 familial Alzheimer's disease (AD) cases. A significantly higher sigma4 frequency was observed in patients with an age of onset between 55-64 and 65-74 years compared to individuals with later or earlier onset. No difference in ACT A allele frequency was seen in any onset group, nor was any influence of ACT genotypes on the age of onset observed. However, the mean age of onset was lowered by the presence of the ACT/AA and ACT/TT genotypes among APOE sigma3/3 bearers. Possible APOE effects on age of onset were evaluated in 78 affected sib pairs. An earlier age of onset was observed in siblings with an sigma4 allele compared to siblings without an sigma4 allele. This supports the notion that the sigma4 allele promotes an earlier age of onset. However, in siblings with the same APOE genotype, a wide range of onset was seen, indicating that unknown genetic or environmental factors affect the expression of AD.

Abstract: OBJECTIVE: To study the progression of Alzheimer's disease (AD) at a very early stage and to evaluate clinical markers of presymptomatic AD. SETTING: Longitudinal study at a university hospital. SUBJECTS: A Swedish family harboring a double mutation at codons 670/671 of the APP gene on chromosome 21 was followed longitudinally for 3 years. Both mutation carriers and noncarriers participated. OUTCOME MEASUREMENTS: Results from clinical investigations, electroencephalography, neuropsychological and neuroradiological examinations including magnetic resonance imaging, single-photon emission computed tomography and positron emission tomography were assessed and compared on two or more occasions. MAIN OUTCOME: During follow-up, 1 initially asymptomatic mutation carrier who was near the expected age of onset for this family, developed cognitive symptoms, and at the end of the follow-up fulfilled the diagnostic criteria for AD. One mutation carrier with cognitive symptoms at the first examination showed clinical deterioration and was diagnosed with AD. One demented mutation carrier died and was shown to have typical AD neuropathology at autopsy. The two remaining asymptomatic mutation carriers, as well as all the noncarriers were asymptomatic. These mutation carriers who were near the expected age of onset of AD but without clinical signs of the disease, did not show changes in either electrophysiological parameters or volumes of the temporal lobes. However, in these 2 individuals the blood flow in the temporal lobe showed intermediate values between the symptomatic mutation carriers and healthy noncarriers. Two neuropsychological tests showed a deterioration that paralleled clinical symptoms in 1 of the mutation carriers who was close to the expected age of onset and who at the end of the follow-up had clinical signs of AD. In the same subject, brain glucose metabolism was pathologically reduced in the temporal lobes before other clinical symptoms were obvious. CONCLUSION: In this familial form of AD a reduced temporal lobe glucose metabolism was indicative of AD before the expected clinical onset. Reduced glucose metabolism even preceded the development of subjective or objective cognitive dysfunction and might therefore serve as a clinical marker for AD before the onset of clinical symptoms. Reduced cerebral blood flow in the temporal lobes and cognitive deterioration paralleled the clinical decline in the early stage of the disease. Copyrightz1999S.KargerAG,Basel

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Abstract: In an effort to analyze the genetic role of tau in Alzheimer's disease (AD), 17 polymorphisms were identified. Eleven of these polymorphisms were in complete linkage disequilibrium and segregated as two haplotypes, A and B. The A and B haplotypes were investigated in 269 AD cases and 238 controls from two different sources, a clinic-based group (mean age of onset 65+/-9 years), and a population-based group (mean age of onset 80+/-5 years). A synergistic effect between the common tau genotype AA and apolipoprotein E (APOE epsilon4) was found in the clinic-based AD group. Our study suggests that the common tau genotype AA may interact with APOE epsilon4 in increasing the risk of AD in a subgroup of the AD population.

Abstract: As a preliminary part of a longitudinal clinical study of carriers of the Swedish amyloid precursor protein (APP) 670/671 mutation, 13 members of a family were investigated with magnetic resonance imaging (MRI) brain volumetry and single photon emission computed tomography (SPECT) cerebral blood flow (CBF) measurements. Five of the family members were mutation carriers; eight were not carriers. Two carriers were younger than 40 years of age and had no evidence of cognitive dysfunction or structural or functional brain changes. One carrier with 4 years to expected disease onset showed poor performance in episodic memory tests and also slightly low temporal lobe CBF, although there were no clearly abnormal findings. One carrier with mild Alzheimer disease (AD) had no clear structural brain changes, although CBF measurements showed clear reduction of temporal lobe CBF. One carrier with severe AD had both temporal lobe atrophy and CBF reduction. This indicates that in carriers of the APP 670/671 mutation, reduction of regional CBF is more severe than regional atrophy. The clearest change related to development of clinical AD was a reduction of CBF in the basal and lateral temporal lobes. Further longitudinal studies of these subjects are needed to confirm these preliminary findings, which might provide important data regarding early brain changes in AD.

Abstract: We explored the relationship between cerebrospinal fluid (CSF) tau levels as indirect markers of tau-related pathology in Alzheimer's disease (AD) and EEG slowing, a typical neurophysiological finding in the disease. A positive correlation between CSF tau levels and ratio of alpha/delta global field power was found in 14 AD patients (r = 0.65, p = 0.01). This relationship was better approximated by polynomial fit of 2nd degree (p = 0.002). A subgroup of AD patients (n = 7) with higher tau levels and shorter duration of illness showed a strong relationship between CSF tau levels and alpha/theta (r = 0.83, p = 0.02), and alpha/delta (r = 0.87, p = 0.01) ratios of the global field power. There were no significant correlations between EEG slowing and CSF tau levels in 12 patients with mild cognitive dysfunction or in 14 healthy control subjects. That a strong inverse linear correlation exists in AD patients with higher levels of tau and shorter duration of illness may imply that with longer illness duration CSF tau levels decrease due to neuronal death.

Abstract: This study examined whether baseline cognitive performance and 3-year longitudinal changes were influenced by apolipoprotein E epsilon 4 (APOE-epsilon 4) allele. Participants consisted of 20 APOE-epsilon 4 (2 epsilon 2/epsilon 4; 17 epsilon 3/epsilon 4; 1 epsilon 4/epsilon 4) and 54 non-epsilon 4 (12 epsilon 2/epsilon 3; 42 epsilon 3/epsilon 3) very old adults without dementia (M = 81.82 +/- 5.06 years) participating in a population-based longitudinal study. Cognitive performance was indexed by the Mini-Mental State Examination and multiple indexes of memory, visuospatial, and verbal performance. The results indicated no significant baseline differences between the 2 APOE groups in any cognitive performance measure. However, analyses revealed that the APOE-epsilon 4 group experienced greater negative change in recognition memory for faces and words. Changes in tasks assessing other abilities did not vary as a function of APOE status. The authors concluded that APOE-epsilon 4 status may not influence cognitive performance in adults without dementia and speculated that when such effects do occur (e.g., decline in recognition memory), these may be related to impending dementia, rather than to the influence of the specific genotype on cognition in normal aging.

Abstract: BACKGROUND: Psychotic symptoms have been found to be more common in demented elderly persons. Genetic variation in the apolipoprotein E (APOE) gene is reported to be associated with variation in the risk of Alzheimer's dementia. This study reports on variables associated with psychotic symptoms including APOE, in demented and nondemented elderly persons. METHODS: A population of 668 elderly persons was examined. APOE genotype was available in 309 individuals. RESULTS: Psychotic symptoms were found to be associated with dementia, a previous psychiatric history, female gender, being less educated, disability in daily living and institutionalisation. In the nondemented group, psychotic symptoms were equally common in subjects with or without the epsilon 4 present. In the demented subjects, psychotic symptoms were slightly more common, although not significant, in subjects without the epsilon 4 genotype. CONCLUSIONS: There was no statistical significant difference in APOE genotype between subjects with and without psychotic symptoms, stratified by dementic diagnosis.

Abstract: OBJECTIVES: To describe clinical and genealogical data of a Swedish family with a His163Tyr mutation in the presenilin-1 gene (PS1) and to study the Alzheimer disease (AD) penetrance in this family. DESIGN: Interviews with relatives, studies of medical records, analysis of pedigree, physician examination of the affected individuals, and comparison with other families affected by AD with PS1 mutations. SETTING: Large university-affiliated hospital. PATIENTS AND OTHER PARTICIPANTS: Individuals with a His163Tyr mutation in PS1 and their relatives. RESULTS: A study of this family with a history of very early AD onset (mean age, 47 years) has been previously published, but an investigation of the extended family revealed a new pattern of onset, with a mean age at onset of 54 years (range, 44-65 years). In general, families with AD show a tight cluster of age at onset with high penetrance of the disease. However, in this family, an individual whose child carries the PS1 mutation died at age 67 years free from cognitive symptoms, indicating a very late age at onset or nonpenetration of the disease. No association between age at onset and disease duration was found. Furthermore, the disease duration did not differ between those having an early onset compared with those having a late onset. The earliest clinical manifestations were deficits in memory function and disorientation in time and place. Myoclonic jerks and epileptic seizures were common symptoms later in the disease. CONCLUSION: The large range in age at onset in this family with a uniform genetic basis for the disease, a His163Tyr mutation in PS1, supports the existence of other unknown genetic or environmental factors of importance for the expression of the AD phenotype.

Abstract: The hypothesis that mild cognitive impairment (MCI) represents an early stage of Alzheimer's disease (AD) was investigated by reviewing recent research from three sources: asymptomatic and symptomatic individuals carrying mutations that cause AD, hospital-samples of non-demented patients with MCI at the initial examination that are followed longitudinally, and community-based incident cases of AD. Studies with asymptomatic mutation carriers of the amyloid precursor protein and presenilin 1 gene have shown a linear and disease-related decline in most cognitive functions that begins approximately 10 years before the expected clinical onset of AD. However, there is considerable overlap between the level of impairment for mutation carriers and non-carriers of the same age during the early preclinical stage of AD. Hospital-based longitudinal studies have shown that non-demented individuals with isolated mild episodic memory impairment may develop clinically diagnosed AD with widespread cognitive deficits in a few years time. Community-based epidemiological studies on the incidence of AD demonstrate that indices of episodic memory, in addition to measures of general cognitive functioning, are useful in predicting early AD. In contrast, subjective memory impairment or age-associated memory impairment are less powerful predictors of future dementia development. In summary, there is converging evidence to demonstrate that preclinical AD is characterized by a common behavioral phenotype, with cognitive decline in several domains, predominantly in episodic memory. The decline appears to start many years before the clinical onset of AD. Moreover, the progression of the impairment appears to be continuous. Finally, this pattern of performance generalizes across etiology of AD (familial or sporadic), clinical onset (early or late), sample composition (hospital or community), and method of assessment.

Abstract: Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Abstract: BACKGROUND: Recent findings of a reduced cerebral metabolic rate of glucose (CMRGlu) in at-risk relatives of patients with Alzheimer disease (AD) who carry the apolipoprotein E (APOE) epsilon 4 allele suggest a causative role for the E4 isoform in cognitive changes that lead to AD. It is not known whether epsilon 4 allele-associated deficits exist in patients with clinical AD. OBJECTIVE: To determine whether distinct patterns of cerebral hypometabolism exist in patients who carry the epsilon 4 allele. PATIENTS AND METHODS: Information on the CMRGlu and APOE genotype was available for 46 patients at a memory disorders clinic: 31 patients were diagnosed as having probable AD, 3 demented patients did not meet criteria for AD, and 12 patients had mild memory complaints. Positron emission tomography with the use of 18F-fludeoxyglucose was used to calculate the CMRGlu in the frontal and temporoparietal regions of the cortex. Estimates were standardized to the sensorimotor area of the cortex. Linear regression models were constructed to relate the APOE genotype to the CMRGlu, adjusting for cognitive status (ie, the Mini-Mental State Examination score). RESULTS: Distinct patterns of the CMRGlu did not emerge for patients with different APOE genotypes. Bilateral deficits in the CMRGlu were found in the patients with AD. Left-right asymmetry was found in 8 of 12 patients with mild memory complaints: 7 of 8 had CMRGlu ratio less than 0.85 in the left side of the temporoparietal region of the cortex. CONCLUSIONS: The APOE epsilon 4 allele does not appear to be associated with specific deficits in brain metabolism in patients with AD despite evidence that the epsilon 4 allele is associated with preclinical alterations. This finding is consistent with previous epidemiologic results that have demonstrated a higher risk for AD in carriers of the epsilon 4 allele, but no change in the rate of progression of AD.

Abstract: OBJECTIVE: To describe symptoms, signs, neuroimaging results, and neuropathologic findings in patients from a family with chromosome 17q21-linked autosomal dominant frontotemporal dementia. DESIGN: Multiple case report with genetic investigations. SUBJECTS: The disease was observed in a Swedish family and documented in 3 generations. Four siblings are described in this article. RESULTS: A rapidly progressive dementia with genetic linkage to chromosome 17q21 was observed. The mean age of onset was 51 years and the average duration of disease to death was 3 years. Two patients started with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia and akinesia and muscular rigidity, and in 1 patient reckless driving was the first symptom. Loss of spontaneous speech developed later in all patients and emotional bluntness in 3 of the patients. Cerebral perfusion was decreased in the frontal areas in all patients. In the person with apraxia as the onset symptom, the cerebral blood flow was also diminished in the left hemisphere, where a slight atrophy was detected on magnetic resonance imaging scans. At the postmortem examination, slight gliosis of the parietal lobes was observed in this patient. In all patients there was a frontocentral degeneration of the cortex with discrete microvacuolation and gliosis. CONCLUSION: Clinical features of frontotemporal dementia, parkinsonism, an early age of onset, a rapid disease progression, and variable onset symptoms were seen in these patients. Two other clinically distinct diseases, dementia with pallido-ponto-nigral degeneration and a disinhibition-dementia-parkinsonism-amyotrophy complex, have recently been mapped to chromosome 17q21. In the family described in this article, genetic linkage was detected to the same region, suggesting the possibility that these diseases may originate from pathogenic mutations in the same gene.

Abstract: OBJECTIVE: To explore the relationship between possible biological markers of Alzheimer disease that are related to amyloid metabolism and mental functions. PARTICIPANTS: Twelve individuals from a Swedish family with Alzheimer disease and a double mutation at codons 670/671 of the amyloid precursor protein gene participated in the study. DESIGN: Cerebrospinal fluid levels of alpha-secretase cleaved soluble amyloid precursor protein (alpha-sAPP), total sAPP, and amyloid beta-peptide were correlated with data on multiple cognitive functions that covered the whole range of human performance. SETTING: The Alzheimer's Disease Research Centre, Department of Clinical Neuroscience, Section of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden. RESULTS: There were highly significant linear correlations between low levels of alpha-sAPP and poor performance on neuropsychological tests that assessed intelligence, verbal and visuospatial functions, memory, and attention. Within the group of nonmutation carriers, significant correlations were also obtained between the levels of alpha-sAPP and cognitive functions. A less striking association was seen between the levels of total sAPP and cognition. No association was found between the levels of amyloid beta-peptide and cognition. CONCLUSIONS: The strong relationship between alpha-sAPP levels and cognition in both patients with Alzheimer disease and normal-aging persons may imply that alpha-sAPP is involved in basic protective brain processes. Alternatively, less amyloid beta-peptide amounts are produced, leading to diminished plaque formation, when alpha-sAPP is generated.

Abstract: Familial frontotemporal dementia (FTD) is a complex disorder with lack of distinctive histopathological markers found in other types of dementia. Most of the linkage reports from FTD families map the disease loci to chromosome 17q21-22. However, FTD is genetically heterogeneous, as linkage also has been reported to chromosome 3. In the present study, we investigated the genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements. Neuropathological features such as severe frontal lobe degeneration, spongy changes, and gliosis were present in affected family members. We here report probable linkage to chromosome 17q12-21 with a maximum two-point lod score of 2.76 at theta = 0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Linkage to chromosome 3 was excluded, as two-point lod scores of -2.79, and -2.27 at theta = 0.01 for markers D3S1603 and D3S1552, respectively, were obtained. Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease.

Abstract: The aim of this study was to define the co-occurrence of depression and dementia in relation to apolipoprotein E (APOE) polymorphism. Physicians extensively examined 806 persons aged 78 years and over. DNA was extracted from peripheral white blood cells, and APOE genotype was determined using a microsequencing method on microtiter plates. The prevalence of dementia was 22.8% and was found to increase with the number of epsilon 4 alleles present. Depression was found in 11.4% of the demented subjects compared to 3.5% of the nondemented subjects. The overrepresentation of depression in demented subjects was found for each of the common genotypes. Depression was not strongly associated with APOE polymorphism. In spite of the association between dementia and APOE polymorphism, as well as dementia and depression, there was no association between APOE polymorphism and depression.

Abstract: Apolipoprotein E (apoE) levels were compared in cerebrospinal fluid (CSF) taken on two occasions, with an average 15 months follow up, from groups of patients with Alzheimer's disease (AD: n = 18), mild cognitive impairment (MCI; n = 9) and other dementia disorders (ODD; n = 9). In these groups, CSF apoE levels were between 2-3-fold higher than values for a group of 27 healthy age-matched controls. CSF apoE levels in the AD group were significantly increased at follow up, compared to levels obtained on the first sampling occasion. For the same cases it had been shown previously that CSF tau protein levels were increased at follow up [Blomberg, M., Jensen, M., Basun, H., Lannfelt, L. and Wahlund, L-O., Neurosci. Lett., 214 (1996) 163-166]. The AD, but not MCI, ODD or control groups, also showed statistically significant correlations between CSF apoE and tau protein levels at both the first (r = 0.585, P < 0.01) and follow up (r = 0.695, P > 0.001 ) samplings. It is concluded that CSF measures of both apoE and tau may reflect an intimate relationship between these two proteins in AD and could prove useful in monitoring the progression of this condition.

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Abstract: Five men were investigated after having pulmonary aluminosis due to exposure to aluminium pyrotechnic flake powder during the late 1940s. Two of the men had died 6 years and 20 years after exposure respectively, due to their lung disease. One man had died from heart failure 34 years after the end of exposure. Today, more than 40 years after exposure, two men were available for investigation. They had no respiratory symptoms and their vital lung capacities had not deteriorated during these years. One of the two survivors had developed a dementia with motor disturbances, which is not consistent with Alzheimer's dementia. This man had a very high concentration of aluminium in his cerebrospinal fluid. The other survivor had a normal concentration and was not demented.

Abstract: PURPOSE: This study aimed at evaluate the effect of aging on the central nervous system in "successfully aged" elderly subjects. The brain was studied with magnetic resonance imaging and neuropsychological tests at three different occasions during a time period of 5 yr. MATERIALS AND METHODS: Twenty-four successfully aged elderly were repeatedly examined with cerebral MRI and neuropsychological tests. The first examinations were performed in 1987 and then followed-up in 1989 and 1993. Two different MRI systems were used, in 1987 and 1989, a system operating at 0.02 T and in 1993 a system operating at 0.5 T. Ten subjects (42%) did not participate in the follow-up studies. MRI was used to study the degree of and increase in signal hyperintensities in the cerebrum, the basal ganglia, and in the infratentorial areas as well as changes in the volumes of the cerebro spinal fluid (CSF) spaces. RESULTS: At the start of the study in 1987, mild signal hyperintensities were observed in 11 of the 13 subjects who completed the follow up study. A modest increase in signal hyperintensity was found in almost all of the subjects, with the increases in cerebral white matter and basal ganglia signal hyperintensity being statistically significant (p < .03 and p < .05). The increases in periventricular hyperintensity and the hyperintensity from the infratentorial areas did not reach statistical significance. Volumes of the lateral ventricles and the frontal CSF spaces increased significantly (p < .03 in both cases) during the observation period, whereas the other volumes remained unchanged. The neuropsychological tests were unchanged during the observation period with the exception of the psychomotor capacity, which deteriorated. No statistical significant correlations were seen between the degree of or increase in signal hyperintensities and results from any of the neuropsychological tests. CONCLUSION: During a 5-yr observation of successfully aged elderly it was found that there was a mild increase in signal hyperintensity in the cerebral white matter and basal ganglia, as well as an increase in the frontal and ventricular CSF volumes. These changes were not related to changes in psychometric test results, nor were they related to the clinical outcome during the time of observation.

Abstract: OBJECTIVE: To quantify the influence of apolipoprotein E (APOE) polymorphism on cognition and survival in a population sample aged 75 years or older. DESIGN: The Kungsholmen Project established a cohort of 1810 residents in a district in Stockholm, Sweden, aged 75 years or older in 1987. Information on cognition at cohort inception is available for all subjects. Subjects were followed up for mortality to January 1, 1995. SUBJECTS: Included in this study are 1077 subjects (of 1124 genotyped for APOE) with the common epsilon 2/3, epsilon 3/3, and epsilon 3/4 APOE genotypes. RESULTS: The odds of cognitive impairment for the epsilon 3/4 vs epsilon 3/3 genotype declined with age: 4.8 for age 75 through 79 years; 1.7 for age 80 through 84 years; and 1.0 (i.e., no association) for age 85 years or older. Despite this association, APOE polymorphism did not significantly predict survival in subjects younger than 85 years, nor did it predict survival in subjects 85 years or older who were cognitively impaired. Instead, survival varied fourfold with respect to APOE polymorphism in those 85 years or older who had good cognition: Mortality in subjects with the epsilon 2/3 genotype was half that in those who carried the epsilon 3/3 genotype (hazard ratio, 0.5; 95% confidence interval, 0.2 to 0.9), and mortality in subjects with the epsilon 3/4 genotype was twice that in those who carried the epsilon 3/3 genotype (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.5). This fourfold variation resulted in 2-year differences in survival. CONCLUSIONS: The minor sequence variation in the apolipoprotein E isoforms resulted in a fourfold difference in the risk of death among the oldest old (age > or = 85 years) with good cognition. The observed variation in mortality was unlikely to have been caused by cognitive impairment, as APOE polymorphism was not a risk factor for cognitive impairment in this age group.

Abstract: The concentration of tau protein is elevated in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD), suggesting that CSF tau may be a useful biochemical diagnostic marker for this disorder. We investigated CSF tau concentrations on two occasions in AD (n = 18), mild cognitive impairment (MCI, n = 9) and other dementing disease (OD, n = 9) by ELISA (Innotest hTau Antigen, Innogenetics, Belgium). Tau levels were statistically significant higher in the AD group than in MCI and OD groups on both occasions. Twelve of the AD patients showed increasing values of tau at follow-up and six demonstrated diminished values. All AD patients with increasing tau were carriers of one or two epsilon 4 alleles of the apolipoprotein E (APOE, gene. Of those AD cases with decreasing tau levels only three individuals had the epsilon 4 allele, a difference that was statistically significant (P < 0.05). These findings suggest that there may be apolipoprotein E (apoE) isoform-specific differences of tau regulation in AD.

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Abstract: BACKGROUND AND PURPOSE: We investigated apolipoprotein E polymorphism stroke risk in a population sample of 1810 persons aged 75 years or more in Stockholm (the Kungsholmen Project). Information on cognition at cohort inception (from 1987 to 1989) and on stroke occurrence (from 1969 to 1994) is available for the cohort. In the cohort, cognitive impairment is associated with the epsilon 4 allele, and longer survival in subjects aged > or = 85 years with good cognition is associated with the epsilon 2 allele and the absence of epsilon 4. METHODS: We compared stroke incidence in the 1077 of 1124 genotyped subjects who carried epsilon 2/3, epsilon 3/3, or epsilon 3/4 and estimated the proportion of cognitive impairment attributable to stroke. RESULTS: Risk of stroke did not vary with apolipoprotein E polymorphism (P = .82): 24% of 87 incident stroke patients during follow-up compared with 25% of 827 subjects with normal cognition and no stroke diagnosis at baseline carried the epsilon 3/4 genotype. An estimated 9% of cognitive impairment was attributable to stroke. Notably, a reduced epsilon 3/4 frequency of 20% was found in subjects who survived a prior stroke and were included in the cohort, and risk of hemorrhagic stroke tended to be associated with the presence of the epsilon 3/4 genotype and the absence of epsilon 2/3. CONCLUSIONS: This population-based study indicates that apolipoprotein E polymorphism is not a risk factor for ischemic stroke in subjects aged > or = 75 years (although it might possibly influence survival after stroke occurrence and be a risk factor for infrequent hemorrhagic stroke) and that approximately 10% of cognitive impairment in this age group is attributable to stroke.

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Abstract: Four disease-causing mutations have so far been described in the amyloid precursor protein gene on chromosome 21 in familial early-onset Alzheimer's disease. Linkage analysis with a fourteen-allele microsatellite at D21S210 named GT-12 has proven useful in the elucidation of amyloid precursor protein gene involvement in Alzheimer's disease families, as it is closely linked to the gene. Most cases of Alzheimer's disease are thought to be sporadic and not familial. However, evidence from earlier studies suggests an important genetic contribution also in sporadic cases, where gene-environment interaction may contribute to the disease. We have determined frequencies of the GT-12 alleles in 78 Swedish and 49 British sporadic Alzheimer's disease cases and 104 healthy elderly control subjects, to investigate if the disease associates with a particular genotype in GT-12. However, no differences in allele frequencies were observed between any of the groups.

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Abstract: One of the pathological features in Alzheimer's disease (AD) is neurofibrillary tangles in the brain. The main constituent of tangles is the microtubuli-associated protein tau in a hyperphosphorylated state. Tau is also released into cerebrospinal fluid (CSF), and in this study we have used an enzyme linked immunosorbent assay to measure tau in CSF from AD and control cases. Our findings show that tau levels in AD cases are significantly elevated compared to healthy control individuals. We suggest that tau may serve as a biochemical marker of Alzheimer's disease.

Abstract: A random sample of 60 late-onset Alzheimer's disease (AD) cases from a population-based study were apolipoprotein E (apoE) genotyped and clinically examined with a 3-year interval. The epsilon 4 allele carriers had a significantly lower age of disease onset compared to non-epsilon 4 carriers. However, no significant differences were observed between epsilon 4 allele carries and non-carriers for Mini-Mental State Examination (MMSE) test scores at the first examination, in spite of a longer disease duration in the epsilon 4 allele carriers. After 3 years, MMSE test scores were still not significantly different between epsilon 4 carries and non-carriers but more than twice as many non-carriers had died. All other clinical features were similar between epsilon 4 allele carriers and non-carriers. This study indicates that the epsilon 4 allele is associated with a better prognosis of the disease in late-onset AD but that there are probably factors other than the epsilon 4 allele that are important for the AD phenotype.

Abstract: The neuropathologic hallmarks of Alzheimer's disease (AD) are extracellular plaques and intracellular neurofibrillary tangles. A constituent of senile plaques in AD is beta-amyloid, a hydrophobic peptide of 39-43 amino acids and a fragment of the amyloid precursor protein (APP). APP can be metabolized by at least two pathways, one of which involves generation of soluble APP by an unidentified enzyme named alpha-secretase. This cleavage generates alpha-secretase-cleaved, soluble APP (alpha-sAPP), which in this investigation was measured by a new assay in cerebrospinal fluid (CSF) from members of a Swedish AD family with a pathogenic mutation at APP670/671 (ref. 2). Family members who carry the mutation and are diagnosed with AD had low levels of alpha-sAPP (160 +/- 48 ng ml-1), with no overlap compared with non-carriers (257 +/- 48 ng ml-1). Carriers of the presymptomatic mutation showed intermediate alpha-sAPP levels. Today there exists no antemortem marker in AD with sufficient sensitivity and specificity, but measurement of alpha-sAPP represents a new and promising diagnostic marker.

Abstract: The regional cerebral blood flow, brain atrophy, white matter changes and neurophysiologic changes were evaluated in 28 patients with a clinical diagnosis of probable Alzheimer's disease (AD) and in 8 patients with a clinical diagnosis of frontal lobe dementia (FLD) using single photon emission computed tomography, magnetic resonance imaging and electroencephalography (EEG). We found that FLD patients had more severe frontal blood flow reduction and less severe parietal blood flow reduction compared to AD patients. Among patients with mild dementia the EEG changes were less severe in the FLD group. No significant differences were found in white matter changes or in regional atrophy.

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Abstract: The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-containing plaques and neurofibrillary tangles. The main constituent of senile plaques is amyloid beta-peptide (A beta) and in recent years, pathogenic mutations in the amyloid precursor protein (APP) gene have been discovered in some AD families. The APP670/671 mutation, found in a Swedish AD family, has revealed over-production of A beta as one pathogenic mechanism for the development of AD. In the present study we have used an immunoassay to measure A beta levels in cerebrospinal fluid (CSF) from APP670/671 mutation-carriers and non-carriers. A correlation was seen between decrease in A beta levels and duration of disease although no difference was found in levels of A beta between the groups (14.5 +/- 3.3 ng/ml versus 14.9 +/- 2.3 ng/ml).

Abstract: Fifteen out of 25 successfully aged individuals completed a 5 year EEG follow-up study from the eighth to ninth decade of life with comprehensive neuropsychological investigation. One subject suffered from stroke and one developed symptoms of dementia during the follow-up. Of 13 subjects who completed the follow-up as being healthy, MRI showed subtle enlargement of ventricles or subarachnoid spaces and mild signal hyperintensities in a few regions in 2 subjects. General cognitive decline was not observed (WAIS-R IQ: 113.4 at entry, 114.3 five years later). There were no EEG dominant frequencies below 8 c-sec and no more background slowing than a few theta waves per 10 sec, either at entry or 5 years later. Intermittent slowing was observed in 9 subjects at entry and in 8 subjects 5 years later. The prevalence of intermittent slowing was suggested to increase with advancing age when compared to previous studies with younger elderly. However, intermittent slowing occurred only a few times in an EEG test and lasted for less than 2 sec. Moreover, the presence of intermittent slowing did not correlate with any neuropsychological decline or any MRI change. This type of intermittent slowing was regarded as non-specific and clinically silent.

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Abstract: The aim of the study was to investigate whether the regional distribution of white matter hyperintensities (WMH) observed by magnetic resonance imaging differed between vascular dementia and patients with late onset Alzheimer's disease. Another aim was to investigate the relations between the occurrence and degree of WMH and clinical and laboratory data as well as measures of cognitive decline. White matter hyperintensities were assessed with a low field magnetic resonance imager on 23 subjects with probable Alzheimer's disease, 25 with possible Alzheimer's disease and 31 subjects with vascular dementia. The degree and regional distribution of the WMH (expressed as relative volumes) were calculated and compared in the three groups. The relation between cognitive impairment and the degree of the WMH was also studied. The regional distribution of the WMH differed between the groups with significantly more changes in the posterior part of the brain (p < .0001) as well as in the right hemisphere (p < .0005) in the vascular demented as compared to the patients with Alzheimer's disease. No significant correlations between cognitive impairment and the degree of the WMH were found in any of the groups. The total volume of the WMH as well as the regional distribution of these changes differed significantly between vascular dementia and Alzheimer's disease. White matter hyperintensities seem not to be related to the degree of global cognitive decline in dementia and whether it plays a causative role in the development of dementia symptoms needs to be more thoroughly investigated.

Abstract: Blood cadmium concentrations were studied in Alzheimer's disease (AD) and non-demented subjects. The 29 individuals were randomized from the ongoing population survey on ageing and dementia in Stockholm, the Kungsholmen Project. Smokers had, as expected, higher cadmium levels than non-smokers. Cadmium concentrations in blood were related to diastolic blood pressure in non-smoking, non-demented individuals. In contrast to previous reports no differences in blood cadmium levels were found between AD sufferers and non-demented subjects. Furthermore, there were no correlations between cadmium levels in blood and age or cognitive functions. The importance of quality assurance in sample collection and analysis of cadmium as well as scrutinizing smoking habits is emphasized.

Abstract: OBJECTIVE: To determine whether there is a relationship between serum cobalamin levels, normal aging, and Alzheimer's Disease (AD). DESIGN: Cross-sectional survey. SETTING: A district (Kungsholmen) in Stockholm, Sweden. PARTICIPANTS: Population-based cohort of 545 subjects aged more than 74 years. The sample was selected on the basis of evidence of cognitive impairment from all inhabitants in an area of Stockholm (2368 individuals), both living at home or in institutions. MEASUREMENTS: Serum cobalamin levels and diagnostic evaluation for a diagnosis of dementia and type of dementia. RESULTS: The serum cobalamin levels in non-demented individuals decreased 5.5 pmol/L with an increase of 1 year of age (regression coefficient = -5.53; P < 0.0001). However, the regression coefficient was 0.21 (P = 0.91) in demented people and 2.57 (P = 0.32) in AD subjects. There was no difference between serum cobalamin levels in demented, AD, and non-demented subjects, except for the oldest ages where demented people and AD sufferers showed higher values. AD patients still living in their own homes had significantly lower cobalamin concentrations compared with institutionalized AD sufferers. The prevalence rate of cobalamin deficiency was 15.5% (95% CI = 11.5-19.5) in normal aging and 18.1% (95% CI = 10.3-25.9) in AD. CONCLUSIONS: These data suggest that serum cobalamin levels decrease in normal aging, but not in dementia or AD. A lower cobalamin concentration observed in AD sufferers still living in their own homes compared with institutionalized persons with AD seemed to be related to but not fully explained by eating habits. Patients with AD living in their own homes are at risk of developing cobalamin deficiency, and monitoring of serum cobalamin concentrations might be useful in this group.

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Abstract: OBJECTIVE: To describe clinical and genealogic features in a Swedish family with Alzheimer's disease with a double mutation of the amyloid precursor protein gene at codon 670/671 and to study the effects of anticipation and imprinting. DESIGN: Interviews with relatives, clinical investigations of the diseased, pedigree analysis, studies of medical records, and comparison with other families affected by Alzheimer's disease with amyloid precursor protein mutations. SETTING: The Alzheimer's Disease Research Centre, Department of Clinical Neuroscience, Section of Geriatric Medicine, Karolinska Institute, Huddinge (Sweden) University Hospital. PATIENTS AND OTHER PARTICIPANTS: Individuals with the amyloid precursor protein codon 670/671 mutation and their relatives (N = 66). RESULTS: The trait was traced through eight generations, and an autosomal dominant inheritance with very high penetrance was observed. Onset occurred between 44 and 61 years of age (mean, 53 years). The mean duration of disease was 8.5 years (range, 3 to 13 years). The earliest clinical manifestations were deficits in memory function and abstract reasoning. Myoclonic jerks and seizures were common symptoms late in the disease. Anticipation and imprinting effects were not found in this family. CONCLUSIONS: The disease in this family has a single origin--a double mutation in the amyloid precursor protein gene at codon 670/671 transmitted as an autosomal dominant trait. The wide range in age at onset and the clinical symptoms in this pedigree give a characteristic phenotype similar to that seen in some of the other pedigrees with amyloid precursor protein mutations.

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Abstract: In the present study we have investigated the connection between cerebrospinal fluid spaces and cognitive function in patients with senile dementia of Alzheimer type (SDAT) and in successfully aged control subjects. The cerebrospinal fluid (CSF) volumes were measured using a low field MRI technique, and the cognitive functions were assessed with a number of psychometric tests. We found that the SDAT patients showed significantly larger relative volumes in all examined CSF spaces. The largest differences between the groups were found in the volumes of the temporal horns. We also found a significant correlation between the relative CSF volumes in the basal parts of the brain, and episodic memory tests. Significant correlations were also detected between the relative volumes of the lateral ventricles, and degree of dementia as well as between the relative volumes of the lateral ventricles and episodic memory tests.

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Abstract: The hypothesis that Alzheimer's disease (AD) and vascular dementia (VD) may be associated with specific patterns of neuropsychological dysfunction was tested by assessing sensory-motor performance, attention, memory, visuospatial functions, verbal ability, and intelligence in AD (N = 83) and VD (N = 42) patients stratified into four levels of severity based on the Mini-Mental State Examination. Results showed a progressive deterioration due to severity of dementia in both AD and VD patients in all cognitive tasks, but not in the sensory-motor tasks, and no significant interaction between type and severity of dementia in any measure, indicating a similar pattern and course of neuropsychological deterioration in AD and VD. Yet it was possible to differentiate the two groups with moderate success using tests drawing predominantly on motor speed and, to a lesser extent, on cognitive speed. In all these speeded tests, the AD patients outperformed the VD patients.

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Abstract: The relationship between quantitative measurements of brain white-matter hyperintensity (WMH), assessed by magnetic resonance imaging and neuropsychological functions, was explored in demented patients and healthy aged individuals with and without WMH in 12 brain regions. The prevalence of WMH was significantly higher in vascular dementia compared with Alzheimer's disease, especially in posterior periventricular regions. Results showed no difference in any neuropsychological measurement between healthy aged adults with and without WMH. The demented patients with WMH were more impaired in tests of visuoconstruction, attention, finger-motor speed, and latency of tactile identification of objects compared with patients without WMH. These impairments were related mainly to posterior periventricular WMH. There was no relationship between WMH and global cognitive functioning in the demented patients. The degree of WMH was related to age and blood pressure. The data suggest that specific regional WMH may result in specific neuropsychological impairments.

Abstract: Cerebro-spinal fluid (CSF) and blood levels of aluminium, cadmium, calcium, copper, lead, magnesium, and mercury were studied in 24 subjects with dementia of the Alzheimer type (DAT) and in 28 healthy volunteers. Furthermore, arsenic, bromine, chrome, iron, manganese, nickel, rubidium, selenium, strontium, and zinc were measured only in blood. There were significant changes in the DAT group when compared to the controls. The plasma levels of aluminium, cadmium, mercury and selenium were increased and the contents of iron and manganese were lower in the DAT group as compared to control subjects. In CSF there were low levels of cadmium and calcium and increased content of copper in DAT cases. Iron and zinc levels in blood and calcium in both blood and CSF of DAT patients correlated with memory and cognitive functions. Iron, manganese and strontium levels of DAT sufferers in blood and aluminium in CSF were related with changes in behaviour.

Abstract: Cerebrospinal fluid (CSF) and plasma levels of 18 amino acids were studied in 22 subjects with dementia of the Alzheimer type (DAT) and in 11 healthy volunteers with no clinical or family history of dementia. Significant decreases of plasma taurine and glutamate were seen in the DAT cases compared with the controls. The CSF concentrations of glycine, leucine and valine were also significantly reduced in the DAT cases. Furthermore, in the DAT cases significant decreases were observed in the ratio between CSF and plasma (CSF/P) levels for alanine, glutamine, glycine, phenylalanine and valine, when compared with controls. In the DAT group there were significant correlations between behaviour and CSF glutamine; memory and cognitive functions and CSF valine; copying ability and CSF glutamate. CSF/P ratios of glutamine and glutamate correlated with behaviour and copying performances, respectively. The results of this study provide further evidence for a disruption of amino acid metabolism in DAT.

Abstract: Twenty-four healthy aged individuals with above-average intellectual function were studied with use of a low-field-strength (0.02-T) magnetic resonance (MR) imager. The group was carefully selected so as not to include persons with signs of arteriosclerotic diseases, major somatic disease, or a history of brain disease or dementia in the family. The width of the subarachnoid spaces and lateral ventricles, as well as the frequency and degree of brain white-matter lesions, were described with the use of a visual rating scale. White matter lesions were found in less than 9% of the subjects. The lateral brain ventricles were enlarged in 8% of all individuals and the cortical cerebrospinal fluid (CSF) spaces in more than 40% of all individuals. Moreover, T1 and T2 were estimated in different brain areas, and a positive correlation between T1 in the frontal white matter and age was found. A computer-assisted classification procedure was used to estimate brain tissue and CSF areas. The results of this procedure strongly correlated with the visually estimated ventricular size.