In most subjects with Parkinson's disease and dementia with Lewy bodies, alpha-synuclein (alphaS) immunoreactive pathology is found not only in the brain but also in the autonomic nuclei of the spinal cord. However, neither has the temporal course of alphaS pathology in the spinal cord in relation to the brain progression been established, nor has the extent of alphaS pathology in the spinal cord been analyzed in population-based studies. Using immunohistochemistry, the frequency and distribution of alphaS pathology were assessed semiquantitatively in the brains and spinal cord nuclei of 304 subjects who were aged at least 85 in the population-based Vantaa 85+ study. alphaS pathology was common in the spinal cord; 102 (34%) subjects had classic alphaS pathology in the thoracic and/or sacral autonomic nuclei. Moreover, 134 (44%) subjects showed grain- or dot-like immunoreactivity in neuropil (mini-aggregates) without classic Lewy neurites or Lewy bodies (LBs). The latter type of alphaS accumulation is associated with age, but also the classic alphaS pathology was found more often in the oldest compared to the youngest age group. The severity of alphaS pathology in the spinal cord autonomic nuclei is significantly associated with the extent and severity of alphaS pathology in the brain. Of the subjects, 60% with moderate to severe thoracic alphaS pathology and up to 89% with moderate to severe sacral alphaS pathology had diffuse neocortical type of LB pathology in the brain. alphaS pathology exclusively in the spinal cord was rare. Our study indicates that in general alphaS pathology in the spinal cord autonomic nuclei is associated with similar pathology in the brain.
Pathogenic mutations of the APP gene, leading to early-onset Alzheimer's disease (AD) have been known for more than 20 years. Recently, it was discovered that APP mutations might also be protective. A rare variant A673T reportedly protects against AD and age-related cognitive impairment and might functionally inhibit proteolytic cleavage at the ß-secretase site of APP. We sequenced APP exon 16 in a population-based sample of 515 Finnish subjects aged 85 or older. Neuropathologic data were available in 274. We found the A673T variant in 1 subject (0.2%), who lived until age 104.8 years (second highest age-at-death in the cohort). Neuropathologic analysis showed little beta-amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease score 0). Some vascular amyloid was detected in meningeal arteries suggesting that vascular ß-amyloid accumulation might be less inhibited than the parenchymal. She was demented at the age of 104, most likely because of hippocampal sclerosis. The low amount of parenchymal ß-amyloid pathology at the age of 104.8 years supports the concept that the A673T variant protects the brain against ß-amyloid pathology and AD.
Cortical and cerebrovascular amyloid-? (A?) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) e4 is a major genetic modulator of A? deposition and AD risk. Variants of the amyloid-? protein precursor (A?PP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and A?PP variants in cortical and cerebrovascular A? deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged = 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the e4 allele with cortical (p = 4.91 ? 10-17) and cerebrovascular (p = 9.87 ? 10-11) A? deposition as well as with NIA-RI AD (p = 1.62 ? 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the A?PP locus. In single SNP or haplotype analyses there were no statistically significant A?PP locus associations with cortical or cerebrovascular A? deposition or with NIA-RI AD. We sequenced the promoter of the A?PP gene in 40 subjects with very high A? deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular A? depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE e4 variant. Promoter mutations or common allelic variation in the A?PP gene do not have a major contribution to cortical or cerebrovascular A? deposition, or very late-onset AD in this Finnish population based study.
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Capillary amyloid-ß (capAß) deposition in the cerebral cortex is the neuropathological feature providing the basis for categorizing cerebral amyloid angiopathy (CAA) into two distinct types, CAA-Type1 with capAß and CAA-Type2 without capAß.
We investigated the neuropathological and clinical characteristics of capAß deposition in a prospective population-based study.
Vantaa 85+ includes 601 individuals aged =85 years, of which 300 were studied clinically and neuropathologically. 278 subjects were analyzed for the apolipoprotein E (APOE) genotype. The diagnosis of capAß was determined using immunohistochemistry against Aß, and of CAA using Congo red confirmed by Aß immunohistochemistry, both analyzed in six brain areas. The severity of capAß was graded semi-quantitatively, and the severity of CAA was based on the percentage of affected vessels. Alzheimer's disease (AD)-type neuropathology (CERAD score and Braak stage) was analyzed using standard methods.
CAA-Type1 was present in 86/300, CAA-Type2 in 135/300, and 79/300 had no CAA. CapAß was most frequent in the occipital lobe (79/86). CAA-Type1 was associated with the severity of CAA (p?
We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease.
The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population.
We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus.
We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318?167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1).
The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.
National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
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In most locations except for Russia, tick-borne encephalitis is mainly caused by the European virus subtype. In 2015, fatal infections caused by European and Siberian tick-borne encephalitis virus subtypes in the same Ixodes ricinus tick focus in Finland raised concern over further spread of the Siberian subtype among widespread tick species.
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
Disruption of the circadian rhythms is a frequent preclinical and clinical manifestation of Alzheimer's disease. Furthermore, it has been suggested that shift work is a risk factor for Alzheimer's disease. Previously, we have reported association of intolerance to shift work (job-related exhaustion in shift workers) with a variant rs12506228A, which is situated close to melatonin receptor type 1A gene (MTNR1A) and linked to MTNR1A brain expression levels. Here, we studied association of that variant with clinical and neuropathological Alzheimer's disease in a Finnish whole-population cohort Vantaa 85+ (n = 512, participants over 85 years) and two follow-up cohorts. Rs12506228A was associated with clinical Alzheimer's disease (p = 0.000073). Analysis of post-mortem brain tissues showed association with higher amount of neurofibrillary tangles (p = 0.0039) and amyloid beta plaques (p = 0.0041). We then followed up the associations in two independent replication samples. Replication for the association with clinical Alzheimer's disease was detected in Kuopio 75+ (p = 0.012, n = 574), but not in the younger case-control sample (n = 651 + 669). While melatonin has been established in regulation of circadian rhythms, an independent role has been also shown for neuroprotection and specifically for anti-amyloidogenic effects. Indeed, in vitro, RNAi mediated silencing of MTNR1A increased the amyloidogenic processing of amyloid precursor protein (APP) in neurons, whereas overexpression decreased it. Our findings suggest variation close to MTNR1A as a shared genetic risk factor for intolerance to shift work and Alzheimer's disease in old age. The genetic associations are likely to be mediated by differences in MTNR1A expression, which, in turn, modulate APP metabolism.