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mtDNA common variation is inconsistently reported to modify the risk of Parkinson's disease (PD). We evaluated the impact of the mitochondrial haplogroups, subhaplogroups, coding and non-coding single-nucleotide polymorphisms on PD risk in 241 PD patients and 277 control subjects. After stratification by gender, we found that haplogroup J (OR 0.19; 95% CI 0.069-0.53; P = 0.0014) was associated with a lower PD risk in males. Unexpectedly, subhaplogroup analysis based on the control region (CR) polymorphisms demonstrated that subcluster K1a was more prevalent in healthy controls, while K1c was more frequent in PD patients (P = 0.025 and P = 0.011, respectively; two-tailed Fisher's exact test). Additionally, we confirmed the hypothesis that sublineages (U4 + U5a1 + K+J1c + J2), previously proposed to partially uncouple oxidative phosphorylation (OXPHOS), decrease PD risk (P = 0.027, chi2 with Yates' correction). The putative protective effect of uncoupling mtDNAs against PD might result from decreased production of reactive oxygen species. We propose that stratification into subhaplogroups or by gender could be necessary to reveal the involvement of specific mtDNA sublineages in PD pathogenesis.

Presenilin 2 gene (PSEN2) is one of the causative genes for familial Alzheimer's disease. A delA polymorphism located in PSEN2 promoter was proposed to be a risk factor for early-onset AD. We examined association between AD and PSEN2 polymorphisms located in two 5'UTR regions in group of 217 late-onset AD patients, 109 mild cognitive impairment patients, and 225 non-demented control subjects. No significant differences for genotype and allele distributions of a delA and a novel insAC polymorphisms in the studied groups as compared to controls were observed. Univariate and multivariate risk estimation shows that neither delA, insAC alleles nor the genotypes are risk factors for AD. No significant interaction between the APOE4 and PSEN2 polymorphisms was found. A bioinformatic analysis showed that delA polymorphism influences binding sites of transcription factors involved in the cellular processes related to AD. The rare variants identified in exon 3 of the PSEN2 could have a potential influence on PSEN2 transcript splicing.

The -22c/t polymorphism in the promoter of the presenilin 1 gene is associated with increased risk for Alzheimer's disease (AD) in some populations. It was shown that -22c allele is connected with two-fold decrease in promoter activity. We studied the impact of the polymorphism in groups of Polish late-onset and early-onset AD patients. Our results suggest that -22c/t polymorphism is not connected with AD in Polish population. The -22t allele showed a high degree of linkage disequilibrium with -2797 insertion of 13 bp. An additional -2923g/t polymorphism is also not connected with -22c/t and is not a risk factor for AD.

Background A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. Results The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. Conclusions Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.

Mossbauer studies of Parkinsonian and control Substantia Nigra (SN) show that the overall amount of iron in SN is about the same in PD and control. At least 90% of this iron is ferritin-like and Fe2+ and/or neuromelanin iron, if present at all, can constitute only less than 10% of the overall iron. During storage in formalin, iron is slowly removed from ferritin and bound to a chelating agent.

Background A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 dosage. Results We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10-4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56). Conclusions Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10-15 (EPHA1) and 1.8 × 10-13 (CD33).

Tubulovesicular structures (TVS) have been consistently observed in brain tissue of animals with transmissible spongiform encephalopathies such as natural and experimental scrapie, bovine spongiform encephalopathy, and experimental Creutzfeldt-Jakob disease (CJD). In this communication we demonstrate for the first time the presence of TVS in natural CJD. TVS were detected in all 3 CJD specimens. However, they were rare and were found only in one or two locations per grid. They were seen in distended pre- and postsynaptic terminals and measured approximately 35 nm in diameter, and they were smaller and of higher electron density than synaptic vesicles. Their occurrence in all types of spongiform encephalopathies irrespective of the affected host and the strain of infectious agent emphasizes their biological significance.

We examined the brains of 385 mentally retarded adults aged 23–90 years without Down's syndrome (DS), metabolic disorder, or hydrocephalus to extend our knowledge about the occurrence of Alzheimer-type neuropathology in this population. Relevant measures of neuropathology also were related to selected information available from clinical records. The presence of one or more neurofibrillary tangles (NFT) and/or neuritic plaques (NP) was observed in 63.4% of all cases and varied with age. The prevalence of positive cases was higher when mental retardation was due to head trauma, congenital malformation, or familial factors and when a history of seizures was reported. Comprehensive morphometric analyses of neocortical, hippocampal and parahippocampal areas indicated that recommended agespecific quantitative criteria for the diagnosis of Alzheimer disease [Khachaturian ZS (1985) Arch Neurol 42:1097–1105] were met in 9.5% of cases less than 50 years of age, 54.2% between 50 and 65, 70% between 66 and 75, and 87% of the cases greater than 75 years of age. However, a limited immunohistochemical study revealed that in most cases the NP did not have a neuritic component containing paired helical filaments and in this respect most of the plaques observed in this population may differ from those most strongly associated with Alzheimer disease. In addition, substantial numbers of NFT were seen in frontal cortex, contrasting with results reported in the literature for nonretarded populations. The number of NP per mm2 consistently increased with age for all areas examined, while the relationship between NFT density and age varied across areas, and was clearly not monotonic. Our studies show that the neuropathological lesions currently considered hallmarks of Alzheimer disease are prevalent among non-DS mentally retarded adults, and the regional density of these lesions is high. Thus, while people with DS are affected at an earlier age, clear Alzheimer neuropathology develops in many mentally retarded individuals.

Immunocytochemistry with monoclonal antibodies to the beta-protein and to antigens associated with paired helical filaments (PHF) allows us to selectively stain two major components of neuritic (senile) plaques (NP): PHF and amyloid deposits. Using this method, the structure of NP in the brains of Alzheimer disease victims was compared to their structure in the brains of non-demented aged individuals selected for high numbers of NP. It is demonstrated that the dystrophic neurites participating in the plaque formation contain PHF only when cortical nerve cells in the same brain area form neurofibrillary tangles (NFT). People with many NP and many NFT were always demented, whereas people with many NP but few, if any NFT were not. It is speculated that there is individual susceptibility to the formation of PHF and that their appearance may represent a nonspecific response of the neuronal network to different kinds of injuries, like the deposition of amyloid in Alzheimer disease, or other pathogenic factors associated with various dementive neurodegenerative diseases. It is hypothesized that the deposition of brain amyloid in people resistant to neurofibrillary pathology may induce too little dysfunction for the development of dementia.

Immunocytochemical staining with monoclonal antibodies to the beta-protein on tissue sections which have been pretreated with formic acid is not only a very specific but also a highly sensitive method for the detection of amyloid deposits in the brains of Alzheimer's disease victims. We report here a spectrum of morphological appearance of the brain amyloid deposits which are one of the main histopathological correlates of this disorder. Deposits of the beta-protein are not only found in the well-known lesions [congophilic angiopathy and senile (neuritic) plaques] but are also seen under various morphological forms for which the word "plaques" does not appear an appropriate term: amyloid fibrils are found as large areas of diffuse infiltration of the neuropil, as ribbon-like infiltration in the subpial layer of the cerebral cortex, as granular deposits in the white matter, as diffuse deposits in the molecular layer of the cerebellum and the basal ganglia and as star-shaped deposits in the cerebellar Purkinje cell layer. The morphology of these deposits seems to depend on the cyto- and fibroarchitectonics of the brain region in which they are found, on the amount of amyloid deposited, and also on the type of staining technique used. It is only under specific circumstances that the deposition of amyloid in the neuropil is accompanied by the formation of paired helical filaments in nerve cell processes and their parent perikarya. In conclusion, our studies suggest that the extent of brain amyloidosis in Alzheimer's disease is much wider than so far appreciated.

Quantitative studies of neuritic (senile) plaques in six cortical layers were carried out in brains from people with confirmed clinical and neuropathological diagnosis of senile dementia of the Alzheimer type (SDAT) and Down's syndrome (DS). The same studies were performed on brains of normal old-aged people. In Alzheimer disease (AD) and DS cases the highest numbers of neuritic plaques (NP) were observed in temporal lobe layers III and II and occipital lobe layers III, IV and II. In normal old-aged people the highest numbers of NP were found in temporal lobe III and V and in occipital lobe IV, III, and V layer. The plaque numbers in both temporal and occipital cortices of AD and DS were significantly higher than that of normal old-aged people but there was no difference between AD and DS.