Maria Barcikowska

TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease

BackgroundA 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.ResultsThe 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.ConclusionsOur 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.

Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.

Frontotemporal lobar degeneration (FTLD) is the most common cause of early‐onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans‐activating response element (TAR) DNA binding protein (TDP‐43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD‐MND pedigree with no mutations in known dementia genes.

Homocysteine, apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment.

Background: Alzheimer’s disease (AD) is the most common dementia disorder in elderly people. Currently, the only known genetic factor associated with the development of sporadic AD is the apolipoprotein E (ApoE) 4 allele. There is a need to identify other environmental and genetic risk factors that could modulate the risk of developing sporadic AD. Objective: To analyse the correlation between the ApoE and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma homocysteine levels and vitamins (B12 and folic acid) concentrations in serum from patients with AD and mild cognitive impairment (MCI) as compared with control group. Methods: The study was carried out in 99 AD patients, 98 subjects with MCI and 100 healthy subjects. Diagnosis of probable AD was made according to the NINCDS-ADRDA and DSM-IV criteria. The following factors were analysed: age, gender, duration of disease, concentration of plasma total homocysteine, folic acid and vitamin B12 in the serum and the polymorphism of MTHRF and ApoE genes. The results obtained were analysed by multivariate analysis of regression. Results: We found that plasma total homocysteine is increased in AD patients (p < 0.0001) and depended on the MTHFR T/T genotype in the presence of low folate levels (p < 0.05). The increased frequency of ApoE4 allele in the AD population was independent of homocysteine, folic acid and vitamin B12 levels and MTHFR status. Conclusions: We conclude that the concentration of plasma total homocysteine is increased in AD patients. This may be associated with the T/T genotype in the MTHFR gene; however, the distribution of the MTHRF C677T polymorphism in the Polish population does not differ in AD and controls.

The diagnostic value of EEG in Alzheimer disease : correlation with the severity of mental impairment

Summary The aim of our study was to analyze EEG changes in patients with Alzheimer disease (AD) and to determine how closely EEG reflects the progression of mental impairment in people with AD. Ninety-five patients with probable AD according to National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria treated in our Clinic for Memory Disorders were selected for this study. Patients were divided into three subgroups with mild, marked, and severe dementia according to the results of psychometric scales. The EEG findings were classified using an eight-degree scale according to the background activity, presence and amount of &thgr; and &dgr; waves, focal changes, lateralization of focal changes, synchronization, and presence of sharp and spike waves. A significant correlation between the degree of EEG abnormalities and cognitive impairment was found. We did not observe any correlation between the presence of &dgr; waves and the results of neuropsychological tests. Our study revealed an important diagnostic value of EEG in the estimation of the severity of dementia parallel to psychometric scales.

Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland

Mutations in three causative genes have been identified in patients with an autosomal-dominant form of early-onset Alzheimers disease (EOAD). To determine the spectrum of mutations in a group consisting of 40 Polish patients with clinically diagnosed familial EOAD and 1 patient with mild cognitive impairment (MCI) and family history of AD, we performed a screening for mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) genes. Four previously recognized pathogenic mutations in PSEN1 gene (H163R, M139V) and APP gene (T714A, V715A), and three novel putative mutations in PSEN1 gene (P117R and I213F) and PSEN2 gene (Q228L) were identified. The 34 patients with no mutations detected were older than the patients with mutations. A frequency of APOE4 allele was higher in this group. Frequency of mutations is relatively low (17%), possibly due to used operational definition of a patient with familial EOAD (a patient having at least one relative with early-onset dementia). It could be concluded that screening for mutations in the three genes could be included in a diagnostic program directed at patients with a positive family history or age of onset before 55 years.

Dementia in Parkinson's Disease

The prevalence of dementia, assessed on the basis of the Wechsler scale (WAIS), was determined in a group of 88 patients with idiopathic Parkinsons disease (PD) lasting longer than 4 years. In this group, 19 patients (22%) were diagnosed as demented. They were significantly older at the time of evaluation (72.9 +/- 8.1 vs. 63.6 +/- 11.9), and also at the onset of the disease (61.1 +/- 10.6 vs. 54.4 +/- 12.1) than nondemented patients. Their parkinsonism, as judged on the base of the Activity of Daily Living Scale, was more pronounced (57.4 +/- 13.7 vs. 73.3 +/- 15.6) and they developed psychotic side-effects of L-DOPA treatment (53% vs. 9%) more often. A weak negative correlation between age and intellectual quotient (IQ) was found, and a much stronger positive correlation between education and IQ. 25 patients of those diagnosed previously as non-demented were reassessed for dementia after another 5 years of disease. Only two of them were found demented. Both died and an immunohistochemical study of their brains was performed. In the 2 cases we found neuropathological features of both PD (Lewy bodies) and Alzheimers disease (AD)--neurofibrillary tangles (NFT) and senile plaques (SP). This finding may support the hypothesis that, at least in some cases, dementia in PD could be due to an accompanying AD.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Mitochondrial haplogroup H and Alzheimer's disease--is there a connection?

We evaluated the involvement of the major Caucasian-specific mitochondrial haplogroups (H, I, J, K, T, U, V, W and X), haplogroup clusters (HV, UK, TJ, IWX) and two functional mtSNPs (4216, 4917) in the pathogenesis of Alzheimers disease (AD) in the Polish population. The frequency distribution of mtDNA haplogroups was non-randomly associated with APOE4 status (chi(2)=73.17, df=1, p<0.0001, OR=5.97, 95% CI 3.90-9.12), however, no haplogroup-specific neutralizing of the APOE4 allele influence was detected. Multivariate analysis suggested the opposite-APOE4 status could modulate the effect of mtDNA haplogroups. We found that HV cluster is significantly associated with the risk of AD, regardless of the APOE4 status (OR=1.59, 95% CI, 1.04-2.44, p=0.032). Contrary to the previous studies, we report no evidence for the involvement of haplogroup U, K, J or T in AD risk. We conclude that further analysis of subtypes of haplogroup H would be necessary to decipher the relation of HV cluster with AD.

Genetic variation of Omi/HtrA2 and Parkinson's disease

Variants in the Omi/HtrA2 gene have been nominated as a cause of Parkinsons disease. This sequencing study of Omi/HtrA2 in 95 probands with apparent autosomal dominant inheritance of Parkinsons disease did not identify any pathogenic mutations. In addition, there was no association between common variations in the Omi/HtrA2 gene and susceptibility to Parkinsons disease in any of our four patient-control series (n=2373). Taken together our results do not support a role for Omi/HtrA2 variants in the pathogenesis of Parkinsons disease.

Magnetic resonance imaging-based hippocampal volumetry in patients with dementia of the Alzheimer type

A volumetric magnetic resonance imaging assessment of the hippocampal region was done in 50 patients with Alzheimer-type dementia and 25 members of a control group. There were no significant volumetric differences between the right and left hippocampi. The volumetric hippocampal measurements were 39.4% smaller in dementia of the Alzheimer type than in controls. In the differentiation between the analyzed groups of patients, the method had a sensitivity of 95% and a specificity of 92%. A correlation of the hippocampal volumes with the severity of the dementia and the patient’s age was found. The results confirmed the importance of hippocampal atrophy in the etiology of dementia. In vivo the quantitative assessment of the hippocampal formation is a valuable tool in the diagnosis of Alzheimer’s disease.