APOE Allele Frequency in Southern Greece: Exploring the Role of Geographical Gradient in the Greek Population.

BACKGROUND: the apolipoprotein e4 allele (APOE4) constitutes an established genetic risk factor for Alzheimer's Disease Dementia (ADD). We aimed to explore the frequency of the APOE isoforms in the Greek population of Southern Greece. METHODS: peripheral blood from 175 Greek AD patients, 113 with mild cognitive impairment (MCI), and 75 healthy individuals. DNA isolation was performed with a High Pure PCR Template Kit (Roche), followed by amplification with a real-time qPCR kit (TIB MolBiol) in Roche's Light Cycler PCR platform. RESULTS: APOE4 allele frequency was 20.57% in the ADD group, 17.69% in the MCI group, and 6.67% in the control group. APOE3/3 homozygosity was the most common genotype, while the frequency of APOE4/4 homozygosity was higher in the AD group (8.60%). APOE4 carrier status was associated with higher odds for ADD and MCI (OR: 4.49, 95% CI: [1.90-10.61] and OR: 3.82, 95% CI: [1.59-9.17], respectively). CONCLUSION: this study examines the APOE isoforms and is the first to report a higher APOE frequency in MCI compared with healthy controls in southern Greece. Importantly, we report the occurrence of the APOE4 allele, related to ADD, as amongst the lowest globally reported, even within the nation, thus enhancing the theory of ethnicity and latitude contribution.

TARDBP p.I383V, a recurrent alteration in Greek FTD patients.

BACKGROUND: A significant proportion of FTD (Frontotemporal Degeneration) cases can be attributed to mutations in major genes such as GRN, MAPT and C9orf72. Our previous report on a Greek FTD cohort revealed the presence of the single nucleotide polymorphism (SNP) p.I383V (rs80356740) in the TARDBP gene in three unrelated patients. Our objective was to develop a novel, fast and accurate method for the detection of this particular SNP and evaluate the assay in a larger cohort. METHODS AND RESULTS: A real-time qPCR-melting curve analysis method was developed, validated and tested in 142 FTD patients and 111 healthy control subjects. The SNP was detected in another two patients raising its yield in FTD patients to 3.5% (5 out of 142 patients) while one in 111 healthy controls was found to be a carrier. However, its frequency in the general population has been reported extremely low in international SNP databases (0.002%). CONCLUSION: This fact along with the indicated pathogenicity of this SNP in some bioinformatics tools, suggest that TARDBP p.I383V is recurrent and likely pathogenic for the Greek FTD population. Our high-throughput method could be used for genotyping in other larger patient cohorts and in other populations. Additionally, functional in vitro studies are required for the final adjudication of this TARDBP alteration as a pathogenic alteration.

The impact of COVID-19 pandemic on people with mild cognitive impairment/dementia and on their caregivers.

BACKGROUND: The novel coronavirus disease (COVID-19) was first detected in Mainland China in December 2019, and soon it spread throughout the world, with multiple physical and psychological consequences across the affected populations. AIMS: The aim of the current study was to analyze the impact of COVID-19 pandemic on older adults with mild cognitive impairment (MCI)/dementia and their caregivers as well. MATERIALS AND METHODS: Two hundred and four caregivers took part in the study, completing a self-reported questionnaire about the person with MCI/dementia and their own, since the lockdown period which started in February and ended in May of 2020 in Greece. RESULTS: Results indicated a significant overall decline of the people with MCI/dementia. Further, the domains in which people with MCI/dementia were mostly affected were: communication, mood, movement and compliance with the new measures. Caregivers also reported a great increase in their psychological and physical burden during this period, where the available support sources were limited. DISCUSSION: The pandemic threatens to disrupt the basic routines that promote mental and physical health of both people with MCI/dementia and t heir caregivers. CONCLUSION: Further measures to protect and provide support to people who suffer and their families are needed.

Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.

Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly VCP mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.

Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders.

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer disease (AD), while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. METHODS: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3058 patients clinically diagnosed with AD, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5089 control subjects. RESULTS: We observed a significant association between the R47H variant and AD, while no association was observed with any other neurodegenerative disease included in this study. CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with AD. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

The power of sample size through a multi-scanner approach in MR neuroimaging regression analysis: evidence from Alzheimer's disease with and without depression.

The inconsistency of volumetric results often seen in MR neuroimaging studies can be partially attributed to small sample sizes and variable data analysis approaches. Increased sample size through multi-scanner studies can tackle the former, but combining data across different scanner platforms and field-strengths may introduce a variability factor capable of masking subtle statistical differences. To investigate the sample size effect on regression analysis between depressive symptoms and grey matter volume (GMV) loss in Alzheimer's disease (AD), a retrospective multi-scanner investigation was conducted. A cohort of 172 AD patients, with or without comorbid depressive symptoms, was studied. Patients were scanned with different imaging protocols in four different MRI scanners operating at either 1.5 T or 3.0 T. Acquired data were uniformly analyzed using the computational anatomy toolbox (CAT12) of the statistical parametric mapping (SPM12) software. Single- and multi-scanner regression analyses were applied to identify the anatomical pattern of correlation between GM loss and depression severity. A common anatomical pattern of correlation between GMV loss and increased depression severity, mostly involving sensorimotor areas, was identified in all patient subgroups imaged in different scanners. Analysis of the pooled multi-scanner data confirmed the above finding employing a more conservative statistical criterion. In the retrospective multi-scanner setting, a significant correlation was also exhibited for temporal and frontal areas. Increasing the sample size by retrospectively pooling multi-scanner data, irrespective of the acquisition platform and parameters employed, can facilitate the identification of anatomical areas with a strong correlation between GMV changes and depression symptoms in AD patients.

The Neural Correlates of Impaired Self-Monitoring Among Individuals With Neurodegenerative Dementias.

OBJECTIVE: Self-monitoring is a crucial component of human empathy and necessary for the formation and repair of social relations. Several studies have brought to light possible neuronal substrates associated with self-monitoring, but the information that they have provided is inconclusive. The authors, therefore, studied a large group of patients with dementia to assess what brain structures are necessary for the self-monitoring function.Methods: Seventy-seven patients with dementia of various types were screened using voxel-based morphometry to assess possible volume reduction in the brain structures of patients with self-monitoring problems, and the decrease of socioemotional expressiveness and modification of self-presentation was estimated using the Revised Self-Monitoring Scale. Regression analysis was employed to investigate the correlation between gray matter loss and deficient self-monitoring.Results: The socioemotional expressiveness scores were associated with decreased gray matter volume in the right olfactory cortex, inferior frontal gyrus, superior temporal pole, parahippocampal gyrus, insula, and medial temporal gyrus bilaterally. Self-presentation scores were associated with bilateral gray matter volume reduction in the olfactory cortex, insula, rectus gyrus and inferior frontal gyrus, right superior temporal pole, and parahippocampal gyrus, as well as the left medial temporal gyrus and anterior superior frontal gyrus.Conclusions: These results suggest that patients with dementia present decreased ability of self-monitoring, probably due to impaired insula and orbitofrontal cortex and their disconnection from structures of the salience network.

Defining Neuropsychiatric Inventory scale differences across frontotemporal dementia syndromes.

AIM: The aim of this study was to assess the ability of Neuropsychiatric Inventory (NPI) scale profiles to differentiate between distinct frontotemporal dementia (FTD) subtypes. METHODS: The NPI was used to assess 311 older patients who had been clinically diagnosed with FTD. FTD subtypes included behavioural variant FTD (bvFTD, n = 121), primary progressive aphasia (semantic variant (n = 69), non-fluent agrammatic variant (n = 31), and logopenic variant (n = 0)), FTD-motor neuron disease (n = 4), progressive supranuclear palsy (n = 43), and corticobasal syndrome (n = 43). Total NPI score and scores for each NPI item were correlated across the distinct FTD subtypes. RESULTS: Patients with bvFTD showed significantly greater impairment on their total NPI score than patients with corticobasal syndrome (P < 0.001), non-fluent agrammatic variant primary progressive aphasia (P < 0.001), progressive supranuclear palsy (P = 0.002), and semantic variant primary progressive aphasia (P = 0.010). Aggressiveness, euphoria, apathy, disinhibition, irritability, aberrant motor behaviours, and appetite disturbance were significantly higher in bvFTD than in the other subgroups. The lowest NPI scores were generally shown among those with CBS. However, NPI total and specific item values overlapped among the subtypes. CONCLUSIONS: Patients with bvFTD showed significantly greater neuropsychiatric dysfunction than those with the other FTD subtypes, as measured by the NPI scale. In contrast, patients with corticobasal syndrome had a comparatively healthier profile. Therefore, differential diagnosis among the FTD subtypes may be guided by the NPI, although the subtype is unlikely to be confirmed on the basis of NPI alone.

Frontotemporal dementia spectrum: first genetic screen in a Greek cohort.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative syndromes associated with several causative and susceptibility genes. Herein, we aimed to determine the incidence of the most common causative dementia genes in a cohort of 118 unrelated Greek FTD spectrum patients. We also screened for novel possible disease-associated variants in additional 21 genes associated with FTD or amyotrophic lateral sclerosis. Pathogenic or likely pathogenic variants were identified in 16 cases (13.6%). These included repeat expansions in C9orf72 and loss-of-function GRN variants, and likely pathogenic variants in TARDBP, MAPT, and PSEN1. We also identified 14 variants of unknown significance in other rarer FTD or amyotrophic lateral sclerosis genes that require further segregation and functional analysis. Our genetic screen revealed a high genetic burden in familial Greek FTD cases (30.4%), whereas only two of the sporadic cases (3.5%) carried a likely pathogenic variant. A substantial number of familial cases still remain without an obvious causal variant, suggesting the existence of other FTD genetic causes besides those currently screened in clinical routine.

A specific pattern of gray matter atrophy in Alzheimer's disease with depression.

Considering the high incidence of depressive symptoms in Alzheimer's disease (AD), we conducted a large-sample study to investigate the pattern of gray matter (GM) abnormalities that differentiates depressive from non-depressive AD patients. We included 201 AD patients who underwent MRI assessment and categorized them into depressive and non-depressive subgroups based on the Geriatric Depression Scale (GDS; cut-off score: ≤9). We performed whole-brain voxel-based morphometry analysis in 173 patients after MRI quality control and used between-group comparisons and regression analysis models to analyze the volumetric data controlling for nuisance variables. Depressive AD patients had extensive GM volume loss mainly in the paracentral region, specifically in post- and pre-central gyrus, supplementary motor areas and thalamus compared to non-depressive patients. Similar findings were obtained for the group of 173 patients using regression analysis and GDS score as predictor variable. We provided the first clear demonstration of a unique pattern of GM atrophy that characterizes AD patients with depression which is consistent with regions implicated in the phenomenon of psychomotor retardation that characterizes depression.

Big 5 personality changes in Greek bvFTD, AD, and MCI patients.

Patients with neurodegenerative disease show distinct patterns of personality change, some of which may be traced to focal neurological damage, whereas others may be mediated by cultural reactions to functional impairment. Although such changes are early and pervasive in behavioral variant frontotemporal dementia (bvFTD), and milder changes are seen in Alzheimer disease (AD), no study has examined all Big 5 factors of personality in mild cognitive impairment (MCI) patients. In addition, the influence of culture and ethnicity on disease-related personality changes has seldom been examined. Premorbid and current personality were measured in 47 Greek patients with bvFTD, AD, and MCI on the basis of informant reports using the Traits Personality Questionnaire 5, a 5-factor inventory in the Greek language that accounts for Greek cultural factors. bvFTDs showed greater decreases in conscientiousness compared with ADs and MCIs. ADs and MCIs showed increased neuroticism, whereas the bvFTD patients were rated as having become much less neurotic in the course of their disease. The pattern of personality change in MCIs was very similar to that of ADs, supporting recent evidence that personality changes occur as early as the MCI disease stage. In all the groups, personality changes were similar to those previously described in non-Mediterranean cultures, supporting the hypothesis that they may result directly from disease-specific neurological processes.

Difficulties in detecting behavioral symptoms of frontotemporal lobar degeneration across cultures.

Cross-cultural studies of neurodegenerative disorders are especially important when the disease in question is difficult to diagnose, particularly if symptoms of the illness include behavioral disturbances that may be interpreted differently in different cultures. One such disease is frontotemporal lobar degeneration (FTLD), an early-age-of-onset dementia that disproportionately affects social behavior. We report the demographic and neuropsychologic characteristics of more than 300 patients diagnosed with FTLD in the United States, Greece, and Turkey. We find that patients with the frontal variant of frontotemporal dementia (FTD) are diagnosed at an earlier age and report earlier symptom onset in the United States than in Greece or Turkey. Furthermore, neuropsychologic measures indicate that at diagnosis, FTD patients in the United States are less impaired than patients in Greece and Turkey. Patients with FTD in Greece and Turkey are diagnosed later in the disease, presumably because their behavioral symptoms are not easily detected by the medical system in these countries. Our study underscores the need to create culturally appropriate indices of the behavioral symptoms of FTLD, so that patients may be diagnosed and treated at an earlier stage.