Genetic Predisposition for White Matter Hyperintensities and Risk of Mild Cognitive Impairment and Alzheimer's Disease: Results from the HELIAD Study.

The present study investigated the association of genetic predisposition for white matter hyperintensities (WMHs) with incident amnestic mild cognitive impairment (aMCI) or Alzheimer's disease (AD), as well as whether such an association was influenced by age, sex, and cognitive reserve. Overall, 537 individuals without aMCI or dementia at baseline were included. Among them, 62 individuals developed aMCI/AD at follow up. Genetic propensity to WMH was estimated using a polygenic risk score for WMHs (PRS WMH). The association of PRS WMH with aMCI/AD incidence was examined using COX models. A higher PRS WMH was associated with a 47.2% higher aMCI/AD incidence (p = 0.015) in the fully adjusted model. Subgroup analyses showed significant results in the older age group, in which individuals with a higher genetic predisposition for WMHs had a 3.4-fold higher risk for developing aMCI/AD at follow up (p < 0.001), as well as in the lower cognitive reserve (CR, proxied by education years) group, in which individuals with a higher genetic predisposition for WMHs had an over 2-fold higher risk (p = 0.013). Genetic predisposition for WMHs was associated with aMCI/AD incidence, particularly in the group of participants with a low CR. Thus, CR might be a modifier in the relationship between genetic predisposition for WMHs and incident aMCI/AD.

Development of robust normative data for the neuropsychological assessment of Greek older adults.

OBJECTIVE: Normative data for older adults may be tainted by inadvertent inclusion of undiagnosed individuals at the very early stage of a neurodegenerative process. To avoid this pitfall, we developed norms for a cohort of older adults without MCI/dementia at 3-year follow-up. METHODS: A randomly selected sample of 1041 community-dwelling individuals (age ≥ 65) received a full neurological and neuropsychological examination on two occasions [mean interval = 3.1 (SD = 0.9) years]. RESULTS: Of these, 492 participants (Group 1; 65-87 years old) were without dementia on both evaluations (CDR=0 and MMSE ≥ 26); their baseline data were used for norms development. Group 2 (n = 202) met the aforementioned criteria only at baseline, but not at follow-up. Multiple linear regressions included demographic predictors for regression-based normative formulae and raw test scores as dependent variables for each test variable separately. Standardized scaled scores and stratified discrete norms were also calculated. Group 2 performed worse than Group 1 on most tests (p-values < .001-.021). Education was associated with all test scores, age with most, and sex effects were consistent with the literature. CONCLUSIONS: We provide a model for developing sound normative data for widely used neuropsychological tests among older adults, untainted by potential early, undiagnosed cognitive impairment, reporting regression-based, scaled, and discrete norms for use in clinical settings to identify cognitive decline in older adults. Additionally, our co-norming of a variety of tests may enable intra-individual comparisons for diagnostic purposes. The present work addresses the challenge of developing robust normative data for neuropsychological tests in older adults.

Genetic risk for Alzheimer's disease and adherence to the Mediterranean diet: results from the HELIAD study.

Obejctives: The aim of the current study was to investigate whether genetic risk factors may moderate the association between adherence to the Mediterranean diet and AD incidence.Mehtods: The sample was drawn from the HELIAD study, a longitudinal study with a follow-up interval of 3 years. In total 537 older adults without dementia or AD at baseline were included. Adherence to the Mediterranean diet was assessed at baseline and AD diagnosis was determined at both visits. A Polygenic Index for late onset AD (PGI-AD) was constructed. Cox proportional hazard models adjusted for age, sex, education, baseline Global cognition score and APOE e-4 genotype were employed to evaluate the association between PGI-AD and Mediterranean diet with AD incidence. Next, we examined the association between adherence to the Mediterranean diet and AD risk over time across participants stratified by low and high PGI-AD.Results: Twenty-eight participants developed AD at follow-up. In fully adjusted models both the PGI-AD and the adherence to the Mediterranean diet were associated with AD risk (p < 0.05 for both). In the low PGI-AD group, those with a low adherence had a 10-fold higher risk of developing AD per year of follow-up, than did the participants with a high adherence to the Mediterranean diet (p = 0.011), whereas no such association was found for participants in the high PGI-AD group.Discussion: The association of Mediterranean diet with AD risk is more prominent in the group of older adults with a low polygenic risk for developing AD. Our findings suggest that genetic risk factors should be taken into account when planning interventions aiming to improve cognitive health.

Neuropsychiatric symptoms and white matter hyperintensities in older adults without dementia.

OBJECTIVE: We aimed to examine associations between neuropsychiatric symptoms (NPS) and white matter hyperintensities (WMH) status in older adults without dementia under the hypothesis that WMH increased the odds of having NPS. DESIGN: Longitudinal analysis of data acquired from the National Alzheimer's Coordinating Center Uniform Data Set. SETTINGS: Data were derived from 46 National Institute on Aging - funded Alzheimer's Disease Research Centers. PARTICIPANTS: NACC participants aged ≥50 years with available data on WMH severity with a diagnosis of mild cognitive impairment (MCI) or who were cognitively unimpaired (CU) were studied. Among 4617 CU participants, 376 had moderate and 54 extensive WMH. Among 3170 participants with MCI, 471 had moderate and 88 had extensive WMH. MEASUREMENTS: Using Cardiovascular Health Study (CHS) scores, WMH were coded as no to mild (CHS score: 0-4), moderate (score: 5-6) or extensive (score: 7-8). NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the odds of reporting each of 12 NPS by WMH status separately for individuals with MCI or who were CU. RESULTS: Compared to CU individuals with no to mild WMH, the odds of having elation [9.87, (2.63-37.10)], disinhibition [4.42, (1.28-15.32)], agitation [3.51, (1.29-9.54)] or anxiety [2.74, (1.28-5.88)] were higher for the extensive WMH group, whereas the odds of having disinhibition were higher for the moderate WMH group [1.94, (1.05-3.61)]. In the MCI group, he odds of NPS did not vary by WMH status. CONCLUSIONS: Extensive WMH were associated with higher odds of NPS in CU older adults but not in those with MCI.

Cognitive trajectories preluding the onset of different dementia entities: a descriptive longitudinal study using the NACC database.

OBJECTIVE: To describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e., Alzheimer's disease(AD), Lewy body(LBD), vascular(VD) and frontotemporal dementia(FTD). METHODS: Our analysis focused on data from older (≥ 60years) NACC (National Alzheimer's Coordinating Center) participants. Four distinct presymptomatic dementia groups (AD-LBD-VD-FTD) and a comparison group of cognitively unimpaired(CU) participants were formed. Comprehensive cognitive assessments involving verbal episodic memory, semantic verbal fluency, confrontation naming, mental processing speed - attention and executive function - cognitive flexibility were conducted at baseline and on an approximately yearly basis. Descriptive analyses (adjusted general linear models) were performed to determine and compare the yearly cognitive scores of each group throughout the follow-up. Exploratory analyses were conducted to estimate the rates of cognitive decline. RESULTS: There were 3343 participants who developed AD, 247 LBD, 108 FTD, 155 VD and 3398 composed the CU group. Participants with AD performed worse on episodic memory than those with VD and LBD for about 3 to 4 years prior to dementia onset (the FTD group documented an intermediate course). Presymptomatic verbal fluency and confrontation naming trajectories differentiated quite well between the FTD group and the remaining dementia entities. Participants with incident LBD and VD performed worse than those with AD on executive functions and mental processing speed-attention since about 5 years prior to the onset of dementia, and worse than those with FTD more proximally to the diagnosis of the disorder. CONCLUSIONS: Heterogeneous cognitive trajectories characterize the presymptomatic courses of the most prevalent dementia entities.

Apolipoprotein E Gene in α-Synucleinopathies: A Narrative Review.

In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer's disease-AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of APOE4 on LB pathology were summarized. We found robust evidence that APOE4 carriage constitutes a risk factor for PDD-APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that APOE4 copies confer an increased hazard towards DLB, as well. Again APOE2 and APOE3 appear unrelated to the risk of conversion. Of note, in individuals with DLB APOE4, carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; APOE-PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the APOE gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive-neuropsychiatric- motor-, and sleep-related manifestations) between APOE alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research.

Depressive symptoms in the entire spectrum of cognitive ageing in Greece: evidence from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD).

OBJECTIVES: To study (i) the prevalence of mild and moderate-to-severe depressive symptoms in the entire spectrum of cognitive ageing in Greece and (ii) the relationship between these symptoms and demographic and clinical data. METHODS: The study was based on the randomly selected cohort of the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Depressive symptoms were assessed with the 15-item version of the Geriatric Depression Scale. Participants also received a comprehensive neuropsychological assessment, while the clinical diagnoses of dementia and mild cognitive impairment were established according to international diagnostic criteria. Statistical analyses relied on comparison tests and a logistic (proportional odds) ordinal regression model. RESULTS: Depressive symptoms were detected in 19.5% of the 1936 study participants, while 11.3% of both people with MCI and dementia had moderate-to-severe depressive symptoms. The regression model revealed that older adults with more severe depressive symptoms were more likely female, cognitively impaired, less educated, were treated with psychotropic medication and lived in Attica versus Thessaly. CONCLUSIONS: Since depressive symptoms were detected in almost one in five older adults, healthcare professionals in Greece should safeguard the timely detection and effective treatment of such symptoms and the post-diagnostic care of older adults with depression.

Depressive symptoms are present in approximately 20% of older adults.More than 10% of older individuals with dementia or mild cognitive impairment report moderate-to-severe depressive symptoms.Female sex, lower education, lower cognitive performance, living in urban areas and treatment with psychotropic medication pertain to more severe depressive symptoms in ageing.Timely detection and effective treatment of depressive symptoms are crucial in the clinical practice of the care of older adults.Further research is needed in order to elucidate the complex relationship between depressive symptoms and cognitive impairment in ageing.

Clinical, Neuroimaging, and Genetic Markers in Cerebral Amyloid Angiopathy-Related Inflammation: A Systematic Review and Meta-Analysis.

BACKGROUND: There are limited data regarding the prevalence of distinct clinical, neuroimaging and genetic markers among patients diagnosed with cerebral amyloid angiopathy-related inflammation (CAA-ri). We sought to determine the prevalence of clinical, radiological, genetic and cerebrospinal fluid biomarker findings in patients with CAA-ri. METHODS: A systematic review and meta-analysis of published studies including patients with CAA-ri was conducted to determine the prevalence of clinical, neuroimaging, genetic and cerebrospinal fluid biomarker findings. Subgroup analyses were performed based on (1) prospective or retrospective study design and (2) CAA-ri diagnosis with or without available biopsy. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using Cochran-Q and I2-statistics. RESULTS: We identified 4 prospective and 17 retrospective cohort studies comprising 378 patients with CAA-ri (mean age, 71.5 years; women, 52%). The pooled prevalence rates were as follows: cognitive decline at presentation 70% ([95% CI, 54%-84%]; I2=82%), focal neurological deficits 55% ([95% CI, 40%-70%]; I2=82%), encephalopathy 54% ([95% CI, 39%-68%]; I2=43%), seizures 37% ([95% CI, 27%-49%]; I2=65%), headache 31% ([95% CI, 22%-42%]; I2=58%), T2/fluid-attenuated inversion recovery-hyperintense white matter lesions 98% ([95% CI, 93%-100%]; I2=44%), lobar cerebral microbleeds 96% ([95% CI, 92%-99%]; I2=25%), gadolinium enhancing lesions 54% ([95% CI, 42%-66%]; I2=62%), cortical superficial siderosis 51% ([95% CI, 34%-68%]; I2=77%) and lobar macrohemorrhage 40% ([95% CI, 11%-73%]; I2=88%). The prevalence rate of the ApoE (Apolipoprotein E) ε4/ε4 genotype was 34% ([95% CI, 17%-53%]; I2=76%). Subgroup analyses demonstrated no differences in these prevalence rates based on study design and diagnostic strategy. CONCLUSIONS: Cognitive decline was the most common clinical feature. Hyperintense T2/fluid-attenuated inversion recovery white matter lesions and lobar cerebral microbleeds were by far the most prevalent neuroimaging findings. Thirty-four percent of patients with CAA-ri have homozygous ApoE ε4/ε4 genotype and scarce data exist regarding the cerebrospinal fluid biomarkers and its significance in these patients.

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

BACKGROUND: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. OBJECTIVE: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. METHODS: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. RESULTS: We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). CONCLUSIONS: We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Safety of COVID-19 vaccines in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Data are sparse regarding the safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (MS). OBJECTIVE: To estimate (1) the pooled proportion of MS patients experiencing relapse among vaccine recipients; (2) the rate of transient neurological worsening, adverse events, and serious adverse events; (3) the previous outcomes of interest for different SARS-CoV-2 vaccine types. METHODS: Systematic review and meta-analysis of pharmacovigilance registries and observational studies. RESULTS: Nineteen observational studies comprising 14,755 MS patients who received 23,088 doses of COVID-19 vaccines were included. Mean age was 43.3 years (95% confidence interval (CI): 40-46.6); relapsing-remitting, secondary-progressive, primary-progressive MS and clinically isolated syndrome were diagnosed in 82.6% (95% CI: 73.9-89.8), 12.6% (95% CI: 6.3-20.8), 6.7% (95% CI: 4.2-9.9), and 2.9% (95% CI: 1-5.9) of cases, respectively. The pooled proportion of MS patients experiencing relapse at a mean time interval of 20 days (95% CI: 12-28.2) from vaccination was 1.9% (95% CI: 1.3%-2.6%; I2 = 78%), with the relapse risk being independent of the type of administered SARS-CoV-2-vaccine (p for subgroup differences = 0.7 for messenger RNA (mRNA), inactivated virus, and adenovector-based vaccines). After vaccination, transient neurological worsening was observed in 4.8% (95% CI: 2.3%-8.1%) of patients. Adverse events and serious adverse events were reported in 52.8% (95% CI: 46.7%-58.8%) and 0.1% (95% CI: 0%-0.2%) of vaccinations, respectively. CONCLUSION: COVID-19 vaccination does not appear to increase the risk of relapse and serious adverse events in MS. Weighted against the risks of SARS-CoV-2-related complications and MS exacerbations, these safety data provide compelling pro-vaccination arguments for MS patients.

Mediterranean diet is associated with a lower probability of prodromal Parkinson's disease and risk for Parkinson's disease/dementia with Lewy bodies: A longitudinal study.

BACKGROUND AND PURPOSE: Lifestyle factors have been implicated in the long-lasting neurodegenerative process in prodromal Parkinson's disease (pPD). The aim was to investigate the associations between adherence to a Mediterranean diet (MeDi) and longitudinal changes of pPD probability and the development of Parkinson's disease (PD) or pPD in a Mediterranean older population. METHODS: Data from the Hellenic Longitudinal Investigation of Aging and Diet cohort (community-dwelling individuals, aged ≥ 65 years) were used. A detailed food frequency questionnaire was used to evaluate dietary intake and calculate MeDi adherence score, ranging from 0 to 55, with higher scores indicating higher adherence. The probability of pPD was calculated according to the updated Movement Disorder Society research criteria. RESULTS: In all, 1047 non-PD/dementia with Lewy bodies (DLB) participants were followed for 3 ± 1 years. MeDi adherence was associated with lower increase in pPD probability over time (b = -0.003, 95% confidence interval -0.006 to -0.001, p = 0.010). Forty-nine participants had incident possible/probable pPD (i.e., pPD probability ≥ 30%). Compared to the participants in the lowest quartile of MeDi adherence, those in the higher quartiles had an approximately 60%-70% lower risk for possible/probable pPD (p for trend 0.003). MeDi-pPD associations were driven by both motor and non-motor pPD markers and not from risk markers. Also, 21 participants were diagnosed with PD/DLB at follow-up. For each unit increase in the MeDi score, there was a 9%-10% lower risk for PD/DLB (hazard ratio 0.906 [95% confidence interval 0.823-0.997], p = 0.044). CONCLUSIONS: Mediterranean diet adherence is associated with lower increase in pPD probability over time and lower possible/probable pPD and PD/DLB incidence in older Mediterranean people. More studies are needed to confirm our results in other populations.

Language performance as a prognostic factor for developing Alzheimer's clinical syndrome and mild cognitive impairment: Results from the population-based HELIAD cohort.

OBJECTIVES: There is limited research on the prognostic value of language tasks regarding mild cognitive impairment (MCI) and Alzheimer's clinical syndrome (ACS) development in the cognitively normal (CN) elderly, as well as MCI to ACS conversion. METHODS: Participants were drawn from the population-based Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) cohort. Language performance was evaluated via verbal fluency [semantic (SVF) and phonemic (PVF)], confrontation naming [Boston Naming Test short form (BNTsf)], verbal comprehension, and repetition tasks. An additional language index was estimated using both verbal fluency tasks: SVF-PVF discrepancy. Cox proportional hazards analyses adjusted for important sociodemographic parameters (age, sex, education, main occupation, and socioeconomic status) and global cognitive status [Mini Mental State Examination score (MMSE)] were performed. RESULTS: A total of 959 CN and 118 MCI older (>64 years) individuals had follow-up investigations after a mean of ∼3 years. Regarding the CN group, each standard deviation increase in the composite language score reduced the risk of ACS and MCI by 49% (8-72%) and 32% (8-50%), respectively; better SVF and BNTsf performance were also independently associated with reduced risk of ACS and MCI. On the other hand, using the smaller MCI participant set, no language measurement was related to the risk of MCI to ACS conversion. CONCLUSIONS: Impaired language performance is associated with elevated risk of ACS and MCI development. Better SVF and BNTsf performance are associated with reduced risk of ACS and MCI in CN individuals, independent of age, sex, education, main occupation, socioeconomic status, and MMSE scores at baseline.

Pesticides and tremor: An overview of association, mechanisms and confounders.

Pesticides are a heterogeneous class of chemicals mainly used for the protection of crops from pests. Because of their very widespread use, acute or/and chronic exposure to these chemicals can lead to a plethora of sequelae inflicting diseases, many of which involve the nervous system. Tremor has been associated with pesticide exposure in human and animal studies. This review is aimed at assessing the studies currently available on the association between the various types of pesticides/insecticides and tremor, while also accounting for potential confounding factors. To our knowledge, this is the first coherent review on the subject. After appraising the available evidence, we call for more intensive research on this topic, as well as intonate the need of implementing future preventive measures to protect the exposed populations and to reduce potential disabilities and social drawbacks.

Genetically downregulated Interleukin-6 signalling is associated with a lower risk of frailty.

BACKGROUND: numerous studies point towards a critical role of Interleukin 6 (IL-6) pathway in frailty pathogenesis yet the causal relationship between the two remains elusive. METHODS: we selected genetic variants near the IL-6 receptor locus (IL-6R) associated with reduced C-reactive protein (CRP) levels, a downstream effector of IL-6 pathway, and we used them as genetic proxies of IL-6 signalling downregulation. We then performed a two-sample Mendelian randomisation (MR) to investigate the association with frailty status, as defined by the Frailty Index (FI) in 11,171 individuals from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD) study. MR analysis was repeated after excluding depression or cognition-related FI items as well as following age or sex stratification. Association with frailty was also examined using an alternative instrument, weighted on s-IL-6R levels. Replication was attempted in UK Biobank dataset. RESULTS: genetic predisposition to IL-6 signalling downregulation, weighted on CRP levels, was associated with lower risk of frailty, inserted either as categorical (odds ratio [95% confidence interval] = 0.15 [-3.39, -0.40], P = 0.013) or continuous variable (beta [se] = -0.09 [0.003], P = 0.0009). Sensitivity analyses revealed similar estimates across different MR methods with no evidence for horizontal pleiotropy or heterogeneity. Results remained robust after exclusion of depression or cognition-related FI items and following sex or age stratification. Genetically increased s-IL-6R levels were negatively correlated with frailty and this finding remained significant in a meta-analysis of UK Biobank and HELIAD cohorts. CONCLUSION: our results support a potential causal effect of IL-6 signalling on frailty and further suggest that downregulation of IL-6 levels may reduce frailty risk.

Prevalence and Determinants of Restless Legs Syndrome (Willis-Ekbom Disease) in an Older Greek Population.

OBJECTIVES: The present study aimed to explore the descriptive and analytic epidemiology of restless legs syndrome (RLS) in the older Greek population, with a specific focus on lifestyle indicators. METHODS: Baseline data from the randomly selected non-demented older participants of the population-based HELIAD cohort were analyzed. Multivariable binary logistic regression with RLS diagnosis as the dichotomous dependent outcome was performed. Demographic, socioeconomic, anthropometric, dietary, sleep-related and psychological parameters, physical activity, use of psychoactive substances and personal medical history were investigated for potential associations. RESULTS: A total of 133 from the eligible sample of 1,838 participants were diagnosed with RLS. The mean age-sex standardized prevalence of RLS among the elderly was estimated at 6.1% (95%CI = 5.0-7.2), with a female (8.0%, 95%CI = 6.4-9.6) to male (3.7%, 95%CI = 2.4-5.1) ratio of 2.1. The prevalence of RLS peaked during the 8th decade of life and diminished thereafter. The positive associations of RLS with female sex [OR = 2.06, 95%CI = (1.19-3.57)], anxiety levels [assessed by the 22-point HADS scale, OR = 1.08, 95%CI = (1.03-1.13)] and traumatic brain injury [OR = 2.22, 95%CI = (1.37-3.62)] were reproduced. Good sleep quality was related to 55% [95%CI~(24-83%)] lower odds of having RLS in comparison with both poor and moderate quality. Adherence to the Mediterranean dietary pattern [assessed by a 55-point scale, OR = 1.06, 95%CI = (1.01-1.11)], and low daily energy intake [low-moderate vs. low: OR = 0.45, 95%CI = (0.26-0.79)]; [moderate-high vs. low: OR = 0.69, 95%CI = (0.40-1.22)]; [high vs. low: OR = 0.31, 95%CI = (0.13-0.69)] were related to RLS for the first time. CONCLUSIONS: More emphasis should be placed on the dietary-nutritional aspects of RLS.

Noninvasive Brain Stimulation in Primary Progressive Aphasia: A Literature Review.

Primary progressive aphasia (PPA) is a gradually progressive clinical syndrome in which the first and predominant symptoms involve language and/or speech production that interfere with daily activities. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) appear to have a beneficial impact on many neurodegenerative pathologies. The current review investigated the impact of rTMS and tDCS on PPA patients. English language articles that have been published in the databases PubMed, and Scopus from 2007 to 2022 were included. Fifteen single-case or small-group studies were analyzed and presented. The majority of the literature findings point toward that the application of rTMS or tDCS may have a positive effect in improving symptoms such as verb production, action naming, phonemic-verbal fluency, grammatical comprehension, written spelling, and semantic features. In conclusion, our review provides additional evidence supporting that both types of stimulation may improve linguistic deficits, especially if they combined, speech therapy.

Repetitive Transcranial Magnetic Stimulation in Post-stroke Aphasia: Comparative Evaluation of Inhibitory and Excitatory Therapeutic Protocols: Narrative Review.

OBJECTIVE: Aphasia is a serious consequence of stroke resulting in difficulties in using language for communication with negative effects on patients' quality of life. The use of non-invasive repetitive transcranial magnetic stimulation (rTMS) is a novel approach in aphasia therapy, based on the knowledge gained by functional imaging technics of the brain. AIM: This review evaluates the effectiveness of rTMS on aphasia therapy according to the results of English language studies that have been published in the databases PubMed/Medline, Scopus, and Web of Science from 2011 to 2021. RESULTS: Twenty-seven studies were included in the review with 672 participants. The studies mainly concern the application of inhibitory rTMS on the right inferior frontal gyrus (rIFG) in the subacute and chronic phase, as well as excitatory rTMS of the unaffected language areas of the left cerebral hemisphere in the chronic phase after stroke. Most of the studies concluded that there was statistically significant improvement in various parameters of language including confrontation naming, repetition, and aphasia quotient. Three studies published results that doubt the effectiveness of rTMS. CONCLUSION: rTMS is a safe therapeutic method for aphasia treatment in the subacute and chronic phases after stroke. Its effectiveness is immediate as well as distant with a gradually decreasing therapeutic effect. Moreover, rTMS may supplement speech and language therapy as a priming factor. The most recognized method at this point in time is the application of suppressive rTMS on the right inferior frontal gyrus in combination with speech and language therapy.

Cognitive Neurorehabilitation in Epilepsy Patients via Virtual Reality Environments: Systematic Review.

OBJECTIVE: Epilepsy patients could possibly benefit from the remuneration observed in the use of virtual reality (VR) and virtual environments (VEs), especially in cognitive difficulties associated with visuospatial navigation (memory, attention, and processing speed). AIM: Research questions under consideration in the present systematic review are associated to VEs' efficiency as a cognitive rehabilitation practice in epilepsy and the particular VR methods indicated for epilepsy patients. To meet criteria, studies included participants suffering from any form of epilepsy and a methodological design with a structured rehabilitation program/model. Data were collected online, using academic databases. RESULTS: Fourteen studies were included in the literature review and 6 in the statistical analysis. ROBINS-I protocol was implemented to assess the risk of bias. An inverse variance analysis (random effects) of pooled estimates of differences was implemented, in the form of continuous data. Despite the heterogeneity of the studies, all of them agree on the beneficial aspects of VR and VEs in cognitive rehabilitation in relation to visuospatial memory, attention, and information processing speed. CONCLUSION: We suggest that patients suffering from epilepsy may benefit from the use of VR cognitive rehabilitation interventions, concerning visuospatial memory, attention, and information processing speed. However, further investigation is needed in order to gain a better understanding of the mechanisms involved in cognitive rehabilitation via VEs and establish efficient and dynamic rehabilitation protocols.

Cognitive trajectories preluding the imminent onset of Alzheimer's disease dementia in individuals with normal cognition: results from the HELIAD cohort.

BACKGROUND: The cognitive trajectories of cognitively normal (CN) individuals rapidly progressing to Alzheimer's disease dementia (AD) have not been investigated. AIM: To explore the preclinical pattern of cognitive performance heralding the rapid progression from normal cognition to AD. METHODS: The HELIAD cohort underwent comprehensive neuropsychological assessments (memory, language, attention, executive and visuo-perceptual functions) at baseline and after approximately 3-year intervals. The cognitive trajectories of those with normal cognition at baseline were explored according to the follow-up diagnosis using adjusted generalised estimating equations analyses. RESULTS: A total of 932 predominantly female (61%), older (72.9 ± 4.9), CN participants were followed for 3.09 (± 0.83) years. Among them, 761 individuals remained CN, 29 progressed to AD and 142 developed MCI (33 single-domain amnestic, 41 multidomain amnestic, 37 single-domain non-amnestic and 31 multidomain non-amnestic). Those progressing to AD were already performing worse than the healthy reference in every single cognitive domain at baseline. Cognitive deficits ranged between ~ 0.5SD (attention, executive function and language) and ~ 1.0SD (memory and visuo-perceptual skills). Throughout the 3-year follow-up, memory constantly exhibited the most prominent impairment compared to the remaining cognitive domains while executive function diminished in the most abrupt fashion (~ 0.19SD yearly) separating from the remaining three cognitive functions before the development of full-blown AD. Heterogeneous patterns of cognitive decline clearly differentiated those progressing to MCI from those rapidly converting to AD, as well. DISCUSSION: Poor performance in every cognitive domain may characterise cognitively normal individuals at high risk of fast progression to AD. CONCLUSION: Strict neuropsychological cut-offs fail to detect a considerable number of individuals at high risk of rapid progression to AD.

Application of Machine Learning Techniques in the HELIAD Study Data for the Development of Diagnostic Models in MCI and Dementia.

The increase in the population's life expectancy leads to an increase in the incidence of dementia and, therefore, in diseases such as Alzheimer's. Towards this direction, the HELIAD1 study is the first large-scale epidemiological study aimed at assessing epidemiological data on dementia, mild mental decline, and other neuropsychiatric disorders associated with old age. This is a huge study with several computational challenges, most of which can be addressed by machine learning processes. The objectives of this study were to detect patterns in the HELIAD clinical data that classify with high accuracy various levels of cognitive impairment by training ML algorithms and hence apply derived model on future clinical data to predict with the same accuracy the class variable. We propose a machine learning method based on RUSBoost classifier to identify a critical subset of biomarkers that classify accurately between neurological patients with mild cognitive impairment (MCI) or dementia of the Alzheimer's type (DAT) and the cognitively healthy control (CHC) group. In this study we used a highly skewed (imbalanced) dataset with most observations (majority class) belonging to the CHC group. The method proposed predicts accurately the clinical diagnosis label and effectively classifies the neurological patients from the CHC class. In particular, the classification accuracy (actual vs predicted) for the three classes of the clinical diagnosis was 97%, 78%, and 91% for control, MCI, and dementia class, respectively.