Despite the technological advancements in modern genetic diagnosis, customized genetic panels are still frequently employed for diagnostic purposes due to their rapid, efficient, and cost-effective ability to detect genetic variants. In this study, we utilized a customized genetic panel designed to identify genetic variants associated with neurodegenerative disorders. The panel consisted of 61 genes and was applied to a cohort of 186 unrelated individuals diagnosed with different degenerative cognitive and movement disorders. The identified variants were filtered for a minor allele frequency of less than 1% and classified according to the American College of Medical Genetics (ACMG) guidelines. Our results showed that 20.97% of individuals carried at least one likely pathogenic or pathogenic variant, with 35% of those individuals diagnosed with Alzheimer's disease (AD). The positive diagnostic yield of the panel was 16.67%, calculated based on variant zygosity, inheritance pattern, and concordance with the clinical phenotype. Furthermore, 34.41% of the individuals carried variants of uncertain significance (VUS), and 44.62% carried benign variants. Variants have been found only in 58 genes. Among these, 24.14% showed benign variants, 48.28% had VUS, and 27.59% carried pathogenic or likely pathogenic variants. Principal component analysis analysis based on the variables "age at onset" in addition to the phenotypic scores "MMSE" (global cognitive screening test), "IADL" (instrumental activities of daily living), and "ADL" (basic activities of daily living) distributed the individuals associated with the specific disease and variant in the plot. Notably, the individuals showed AD exhibited an average age at onset of 68 ± 12.5 years and were differentiated in the plot. GBA gene exhibited the highest number of pathogenic variants (9) linked to AD, Parkinson's disease, early onset parkinsonism with epilepsy, fronto-temporal dementia, and mild cognitive impairment. The results highlighted a broad phenotypic heterogeneity associated with genes previously linked to only a limited number of neurodegenerative conditions, underscoring the value of the genetic testing performed. Translationally, although clinical exome sequencing has enabled novel gene discovery in neurodegenerative disorders, targeted genetic panels remain a cost-effective and clinically valuable approach for routine diagnostics. In this context, our study highlights the "real-world" utility and clinical impact of a focused panel-based strategy.

This study investigated the long-term clinical effects of multisession gamma transcranial alternating current stimulation (tACS) over the precuneus in early-stage Alzheimer's disease. Forty-six patients from a previous randomized, double-blind, sham-controlled trial with an open-label extension underwent follow-up at 36 and 72 weeks. Participants received either 8 or 16 weeks of gamma tACS. Both treatment durations showed comparable long-term outcomes. Alzheimer's Disease Assessment Scale-Cognitive Subscale did not significantly worsen at 36 weeks, and Face-Name Association Test remained stable at both follow-up time points, whereas Clinical Dementia Rating-Sum of Boxes and Alzheimer's Disease Cooperative Study-Activities of Daily Living worsened over time. These findings suggest relative preservation of selected cognitive measures, despite worsening in broader clinical and functional outcomes.

BACKGROUND:Socio-cognitive assessment in neurocognitive disorders (NCDs) is rare in clinical practice and no consensus exists as to a uniform operationalization of socio-cognitive measures for NCDs in memory clinics. The SIGNATURE initiative aims to optimize the use of socio-cognitive measures in memory clinics, defining expert recommendations. We report consortium guidelines for the use of socio-cognitive measures in NCDs based on available evidence from the literature and the current state of practices in memory clinics. METHODS:Using a Delphi consensus method supported by a literature review and the results of an international survey, 22 specialists defined recommendations for the context of use, relevance in NCD diagnosis, priorities for future research and facilitators/obstacles of socio-cognitive assessment in major and mild NCDs. RESULTS:Overall, panelists recommended social cognition testing in routine diagnostic assessment to evaluate both socio-cognitive and socio-behavioral alterations. A set of clinical, methodological, implementation and external factors facilitating or hampering the use of socio-cognitive tasks was identified. CONCLUSIONS:This is the first focused endeavor to favor the implementation of socio-cognitive assessment, which is required by DSM-5 but seldom performed despite clear evidence of its clinical relevance for diagnosis and care. Our results provide an initial set of recommendations, refinable through the future actions of the SIGNATURE initiative. Future collaborative clinical research projects should overcome current limitations and foster the use of ecological and cross-culturally validated measures in clinics.

Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies. To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD. This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate. Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up. The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging. Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale–cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study–Activities of Daily Living (−0.55; 95% CI, −0.89 to −0.21; P = .02), and Face-Name Association Test (−1.14; 95% CI, −1.66 to −0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale–cognitive subscale (−0.59; 95% CI, −1.02 to −0.16; P = .007), Alzheimer Disease Cooperative Study–Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration. In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD. ClinicalTrials.gov Identifier: NCT05643326

Importance:Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies. Objective:To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD. Design, Setting, and Participants:This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate. Intervention:Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up. Main Outcomes and Measures:The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging. Results:Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale-cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study-Activities of Daily Living (-0.55; 95% CI, -0.89 to -0.21; P = .02), and Face-Name Association Test (-1.14; 95% CI, -1.66 to -0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale-cognitive subscale (-0.59; 95% CI, -1.02 to -0.16; P = .007), Alzheimer Disease Cooperative Study-Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration. Conclusions and Relevance:In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD. Trial Registration:ClinicalTrials.gov Identifier: NCT05643326.

Abstract Background Gamma (γ) brain oscillations are dysregulated in Alzheimer’s disease (AD) and can be modulated using transcranial alternating stimulation (tACS). In the present paper, we describe the rationale and design of a study assessing safety, feasibility, clinical and biological efficacy, and predictors of outcome of a home-based intervention consisting of γ-tACS over the precuneus. Methods In a first phase, 60 AD patients will be randomized into two arms: ARM1, 8-week precuneus γ-tACS (frequency: 40 Hz, intensity: 2 mA, duration: 5 60-min sessions/week); and ARM2, 8-week sham tACS (same parameters as the real γ-tACS, with the current being discontinued 5 s after the beginning of the stimulation). In a second phase, all participants will receive 8-week γ-tACS (same parameters as the real γ-tACS in the first phase). The study outcomes will be collected at several timepoints throughout the study duration and include information on safety and feasibility, neuropsychological assessment, blood sampling, electroencephalography, transcranial magnetic stimulation neurotransmitter measures, and magnetic resonance imaging or amyloid positron emission tomography. Results We expect that this intervention is safe and feasible and results in the improvement of cognition, entrainment of gamma oscillations, increased functional connectivity, reduction of pathological burden, and increased cholinergic transmission. Conclusions If our expected results are achieved, home-based interventions using γ-tACS, either alone or in combination with other therapies, may become a reality for treating AD. Trial registration PNRR-POC-2022–12376021.

Background: Early in-vivo diagnosis of Alzheimer’s disease (AD) is crucial for accurate management of patients, in particular, to select subjects with mild cognitive impairment (MCI) that may evolve into AD, and to define other types of MCI non-AD patients. The application of artificial intelligence to functional brain [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography(CT) aiming to increase diagnostic accuracy in the diagnosis of AD is still undetermined. In this field, we propose a radiomics analysis on advanced imaging segmentation method Statistical Parametric Mapping (SPM)-based completed with a Machine-Learning (ML) application to predict the diagnosis of AD, also by comparing the results with following Amyloid-PET and final clinical diagnosis. Methods: From July 2016 to September 2017, 43 patients underwent PET/CT scans with FDG and Florbetaben brain PET/CT and at least 24 months of clinical/instrumental follow-up. Patients were retrospectively evaluated by a multidisciplinary team (MDT = Neurologist, Psychologist, Radiologist, Nuclear Medicine Physician, Laboratory Clinic) at the G. Giglio Institute in Cefalù, Italy. Starting from the cerebral segmentations applied by SPM on the main cortical macro-areas of each patient, Pyradiomics was used for the feature extraction process; subsequently, an innovative descriptive-inferential mixed sequential approach and a machine learning algorithm (i.e., discriminant analysis) were used to obtain the best diagnostic performance in prediction of amyloid deposition and the final diagnosis of AD. Results: A total of 11 radiomics features significantly predictive of cortical beta-amyloid deposition (n = 6) and AD (n = 5) were found. Among them, two higher-order features (original_glcm_Idmn and original_glcm_Id), extracted from the limbic enthorinal cortical area (ROI-1) in the FDG-PET/CT images, predicted the positivity of Amyloid-PET/CT scans with maximum values of sensitivity (SS), specificity (SP), precision (PR) and accuracy (AC) of 84.92%, 75.13%, 73.75%, and 79.56%, respectively. Conversely, for the prediction of the clinical-instrumental final diagnosis of AD, the best performance was obtained by two higher-order features (original_glcm_MCC and original_glcm_Maximum Probability) extracted from ROI-2 (frontal cortex) with a SS, SP, PR and AC of 75.16%, 80.50%, 77.68%, and 78.05%, respectively, and by one higher-order feature (original_glcm_Idmn) extracted from ROI-3 (medial Temporal cortex; SS = 80.88%, SP = 76.85%, PR = 75.63%, AC = 78.76%. Conclusions: The results obtained in this preliminary study support advanced segmentation of cortical areas typically involved in early AD on FDG PET/CT brain images, and radiomics analysis for the identification of specific high-order features to predict Amyloid deposition and final diagnosis of AD.

Neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) represent a heterogeneous group of non-cognitive symptoms that are virtually present in all patients during the course of their disease. The aim of this study is to examine the prevalence and natural history of BPSD in a large cohort of patients with behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) in three stages: (i) pre-T0 (before the onset of the disease); (ii) T0 or manifested disease (from the onset to 5 years); (iii) T1 or advanced (from 5 years onwards). Six hundred seventy-four clinical records of patients with bvFTD and 1925 with AD, from 2006 to 2018, were studied. Symptoms have been extracted from Neuropsychiatric Inventory (NPI) and from a checklist of BPSD for all periods observed. In our population, BPSD affect up to 90% of all dementia subjects over the course of their illness. BPSD profiles of the two dementia groups were similar but not identical. The most represented symptoms were apathy, irritability/affective lability, and agitation/aggression. Considering the order of appearance of neuropsychiatric symptoms in AD and bvFTD, mood disorders (depression, anxiety) come first than the other BPSD, with the same prevalence. This means that they could be an important "red flag" in detection of dementia. With the increase of disease severity, aberrant motor behavior and wandering were significantly more present in both groups. Differences between BPSD in AD and bvFTD resulted only in prevalence: Systematically, in bvFTD, all the symptoms were more represented than in AD, except for hallucinations, depression, anxiety, and irritability. Given their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and considered as an additional important diagnostic and therapeutic target both in patients with AD and bvFTD.

Background: Family caregivers of patients with dementia are at high risk of stress and burden, and quarantine due to the coronavirus disease 2019 (COVID-19) pandemic may have increased the risk of psychological disturbances in this population. The current study was carried out during the national lockdown declared in March 2020 by the Italian government as a containment measure of the first wave of the coronavirus pandemic and is the first nationwide survey on the impact of COVID-19 lockdown on the mental health of dementia informal caregivers. Methods: Eighty-seven dementia centers evenly distributed on the Italian territory enrolled 4,710 caregiver–patient pairs. Caregivers underwent a telephone interview assessing classical symptoms of caregiver stress and concern for the consequences of COVID-19 infection on patient’s health. We calculated prevalence of symptoms and regressed them on various potential stress risk factors: caregivers’ sociodemographic characteristics and lifestyle, patients’ clinical features, and lockdown-related elements, like discontinuity in medical care. Results: Approximately 90% of caregivers reported at least one symptom of stress, and nearly 30% reported four or more symptoms. The most prevalent symptoms were concern for consequences of COVID-19 on patient’s health (75%) and anxiety (46%). The main risk factors for stress were identified as a conflicting relationship with the patient and discontinuity in assistance, but caregiver’s female sex, younger age, lower education, and cohabitation with the patient also had an impact. Availability of help from institutions or private individuals showed a protective effect against sense of abandonment but a detrimental effect on concern about the risk for the patient to contract COVID-19. The only protective factor was mild dementia severity, which was associated with a lower risk of feeling isolated and abandoned; type of dementia, on the other hand, did not affect stress risk. Conclusion: Our results demonstrate the large prevalence of stress in family caregivers of patients with dementia during the COVID-19 pandemic and have identified both caregivers and situations at a higher risk of stress, which should be taken into account in the planning of interventions in support of quarantined families and patients.

Introduction Previous studies showed that quarantine for pandemic diseases is associated with several psychological and medical effects. The consequences of quarantine for COVID-19 pandemic in patients with dementia are unknown. We investigated the clinical changes in patients with Alzheimer’s disease and other dementias, and evaluated caregivers’ distress during COVID-19 quarantine. Methods The study involved 87 Italian Dementia Centers. Patients with Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Family caregivers of patients with dementia were interviewed by phone in April 2020, 45 days after quarantine declaration. Main outcomes were patients’ changes in cognitive, behavioral, and motor symptoms. Secondary outcomes were effects on caregivers’ psychological features. Results 4913 patients (2934 females, 1979 males) fulfilled the inclusion criteria. Caregivers reported a worsening in cognitive functions in 55.1% of patients, mainly in subjects with DLB and AD. Aggravation of behavioral symptoms was observed in 51.9% of patients. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioral worsening (odds ratio 1.85 [95% CI 1.42–2.39], 1.84 [95% CI 1.43–2.38], respectively). On the contrary, pandemic awareness was a protective factor for the worsening of cognitive and behavioral symptoms (odds ratio 0.74 [95% CI 0.65–0.85]; and 0.72 [95% CI 0.63–0.82], respectively). Approximately 25.9% of patients showed the onset of new behavioral symptoms. A worsening in motor function was reported by 36.7% of patients. Finally, caregivers reported a high increase in anxiety, depression, and distress. Conclusion Our study shows that quarantine for COVID-19 is associated with an acute worsening of clinical symptoms in patients with dementia as well as increase of caregivers’ burden. Our findings emphasize the importance to implement new strategies to mitigate the effects of quarantine in patients with dementia.

OBJECTIVE:To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1 mutation causing SCA48.METHODS:We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis) were performed on multiple family members.RESULTS:Patients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with prominent cognitive decline and behavioral changes. Whole-exome sequencing identified a novel heterozygous frameshift variant c.731_732delGC (p.C244Yfs*24) in STUB1 segregating with the disease. This variant was present in a linkage peak on chromosome 16p13.3. Neuropathologic examination of 3 cases revealed a consistent pattern of ubiquitin/p62-positive neuronal inclusions in the cerebellum, neocortex, and brainstem. In addition, tau pathology was present in 1 case.CONCLUSIONS:This study confirms previous findings of heterozygous STUB1 mutations as the cause of SCA48 and highlights its prominent cognitive involvement, besides cerebellar ataxia and movement disorders as cardinal features. The presence of intranuclear inclusions is a pathologic hallmark of the disease. Future studies will provide more insight into its pathologic heterogeneity.

Background: To control the spread of the new Coronavirus (SARS-CoV-2), several governments planned quarantine. The effects of quarantine on patients with dementia and caregivers are unknown. We aimed to describe the clinical changes in patients with different dementias through a detailed caregivers' interview. Besides, we evaluated caregivers' psychological symptoms and the impact on public health services. Methods: Family caregivers of patients with dementia, followed at 87 Italian Dementia Centres, were interviewed 45 days after quarantine declaration. Patients with Alzheimer's Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Main outcomes were patients' changes in cognitive, behavioural, and motor symptoms. Secondary outcomes were changes in caregivers' burden, and reorganization of health services. Findings: Between April 14 and April 27, 2020, we screened 4913 patients with dementia. An acute worsening in cognitive functions (+55·1%) and in behavioural symptoms (+51·9%) was reported. Patients with DLB and AD showed the greatest worsening. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioural worsening (odds ratio 1·85 [95% CI 1·42-2·39]; and 1·84 [1·43-2·38], respectively). During the quarantine period, 25·9% of patients showed the onset of new behavioural symptoms. A worsening in motor function was reported by 36·7% of patients. Awareness of the pandemic was negatively associated with increase in cognitive and behavioural symptoms (odds ratio 0·74 [0·65-0·85]; and 0·72 [0·63-0·82], respectively). Finally, an increase of caregiver's anxiety and depression was reported. Interpretation: Our study shows, for the first time, that quarantine is associated with an acute and dramatic worsening of clinical symptoms in demented patients as well as increase of caregiver's burden. Primary care physicians and health services need to implement new strategies in order to mitigate the effects of quarantine in patients with dementia. Funding Statement: Italian Society for the Study of Dementias, SINdem.Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Ethics Approval Statement: The study was initially approved by the Ethics Committee of the Coordinating Centre (University of Torino on April 7, 2020, n.00150/2020) and then by the local ethics boards. Participants gave first oral and then written fully informed consent to the study.

BACKGROUND:In March 2020, the World Health Organization declared a global pandemic due to the novel coronavirus SARS-CoV-2 and several governments planned a national quarantine in order to control the virus spread. Acute psychological effects of quarantine in frail elderly subjects with special needs, such as patients with dementia, have been poorly investigated. The aim of this study was to assess modifications of neuropsychiatric symptoms during quarantine in patients with dementia and their caregivers. METHODS:This is a sub-study of a multicenter nation-wide survey. A structured telephone interview was delivered to family caregivers of patients with diagnosis of Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VD), followed regularly at 87 Italian memory clinics. Variations in behavioral and psychological symptoms (BPSD) were collected after 1 month since quarantine declaration and associations with disease type, severity, gender, and caregiver's stress burden were analyzed. RESULTS:A total of 4,913 caregivers participated in the survey. Increased BPSD was reported in 59.6% of patients as worsening of preexisting symptoms (51.9%) or as new onset (26%), and requested drug modifications in 27.6% of these cases. Irritability, apathy, agitation, and anxiety were the most frequently reported worsening symptoms and sleep disorder and irritability the most frequent new symptoms. Profile of BPSD varied according to dementia type, disease severity, and patients' gender. Anxiety and depression were associated with a diagnosis of AD (OR 1.35, CI: 1.12-1.62), mild to moderate disease severity and female gender. DLB was significantly associated with a higher risk of worsening hallucinations (OR 5.29, CI 3.66-7.64) and sleep disorder (OR 1.69, CI 1.25-2.29), FTD with wandering (OR 1.62, CI 1.12-2.35), and change of appetite (OR 1.52, CI 1.03-2.25). Stress-related symptoms were experienced by two-thirds of caregivers and were associated with increased patients' neuropsychiatric burden (p<0.0001). CONCLUSION:Quarantine induces a rapid increase of BPSD in approximately 60% of patients and stress-related symptoms in two-thirds of caregivers. Health services need to plan a post-pandemic strategy in order to address these emerging needs.

Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 x 10(-5); odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 x 10(-2); OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

Background Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features. Methods We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed. Results All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset. Conclusions We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. (c) 2019 International Parkinson and Movement Disorder Society

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Neuronal intranuclear inclusion disease (NIID) is a rare heterogeneous progressive neurodegenerative disease characterized by the presence of eosinophilic hyaline intranuclear inclusions in neuronal and glial cells of the CNS, peripheral cells of the autonomic nervous system, visceral organs and skin. The clinical presentation is broadly heterogeneous and includes limb weakness, dementia, seizures, ataxia, and parkinsonism. High-intensity signal in the corticomedullary junction on brain MRI is a characteristic finding in NIID. We describe a 65-year-old patient presenting with mild cognitive impairment, evolving in dementia with behavioral disturbances and parkinsonism. Brain MRI showed mild global cortical atrophy, more pronounced in the cingulate and temporal cortex and mild leukoaraiosis, but no high-intensity signal in corticomedullary junction on diffusion weighted imaging. Neuropathological examination showed p62- and optineurin-positive neuronal intranuclear inclusions in the hippocampus and in some subcortical structures. Glial cells did not present any intranuclear inclusions, and no spongiotic changes proximal to the U-fibers or diffuse myelin pallor were disclosed in the white matter. We report on a case with pathological features of NIID showing different neuroimaging and pathological findings. We noted an absence of typical MRI abnormalities, lack of intranuclear inclusions in glial cells, and prominent involvement of hippocampal neurons, refining the clinico-pathological spectrum of the disease.

Introduction. Dementia is one of the main diseases linked to aging and leading to disability. The gender perspective of this disease has not been studied in a complete and dedicated way and this constitutes a great limitation because dementia, like other diseases, appears to have a gender-related expression. The aim of this research is to contribute to the study of gender differences in a large cohort of patients affected by Alzheimer’s disease. Methods and patients. The study population included the clinical records of 1925 patients with Alzheimer’s disease, diagnosed according to NINCDS-ADRDA criteria and to NIA-AA, from the e-database of the Neurogenetic Regional Centre (NRC) of Lamezia Terme (Southern Italy). The mean age of the sample was 71.5 ± 8.9 years and follow-up was an average of 4 years. The variables included in the analysis and differentiated for gender were the prevalence and the onset of the disease, the time elapsed between the onset and the first consultation, duration of follow-up, duration of the disease, education, cardiovascular and metabolic risk factors. A check list of symptoms and signs was compiled from the cognitive and behavioral history and categorized in 12 clusters. Statistical analysis was performed using IBM SPSS 20 (significance was given by p <0.05). Results. Women were more numerically represented in the sample (67.1%). There were no differences according to gender in the time elapsed between onset of symptoms and the first consultation, in the follow-up period and in the duration of disease. Women were more cognitively impaired at baseline (MMSE score 15.9 ± 5.9 vs 17 ± 6.5), had a lower level of education (5.6 years vs 6.51 years) and presented higher comorbidity and incidence of depression (p = 0.000) and anxiety (p = 0.002). Men displayed a more rapid decline at the end of the follow-up, losing 3.85 ± 4.66 points vs 2.93 ± 4.39 at MMSE; they showed a statistically significant prevalence in behavioral symptoms (p = 0.009), including irritability (p = 0.000) and agitation (p = 0.041), and some cognitive deficits, such as language impairments (p = 0.000), apraxia (p = 0.005), spatial disorientation (p = 0.006) and acalculia (p = 0.035). APOE results were not representative in terms of gender differences but confirmed a possible impact of the ε4 allele on cognitive decline. Discussion. Behind the classical memory impairment and temporal disorientation, that are present in about all men and woman, a different AD phenotype between the two genders emerges from this work. Our results revealed a poorlyeducated female sample, with a worse cognitive impairment and mood disorders. Men showed a more rapid cognitive impairment and an aggressive behavioral picture. The identification of specific gender aspects, cognitive and behavioral, could be a valuable aid for a faster identification of Alzheimer’s disease and its better management.