ObjectiveSeveral studies have demonstrated a higher frequency of seizures and epilepsy in Alzheimer's disease and other forms of dementia as compared with healthy elderly individuals. However, incidence and prevalence of epilepsy in the general population of dementia are unknown since most previous studies were performed in secondary-tertiary referral centres. In addition, all prior studies but one provided "period" rather than "point" prevalence estimates.MethodsWe assessed point prevalence estimate of epileptic manifestations requiring antiepileptic medication in patients Alzheimer's disease, vascular dementia, and fronto-temporal dementia from a secondary clinical setting.ResultsPoint prevalence estimates were 6.4% (95% CI: 1.5 to 11.3) in Alzheimer's disease, 8.9% (95% CI: 1.4 to 16.4), in vascular dementia, and 6% (95% CI: 1.3 to 10.7) in fronto-temporal dementia, rates that were greater than those observed in the healthy elderly population. Regardless of the etiology of dementia, epilepsy was characterized by unprovoked seizures that lacked distinguishing clinical features.SignificanceThese findings support epilepsy as part of the spectrum of dementia. The similar point prevalence of definite epilepsy requiring AED treatment in Alzheimer's disease and non Alzheimer dementias raised the possibility of similar underlying mechanism of epileptogenesis. Although this was not a population-based study, accurate point prevalence data from clinic setting would be important to better define the burden of epilepsy in dementia and the demands on health services to manage the condition.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, characterized by varying clinical and pathological features. TARDBP gene has been described worldwide within the FTD/ALS spectrum but its association with right and left temporal variant of FTD (tvFTD) is still unclear. This study aimed to reclassify a Sardinian FTD cohort according to proposed criteria for the semantic behavioral variant FTD (sbvFTD), explore TARDBP mutations' association with tvFTD, and review related literature. From our FTD cohort of 94 patients, ten fulfilled the criteria for sbvFTD. Therefore, in light of the diagnostic reclassification carried out, we describe the largest series of unrelated patients with TARDBP p.A382T missense mutation, including four new cases of tvFTD: two sbvFTD and two svPPA, exhibiting semantic and behavioral disorders and showing predominant right and left anterior temporal lobe involvement, respectively. We present for the first time two sbvFTD cases carrying the pA382T TARDBP mutation. Comparison with C9orf72 and non-mutated patients revealed lower age at onset (p = 0.006), and a higher prevalence of tvFTD, particularly sbvFTD (p < 0.001), and motor neuron disease in TARDBP carriers (p < 0.001). Our findings along with a review of the literature highlighted TARDBP mutations' association with sbvFTD and semantic dementia, suggesting a genetic role in temporal variants of FTD and emphasizing the need for TARDBP mutation screening in these cases. Reclassifying FTD cohorts, including the sbvFTD phenotype, could aid in better defining the clinical spectrum of tvFTD and guide differential diagnosis across different FTD populations with TARDBP or other FTD-related mutations.

C9orf72 mutation is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Recently, several reports of patients with FTD who carried the C9orf72 mutation and also manifested epilepsy have been published, since seizures occur in FTD at a higher rate than in the general population, the possible association between epilepsy and C9orf72 mutation remains to be clarified. In the attempt to understand whether epilepsy contributes to the phenotype of the C9orf72 mutation, we compared epilepsy occurrence in patients with FTD who carried the C9orf72 mutation and those who did not. In our sample of 84 patients with FTD, 7.1% of cases reported epilepsy, with no significant differences between subsamples of patients with FTD stratified according to the presence of the C9orf72 mutation or to family history of FTD/parkinsonism/motor neuron disease. Our findings did not support to the possibility that epilepsy represents a characteristic feature of the C9orf72 mutation, as suggested by recent case reports published in the English literature.

C9orf72 mutation (C9+) is a common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. C9+ clinical phenotype is heterogeneous and epilepsy has been recently described in few cases. We report a 47-year-old patient who developed reflex reading epilepsy (RRE) at the age of 19. After the first years with exclusive reflex seizures, afterwards the patients developed drug-resistant, unprovoked seizures and progressive cognitive deterioration. In the last years, a progressive motor impairment with spastic tetraparesis also occurred. During the hospitalization, the patient underwent an extensive workup identifying C9+ expansion and a family history suggestive for an autosomal dominant inheritance. This report, together with the few cases already described, raises the possibility that epileptic manifestations are part of the clinical phenotype of C9ORF72 mutation and reflect hyperexcitability of cortical networks involved in neurodegeneration.

To study for the first time the incidence of adult-onset CNS tumors in Southern Sardinia, Italy. Clinical records of patients > 18 years old who were diagnosed with primary CNS tumors during 2016–2019 in the study area were reviewed. Meningiomas, cranial/paraspinal nerve tumors, lymphomas, and pituitary tumors were excluded. Cases were classified according to the 2016 WHO classification of CNS tumors and to the morphology codes from the International Classification of Diseases—Oncology, third edition. Age-adjusted incidence rates were calculated by the direct method to the 2011–2020 European standard population. Kulldorff’s spatial scan statistic was used to identify geographic clusters of patients who shared increased/decreased tendency to develop CNS tumors. CNS tumors were diagnosed in 234 incident patients, but histological diagnosis was available in 222/234 patients (95%) aged 64.3 ± 13.5 years at diagnosis. Crude incidence rate was 7.1 per 100,000 persons-year (95% CI, 6.2–8.1), 6.2 per 100,000 persons-year (95% CI, 5.4–7.0) when age-adjusted. CNS tumors were more frequent in men and after age 40. Glioblastoma accounted for 76% of the total (adjusted rate, 4.7 per 100,000 persons-year; 95% CI, 4.0–5.4). Spatial analysis revealed geographic variations of glioblastoma incidence within the study area. Although the distribution of tumor diagnoses in Sardinia reflects expected age and gender-related patterns in western populations, our findings would indicate a slightly higher incidence of glial tumors, glioblastoma in particular, in Sardinia than in other European countries. The identification of spatial clusters of high/low risk will serve as a resource for etiological research.

Sardinians have distinctive genetic characteristics from other Europeans, including mainland Italians. We aim to determine the frequency and the impact of C9orf72 and TARDBP mutations in a Sardinian cohort of FTD patients.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Anti Leucine-Rich Glioma Inactivated 1 encephalitis (LGI1) is a rare autoimmune disorder caused by antibodies to synaptic voltage-gated potassium channels. Its typical manifestation includes seizures (mostly tonic-dystonic), hyponatremia, memory disturbances and behavioural changes. Patients may have temporal lobe abnormalities on EEG and brain MRI, instead CSF is often normal. In less than 10% of cases it is associated with cancer (commonly thymoma).

CNS tumors (CNST) carry a substantial source of morbidity and mortality in the world, but epidemiological data are poor. This study evaluated the incidence of primitive CNST in the adult population of Southern Sardinia over a four-year span and identified incidence clusters over the area under study.

In genetic prion diseases (gPrD), five genetic variants (E200K, V210I, V180I, P102L, and D178N) are responsible for about 85% of cases. The R208H is one of the several additional rare mutations and to date, only 16 cases carrying this mutation have been reported worldwide. To describe the phenotypic features of 5 affected patients belonging to apparently unrelated Sardinian (Italian) families with R208H gPrD, and provide evidence for a possible founder effect are the aims of this study. The R208H PRNP mutation has a much higher relative frequency in Sardinia than elsewhere in Italy (72% vs. 4.4% of gCJD cases). Our cohort shared similar phenotypic features to the previously described patients with R208H-129M haplotype with most patients showing the classical Creutzfeldt-Jakob disease (CJD) phenotype. The analysis of 10 controls and 5 patients by NGS sequencing identified 4 haplotypes, 3 associated with the wild type variant, and one (H1) shared by all patients carrying the 208His variant. This is the first report of a regional cluster for R208H mutation in gPrD and the first report of the presence of a common ancestor for this Sardinian R208H cluster, confirming the probable consequences of genetic isolation process even for rare diseases.

Dementia with Lewy body is a neurodegenerative disorder affecting both cognitive and motor domains. Motor impairment manifests predominantly as a symmetrical/mild asymmetrical parkinsonian syndrome that is only mildly responsive to Levodopa. To characterize motor dysfunction in dementia with Lewy body, we quantitatively assessed upper limb movements using a motion-capture system. Ten patients and ten healthy controls were tested while performing the hand-to-mouth movement of which speed, smoothness and accuracy features were measured. The results showed that individuals with dementia with Lewy body required a longer time to complete the task, particularly due to a prolonged duration of the adjusting phase (i.e., when approaching the target/mouth). The overall motor performance of dementia with Lewy body patients closely resembled what previously observed in patients affected by both Parkinson's disease and ataxia while performing the same task. Moreover, the severity of parkinsonian symptoms as assessed by the UPDRS-III scale impacted on the velocity of movement alone whereas impairment of executive functions correlated with variables related to the phase of targeting the mouth. This study provides new information about upper limb motor dysfunction in dementia with Lewy body.

Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease, which affects domains outside of the motor system. Recent findings have suggested that scalp electroencephalography (EEG) analysis may represent a useful tool for the monitoring of the disease. Here, we investigated functional connectivity in a set of ALS patients using source-reconstructed EEG time series comparing the results to age-matched healthy controls. Source based functional connectivity was estimated using a measure of amplitude envelope correlation (AEC) after performing orthogonalisation procedure in the time domain. The results of this study show that alpha band functional connectivity at source level discloses different patterns of inter-regional synchronization in ALS patients compared to healthy subjects. These findings suggest that ALS induces a strong frequency-specific reduction of functional connectivity patterns and that these changes are not limited to motor connections.

•Pulvinar sign is considered a diagnostic marker in variant Creutzfeldt-Jacob disease. •Pulvinar sign has been reported in potentially treatable encephalopathies. •We report the first case of pulvinar sign associated with anti-CV2 encephalitis.

The Capgras syndrome (CS) is a rare psychiatric disorder. CS is classified as a delusional misidentification syndrome. Initially, CS was described in paranoid schizophrenia and schizoaffective disorders. CS has also been reported in neurodegenerative diseases such as Alzheimer’s disease and Lewy body dementia. To date, there are very few descriptions of the occurrence of CS in idiopathic Parkinson’s disease (PD), with or without dementia. Considering the recent observation of two new cases in PD patients, a systematic overview of the literature published between 1976 and 2016 reporting CS in PD was conducted. The purpose of this article is to examine the phenomenon in people with PD with and without dementia, the psychopathologic context in which it happened, the role played by the dopaminergic medications and to define useful therapeutic strategies. Our CS cases occurred in two elderly patients with advanced PD and cognitive impairment, respectively, after an acute stressor event and after an increase of the total daily dose of levodopa. In light of our observations and the cases reported in the literature, we argue that CS is an acute or subacute psychotic disorder occurring mostly in PD with dementia. Besides, the increase in brain dopamine levels induced by acute stressful events and/or dopamine-enhancing medications should be considered as a possible causal mechanism of CS in patients with advanced stages of PD and cognitive decline.

BACKGROUND:Dementia with Lewy bodies (DLB) is the second most frequent diagnosis of progressive degenerative dementia in older people. Delusions are common features in DLB and, among them, Capgras syndrome represents the most frequent disturbance, characterized by the recurrent and transient belief that a familiar person, often a close family member or caregiver, has been replaced by an identical-looking imposter. However, other delusional conditions near to misidentification syndromes can occur in DLB patients and may represent a major psychiatric disorder, although rarely studied systematically.CASE PRESENTATION:We reported on a female patient affected by DLB who presented with an unusual delusion of duplication. Referring to the female professional caregiver engaged by her relatives for her care, the patient constantly described the presence of two different female persons, with a disorder framed in the context of a delusion of duplication. A brain 99Tc-hexamethylpropyleneamineoxime SPECT was performed showing moderate hypoperfusion in both occipital lobes, and associated with marked decreased perfusion in parieto-fronto-temporal lobes bilaterally.CONCLUSIONS:An occipital hypoperfusion was identified, although in association with a marked global decrease of perfusion in the remaining lobes. The role of posterior lobes is certainly important in all misidentification syndromes where a natural dissociation between recognition and identification is present. Moreover, the concomitant presence of severe attentional and executive deficits evocative for a frontal syndrome and the marked global decrease of perfusion in the remaining lobes at the SPECT scan also suggest a possible dysfunction in an abnormal connectivity between anterior and posterior areas.

Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients.

Recently, mutations in the TANK-binding kinase 1 (TBK1) gene were identified as a cause for amyotrophic lateral sclerosis (ALS) with or without comorbid frontotemporal dementia. We have assessed the frequency and clinical characteristics of TBK1 mutations in a cohort of ALS patients of Sardinian ancestry. Whole-exome sequencing was performed on Hiseq2000 platform (Illumina). Genome analysis Toolkit was used to align and to code variants according to Human Genome (UCSC hg19). Mutation was confirmed with Sanger sequence. In our screening of 186 Sardinian ALS cases, we found 3 (1.6%) patients carrying 3 distinct novel genetic variants: a nonsynonymous SNV c.1150C>T leading to a p.Arg384Thr change in exon 9; a nonsynonymous SNV c.1331G>A causes a p.Arg444Gln change in exon 11; and a frameshift deletion c.2070delG (p.Met690fs) at the exon 20 of the gene leading to a stop at 693 codon. The latter patients also carried missense mutation c.98C>T of the SQSTM1 gene causing a substitution of an arginine with a valine at the position 33 (p.Arg33Val). All variants were found to be deleterious according to in silico predictions. All cases were apparently sporadic and one of them showed frontotemporal dementia associated to ALS. These mutations were not found in 2 cohorts of 6780 ethnic-matched controls. We have found that TBK1 mutations account for 1.6% of Sardinian ALS cases. Our data support the notion that TBK1 is a novel ALS gene, providing important evidence complementary to the first descriptions.

We investigated intrafamilial phenotypic variability in carriers of the C9orf72 mutation, analysing clinical, neuropsychological and imaging characteristics of various members from a large Sardinian kindred with FTD or ALS. We compared these with those of C9+patients in our ALS and FTD cohorts. Results showed that three patients carried the C9orf72 mutation: two with ALS and one with FTD and Parkinsonism. C9+patients in our bvFTD Sardinian cohort had a higher frequency of Parkinsonism than non-mutated patients (75% vs. 36.3%, p<0.02). Parkinsonism was present in 2.7% of our ALS cohort and 3.3% of the C9+patients. The prevalence of Parkinsonism in C9+patients in the bvFTD and ALS cohorts showed a statistically significant difference (p<0.006). In conclusion, Parkinsonism was frequently associated with FTD but not ALS in a large Sardinian family, a finding reflected in the wider C9orf72 associated Sardinian ALS and FTD populations.