Prediagnostic Blood Metal Levels and the Risk of Parkinson's Disease: A Large European Prospective Cohort.

BACKGROUND: Metals have been postulated as environmental concerns in the etiology of Parkinson's disease (PD), but metal levels are typically measured after diagnosis, which might be subject to reverse causality. OBJECTIVE: The aim of this study was to investigate the association between prediagnostic blood metal levels and PD risk. METHODS: A case-control study was nested in a prospective European cohort, using erythrocyte samples collected before PD diagnosis. RESULTS: Most assessed metals were not associated with PD risk. Cadmium has a suggestive negative association with PD (odds ratio [95% confidence interval] for the highest quartile, 0.70 [0.42-1.17]), which diminished among never smokers. Among current smokers only, lead was associated with decreased PD risk (0.06 [0.01-0.35]), whereas arsenic showed associations toward an increased PD risk (1.85 [0.45-7.93]). CONCLUSIONS: We observe no strong evidence to support a role of metals in the development of PD. In particular, smoking may confound the association with tobacco-derived metals. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diabetes mellitus, prediabetes and the risk of Parkinson's disease: a systematic review and meta-analysis of 15 cohort studies with 29.9 million participants and 86,345 cases.

A diagnosis of diabetes mellitus and prediabetes has been associated with increased risk of Parkinson's disease (PD) in several studies, but results have not been entirely consistent. We conducted a systematic review and meta-analysis of cohort studies on diabetes mellitus, prediabetes and the risk of PD to provide an up-to-date assessment of the evidence. PubMed and Embase databases were searched for relevant studies up to 6th of February 2022. Cohort studies reporting adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for the association between diabetes, prediabetes and Parkinson's disease were included. Summary RRs (95% CIs) were calculated using a random effects model. Fifteen cohort studies (29.9 million participants, 86,345 cases) were included in the meta-analysis. The summary RR (95% CI) of PD for persons with diabetes compared to persons without diabetes was 1.27 (1.20-1.35, I2 = 82%). There was no indication of publication bias, based on Egger's test (p = 0.41), Begg's test (p = 0.99), and inspection of the funnel plot. The association was consistent across geographic regions, by sex, and across several other subgroup and sensitivity analyses. There was some suggestion of a stronger association for diabetes patients reporting diabetes complications than for diabetes patients without complications (RR = 1.54, 1.32-1.80 [n = 3] vs. 1.26, 1.16-1.38 [n = 3]), vs. those without diabetes (pheterogeneity=0.18). The summary RR for prediabetes was 1.04 (95% CI: 1.02-1.07, I2 = 0%, n = 2). Our results suggest that patients with diabetes have a 27% increased relative risk of developing PD compared to persons without diabetes, and persons with prediabetes have a 4% increase in RR compared to persons with normal blood glucose. Further studies are warranted to clarify the specific role age of onset or duration of diabetes, diabetic complications, glycaemic level and its long-term variability and management may play in relation to PD risk.

Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation.

BACKGROUND: Distal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ. METHODS: We used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ. RESULTS: A homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed. CONCLUSION: In conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel.

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease.

BACKGROUND: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. METHODS: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11 C]UCB-J, [11 C]SA-4503, and [18 F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. RESULTS: Reduced [11 C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11 C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11 C]SA-4503 and [18 F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11 C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. CONCLUSIONS: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Alcohol Consumption and Risk of Parkinson's Disease: Data From a Large Prospective European Cohort.

BACKGROUND: Parkinson's disease (PD) etiology is not well understood. Reported inverse associations with smoking and coffee consumption prompted the investigation of alcohol consumption as a risk factor, for which evidence is inconclusive. OBJECTIVE: To assess the associations between alcohol consumption and PD risk. METHODS: Within NeuroEPIC4PD, a prospective European population-based cohort, 694 incident PD cases were ascertained from 209,998 PD-free participants. Average alcohol consumption at different time points was self-reported at recruitment. Cox regression hazard ratios were estimated for alcohol consumption and PD occurrence. RESULTS: No associations between baseline or lifetime total alcohol consumption and PD risk were observed. Men with moderate lifetime consumption (5-29.9 g/day) were at ~50% higher risk compared with light consumption (0.1-4.9 g/day), but no linear exposure-response trend was observed. Analyses by beverage type also revealed no associations with PD. CONCLUSION: Our data reinforce previous findings from prospective studies showing no association between alcohol consumption and PD risk. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines.

Previously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83+/-, which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson's disease (PD). In our studies, we inoculated MSA and control patient samples into Tg mice constructed using a P1 artificial chromosome to express wild-type (WT), A30P, and A53T human α-synuclein on a mouse α-synuclein knockout background [Tg(SNCA+/+)Nbm, Tg(SNCA*A30P+/+)Nbm, and Tg(SNCA*A53T+/+)Nbm]. In contrast to studies using TgM83+/- mice, motor deficits were not observed by 330-400 days in any of the Tg(SNCA)Nbm mice after inoculation with MSA brain homogenates. However, using a cell-based bioassay to measure α-synuclein prions, we found brain homogenates from Tg(SNCA*A53T+/+)Nbm mice inoculated with MSA patient samples contained α-synuclein prions, whereas control mice did not. Moreover, these α-synuclein aggregates retained the biological and biochemical characteristics of the α-synuclein prions in MSA patient samples. Intriguingly, Tg(SNCA*A53T+/+)Nbm mice developed α-synuclein pathology in neurons and astrocytes throughout the limbic system. This finding is in contrast to MSA-inoculated TgM83+/- mice, which develop exclusively neuronal α-synuclein aggregates in the hindbrain that cause motor deficits with advanced disease. In a crossover experiment, we inoculated TgM83+/- mice with brain homogenate from two MSA patient samples or one control sample first inoculated, or passaged, in Tg(SNCA*A53T+/+)Nbm animals. Additionally, we performed the reverse experiment by inoculating Tg(SNCA*A53T+/+)Nbm mice with brain homogenate from the same two MSA samples and one control sample first passaged in TgM83+/- animals. The TgM83+/- mice inoculated with mouse-passaged MSA developed motor dysfunction and α-synuclein prions, whereas the mouse-passaged control sample had no effect. Similarly, the mouse-passaged MSA samples induced α-synuclein prion formation in Tg(SNCA*A53T+/+)Nbm mice, but the mouse-passaged control sample did not. The confirmed transmission of α-synuclein prions to a second synucleinopathy model and the ability to propagate prions between two distinct mouse lines while retaining strain-specific properties provides compelling evidence that MSA is a prion disease.

Perspective: Clinical relevance of the dichotomous classification of Alzheimer's disease biomarkers: Should there be a "gray zone"?

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be.

MSA prions exhibit remarkable stability and resistance to inactivation.

In multiple system atrophy (MSA), progressive neurodegeneration results from the protein α-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human α-synuclein (TgM83+/-), inducing neurological disease following intracranial inoculation with brain homogenate from deceased patient samples. Noting the similarities between α-synuclein prions and PrP scrapie (PrPSc) prions responsible for Creutzfeldt-Jakob disease (CJD), we investigated MSA transmission under conditions known to result in PrPSc transmission. When peripherally exposed to MSA via the peritoneal cavity, hind leg muscle, and tongue, TgM83+/- mice developed neurological signs accompanied by α-synuclein prions in the brain. Iatrogenic CJD, resulting from PrPSc prion adherence to surgical steel instruments, has been investigated by incubating steel sutures in contaminated brain homogenate before implantation into mouse brain. Mice studied using this model for MSA developed disease, whereas wire incubated in control homogenate had no effect on the animals. Notably, formalin fixation did not inactivate α-synuclein prions. Formalin-fixed MSA patient samples also transmitted disease to TgM83+/- mice, even after incubating in fixative for 244 months. Finally, at least 10% sarkosyl was found to be the concentration necessary to partially inactivate MSA prions. These results demonstrate the robustness of α-synuclein prions to denaturation. Moreover, they establish the parallel characteristics between PrPSc and α-synuclein prions, arguing that clinicians should exercise caution when working with materials that might contain α-synuclein prions to prevent disease.

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.

Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) prion causes the rare human disorder Creutzfeldt-Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T-YFP) and TgM83(+/-) mice expressing α-synuclein (A53T). The TgM83(+/-) mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83(+/+) mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83(+/-) mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T-YFP in cultured cells, whereas none of six Parkinson's disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

Propagation of prions causing synucleinopathies in cultured cells.

Increasingly, evidence argues that many neurodegenerative diseases, including progressive supranuclear palsy (PSP), are caused by prions, which are alternatively folded proteins undergoing self-propagation. In earlier studies, PSP prions were detected by infecting human embryonic kidney (HEK) cells expressing a tau fragment [TauRD(LM)] fused to yellow fluorescent protein (YFP). Here, we report on an improved bioassay using selective precipitation of tau prions from human PSP brain homogenates before infection of the HEK cells. Tau prions were measured by counting the number of cells with TauRD(LM)-YFP aggregates using confocal fluorescence microscopy. In parallel studies, we fused α-synuclein to YFP to bioassay α-synuclein prions in the brains of patients who died of multiple system atrophy (MSA). Previously, MSA prion detection required ∼120 d for transmission into transgenic mice, whereas our cultured cell assay needed only 4 d. Variation in MSA prion levels in four different brain regions from three patients provided evidence for three different MSA prion strains. Attempts to demonstrate α-synuclein prions in brain homogenates from Parkinson's disease patients were unsuccessful, identifying an important biological difference between the two synucleinopathies. Partial purification of tau and α-synuclein prions facilitated measuring the levels of these protein pathogens in human brains. Our studies should facilitate investigations of the pathogenesis of both tau and α-synuclein prion disorders as well as help decipher the basic biology of those prions that attack the CNS.

α-synuclein genetic variability: A biomarker for dementia in Parkinson disease.

OBJECTIVE: The relationship between Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB) has long been debated. Although PD is primarily considered a motor disorder, cognitive impairment is often present at diagnosis, and only ∼20% of patients remain cognitively intact in the long term. Alpha-synuclein (SNCA) was first implicated in the pathogenesis of the disease when point mutations and locus multiplications were identified in familial parkinsonism with dementia. In worldwide populations, SNCA genetic variability remains the most reproducible risk factor for idiopathic PD. However, few investigators have looked at SNCA variability in terms of cognitive outcomes. METHODS: We have used targeted high-throughput sequencing to characterize the 135kb SNCA locus in a large multinational cohort of patients with PD, PDD, and DLB and healthy controls. RESULTS: An analysis of 43 tagging single nucleotide polymorphisms across the SNCA locus shows 2 distinct association profiles for symptoms of parkinsonism and/or dementia, respectively, toward the 3' or the 5' of the SNCA gene. In addition, we define a specific haplotype in intron 4 that is directly associated with PDD. The PDD risk haplotype has been interrogated at single nucleotide resolution and is uniquely tagged by an expanded TTTCn repeat. INTERPRETATION: Our data show that PD, PDD, and DLB, rather than a disease continuum, have distinct genetic etiologies albeit within one genomic locus. Such results may serve as prognostic biomarkers to these disorders, to inform physicians and patients, and to assist in the design and stratification of clinical trials aimed at disease modification. Ann Neurol 2016;79:991-999.

Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses.

INTRODUCTION: Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors. METHODS: We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance. RESULTS: A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease. DISCUSSION: Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.

Is the time ripe for new diagnostic criteria of cognitive impairment due to cerebrovascular disease? Consensus report of the International Congress on Vascular Dementia working group.

BACKGROUND: Long before Alzheimer's disease was established as the leading cause of dementia in old age, cerebrovascular lesions were known to cause cognitive deterioration and associated disability. Since the middle of the last century, different diagnostic concepts for vascular dementia and related syndromes were put forward, yet no widely accepted diagnostic consensus exists to date. DISCUSSION: Several international efforts, reviewed herein, are ongoing to define cognitive impairment due to cerebrovascular disease in its different stages and subtypes. The role of biomarkers is also being discussed, including cerebrospinal fluid proteins, structural and functional brain imaging, and genetic markers. The influence of risk factors, such as diet, exercise and different comorbidities, is emphasised by population-based research, and lifestyle changes are considered for the treatment and prevention of dementia. CONCLUSION: To improve the diagnosis and management of vascular cognitive impairment, further progress has to be made in understanding the relevant pathomechanisms, including shared mechanisms with Alzheimer's disease; bringing together fragmented research initiatives in coordinated international programs; testing if known risk factors are modifiable in prospective interventional studies; and defining the pre-dementia and pre-clinical stages in line with the concept of mild cognitive impairment due to Alzheimer's disease.

Why has therapy development for dementia failed in the last two decades?

The success rate of the pharmaceutical research and development (R&D) for dementia drugs has been abysmally low, in the last two decades. Also low has been the number of pipeline drugs in development, compared to other therapy areas. However, the rationale of early terminations has not been reported in the majority of trials. These are key findings of the recently published pharmaceutical pipeline analysis by the UK-based Office of Health Economics (OHE). Our understanding of main challenges include (1) the significant gaps of knowledge in the nosology and complexity of the underpinning biological mechanisms of the commonest, not familial, forms of late onset dementias; (2) low signal-to-noise ratio, notwithstanding the lack of validated biomarkers as entry and/or end-point criteria; (3) recruitment and retention, particularly in the asymptomatic and early disease stages. A number of current and future strategies aimed at ameliorating drug development are outlined and discussed.

A novel GBA2 gene missense mutation in spastic ataxia.

Autosomal recessive cerebellar ataxias (ARCA) encompass a heterogeneous group of rare diseases that affect the cerebellum, the spinocerebellar tract and/or the sensory tracts of the spinal cord. We investigated a consanguineous Cypriot family with spastic ataxia, aiming towards identification of the causative mutation. Family members were clinically evaluated and studied at the genetic level. Linkage analysis at marker loci spanning known ARCA genes/loci revealed linkage to the APTX locus. Thorough investigation of the APTX gene excluded any possible mutation. Whole genome linkage screening using microsatellite markers and whole genome SNP homozygosity mapping using the Affymetrix Genome-Wide Human SNP Array 6.0 enabled mapping of the disease gene/mutation in this family to Chromosome 9p21.1-p13.2. Due to the large number of candidate genes within this region, whole-exome sequencing of the proband was performed and further analysis of the obtained data focused on the mapped interval. Further investigation of the candidate variants resulted in the identification of a novel missense mutation in the GBA2 gene. GBA2 mutations have recently been associated with hereditary spastic paraplegia and ARCA with spasticity. We hereby report a novel GBA2 mutation associated with spastic ataxia and suggest that GBA2 mutations may be a relatively frequent cause of ARCA.

Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

The impacts of social restrictions during the COVID-19 pandemic on the physical activity levels of over 50-year olds: The CHARIOT COVID-19 Rapid Response (CCRR) cohort study.

OBJECTIVES: To quantify the associations between shielding status and loneliness at the start of the COVID-19 pandemic, and physical activity (PA) levels throughout the pandemic. METHODS: Demographic, health and lifestyle characteristics of 7748 cognitively healthy adults aged >50, and living in London, were surveyed from April 2020 to March 2021. The International Physical Activity Questionnaire (IPAQ) short-form assessed PA before COVID-19 restrictions, and up to 6 times over 11 months. Linear mixed models investigated associations between shielding status and loneliness at the onset of the pandemic, with PA over time. RESULTS: Participants who felt 'often lonely' at the outset of the pandemic completed an average of 522 and 547 fewer Metabolic Equivalent of Task (MET) minutes/week during the pandemic (95% CI: -809, -236, p<0.001) (95% CI: -818, -275, p<0.001) than those who felt 'never lonely' in univariable and multivariable models adjusted for demographic factors respectively. Those who felt 'sometimes lonely' completed 112 fewer MET minutes/week (95% CI: -219, -5, p = 0.041) than those who felt 'never lonely' following adjustment for demographic factors. Participants who were shielding at the outset of the pandemic completed an average of 352 fewer MET minutes/week during the pandemic than those who were not (95% CI: -432, -273; p<0.001) in univariable models and 228 fewer MET minutes/week (95% CI: -307, -150, p<0.001) following adjustment for demographic factors. No significant associations were found after further adjustment for health and lifestyle factors. CONCLUSIONS: Those shielding or lonely at pandemic onset were likely to have completed low levels of PA during the pandemic. These associations are influenced by co-morbidities and health status.

A genome-wide investigation of SNPs and CNVs in schizophrenia.

We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

Practice Effect of Repeated Cognitive Tests Among Older Adults: Associations With Brain Amyloid Pathology and Other Influencing Factors.

Background: Practice effects (PE), after repeated cognitive measurements, may mask cognitive decline and represent a challenge in clinical and research settings. However, an attenuated practice effect may indicate the presence of brain pathologies. This study aimed to evaluate practice effects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale, and their associations with brain amyloid status and other factors in a cohort of cognitively unimpaired older adults enrolled in the CHARIOT-PRO SubStudy. Materials and Methods: 502 cognitively unimpaired participants aged 60-85 years were assessed with RBANS in both screening and baseline clinic visits using alternate versions (median time gap of 3.5 months). We tested PE based on differences between test and retest scores in total scale and domain-specific indices. Multiple linear regressions were used to examine factors influencing PE, after adjusting for age, sex, education level, APOE-ε4 carriage and initial RBANS score. The latter and PE were also evaluated as predictors for amyloid positivity status based on defined thresholds, using logistic regression. Results: Participants' total scale, immediate memory and delayed memory indices were significantly higher in the second test than in the initial test (Cohen's dz = 0.48, 0.70 and 0.35, P < 0.001). On the immediate memory index, the PE was significantly lower in the amyloid positive group than the amyloid negative group (P = 0.022). Older participants (≥70 years), women, non-APOE-ε4 carriers, and those with worse initial RBANS test performance had larger PE. No associations were found between brain MRI parameters and PE. In addition, attenuated practice effects in immediate or delayed memory index were independent predictors for amyloid positivity (P < 0.05). Conclusion: Significant practice effects on RBANS total scale and memory indices were identified in cognitively unimpaired older adults. The association with amyloid status suggests that practice effects are not simply a source of measurement error but may be informative with regard to underlying neuropathology.

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.