Brain communications最新文献

Short tandem repeats (STRs) are recognized contributors to various neurodegenerative disorders, with evidence supporting genetic pleiotropy among these STRs. Multiple STRs have been associated with amyotrophic lateral sclerosis (ALS), although the strength of evidence supporting each association varies. To establish the role of disease-associated repeat expansions as pleiotropic risk factors in ALS susceptibility and progression, we genotyped a panel of 39 STRs, known to cause neurological diseases, within Project MinE in 6519 patients and 2412 controls, utilizing 100 and 150 bp short-read sequencing technology. Pathogenic allele frequencies were compared to those in a control cohort comprising 4930 Genome Aggregation Database (gnomAD) genomes. Repeat sizes and motif changes were detected using ExpansionHunter and ExpansionHunter Denovo. We developed a model to predict genotyping failures in STRs and established a best-practice protocol for assessing the accuracy of STR genotyping in short-read sequencing data. Following our genotyping assessment, 11 out of the 39 STRs exhibited insufficient genotyping accuracy, warranting caution in studying these STRs using these tools in combination with short-read sequencing. Furthermore, the observed differences in STR genotyping accuracy across studies applying different sequencing technologies and genotyping tools in control cohorts highlight the importance of a carefully designed experimental setup when interpreting potential disease-associated STR findings. Pathogenic C9orf72 and premutated ATXN2 expansions were confirmed to be significantly associated with ALS susceptibility. Additionally, pathogenic C9orf72 expansions were significantly associated with reduced mean ALS survival by 11.5 months and an earlier mean age at onset by 2.4 years. Premutation expansions in ATXN1 showed a nominally significant association with ALS susceptibility, while pathogenic expansions in NIPA1 displayed a nominally significant association with ALS survival. Previously reported ALS-associated pleiotropy in HTT and STMN2 could not be confirmed. Motif changes were identified in BEAN1, RFC1, ATXN8, C9orf72, DAB1, FXN and SAMD12; however, none of the motif changes were linked to ALS. Re-evaluation of clinical data from patients with ALS and a repeat expansion typically associated with another disease revealed that 7% of these patients' diagnoses had to be reclassified to the disease associated with the repeat expansion (e.g. Kennedy's disease or spinocerebellar ataxia). This underscores the value of broad STR screening in neurodegenerative cases. Pathogenic and premutation STRs were also found in controls in unexpected high frequencies, suggesting reduced penetrance or underdiagnosis, and highlighting the need for caution when interpreting genetic associations with disease without a proper control cohort.

In Alzheimer's disease (AD), accelerated long-term forgetting (ALF), where information is retained normally over 10-30 min but lost at an accelerated rate over subsequent days to weeks, develops several years before symptom onset. However, the neuroanatomical changes underpinning ALF remain undetermined. Eighteen presymptomatic autosomal dominant AD mutation carriers and 12 non-carriers underwent ALF assessment with a list, a story, and visual figure, testing 30-min and 7-day recall of each, separately. T₁ and diffusion-weighted MRI were acquired. Cortical thickness was estimated for 13 pre-defined grey matter regions, with streamline tractography assessing associated structural connectivity. In mutation carriers, lower verbal ALF performance (list and story) was strongly associated with thinner prefrontal cortex (PFC) across four contiguous regions bilaterally. This association was absent in non-carriers. No associations were found between ALF and the thickness/volume of medial temporal lobe (MTL) structures. The association between ALF and PFC connectivity was weaker than for cortical thickness. Our results suggest that early subtle pathological change in PFC underpins ALF development, highlighting the central role of PFC dysfunction in very early AD-related cognitive decline. ALF may represent a qualitatively different (non-MTL driven) form of forgetting compared with the short interval forgetting that develops at later disease stages.

Top-down attention (i.e. the goal-directed (de-)prioritization of information) is fundamental for successful everyday life. Attention deficits caused by brain lesions, like visuospatial neglect or extinction, are therefore of major importance and call for effective therapies. Transcranial direct current stimulation (tDCS), a non-invasive, electric brain stimulation technique, has been discussed as a potential therapeutic tool. Recent research suggests that anodal tDCS over the frontal eye field (FEF) might increase visual search performance even in healthy participants, substantiating the potential therapeutic efficacy of tDCS (e.g. for stroke rehabilitation). In two pre-registered experiments, we investigated the robustness of these findings. In the first experiment, the right FEF was anodally stimulated, supposedly increasing neural activity; in the second experiment, anodal tDCS was delivered over the left FEF, and the size of the visual search field was manipulated. In neither of the two experiments, previous findings of enhanced visual search performance due to tDCS could be reproduced. In contrast, Bayesian statistics indicated evidence against reliable top-down attention-guided visual search improvements through FEF tDCS in healthy participants. Although effects might be stronger in patient populations, the present results do not suggest tDCS over FEF to be a very strong candidate as a therapeutical approach in attention disorders.

Alzheimer's disease is associated with lower circumpapillary retinal nerve fibre layer thickness (cpRNFLT). It remains unclear if dementia risk states, i.e. mild cognitive impairment (MCI) and mild neurocognitive disorder (NCD) might associate with cpRNFLT and whether specific domains of cognitive function are related. The present study compared systematically all cognitive domains as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) with pointwise analyses of the cpRNFLT and whether cpRNFLT variation can predict MCI and mild NCD. Spectral domain optical coherence tomography scans (768 A-scans of cpRNFLT) were analysed from 1300 participants with reliable measurements, without eye diseases, and further exclusion due to brain disorders. The study was conducted in the framework of the population-based Leipzig Research Centre for Civilization Diseases-(LIFE)-Adult study. The six DSM-5 domains were operationalized by means of both (sub-)scales of the 'Consortium to Establish a Registry for Alzheimer Disease' (CERAD-Plus) neuropsychological test battery and the 'Reading the Mind in the Eyes' test. Age, sex, education and scanning radius were used as additional regressors to adjust for demographics and eye anatomy. 2133 eyes of 1300 subjects were selected (age range 60-79 years). After adjustment for multiple comparisons, in the domain 'attention', worse performance was related to significantly thinner cpRNFL, especially in male participants, most pronounced for temporal and nasal-superior locations. For the domain 'executive function' significantly thicker cpRNFL was found nasally in female participants. There were no significant (P < 0.05) cpRNFLT locations for the DSM-5 domains 'learning/memory', 'perceptual-motor abilities', 'language' and 'social cognition'. Subjects with MCI had thinner cpRNFL temporal-superior compared to subjects with normal cognition. Furthermore, alterations of cpRNFLT in MCI and mild NCD, and subgroups amnestic MCI and amnestic mild NCD existed, for the latter mainly in temporal regions. Compared to cognitively unimpaired, analyses revealed hippocampal volume decreases in MCI and mild NCD groups, and comparable white matter lesion volume, compatible with Alzheimer aetiology. cpRNFL fibre thinning was most prominently associated with lower performance in the attention domain. Highly location specific thinning involved predominantly retinal locations superior and temporal to the optic disc. Thinning in temporal-superior segment was associated with MCI. Temporal thinning indicated amnestic MCI and amnestic mild NCD. Executive function, MCI, and mild NCD presented a concordantly negative association of cognition and RNFLT nasally. As cpRNFLT is obtained conveniently within seconds, our results might assist clinicians by earlier identification of patients at risk for developing cognitive decline associated with diseases like Alzheimer's disease.

White matter hyperintensities (WMHs) are radiological abnormalities indicative of cerebrovascular dysfunction associated with increased risk for cognitive decline. WMHs increase in prevalence with older age, and there are known sex differences as older women harbour higher WMH burden than men. Some have hypothesized that the increase in this dementia-related risk factor is related to the menopausal transition. To untangle the effects of age and menopause, we leveraged a large cross-sectional sample of women from the UK Biobank (n = 9560) to investigate differences in WMH volumes across menopausal status using a strict age-matching procedure. Surprisingly, we find higher WMH volumes in premenopausal women compared to postmenopausal women in certain analysis schemes, especially as compared to surgically postmenopausal women. These results reached significance mostly in analyses where the postmenopausal groups had a longer time since menopause. Our results pertaining to menopause-related characteristics, such as age at menopause or menopause hormonal therapy, did not replicate the literature reporting an association with WMH volumes. Cardiometabolic factors, such as smoking and blood pressure, were significant predictors of WMH volume in the full sample without age-matching. These effects were not significantly different across menopausal status, with the exception of blood pressure medication use, which was associated with higher WMH volumes to a larger extent in premenopausal women relative to postmenopausal women. Our findings are in the opposite direction of reported effects of higher WMH volumes following the menopausal transition, which could be due to variations in age correction techniques or idiosyncrasies in the UK Biobank sample, especially as it relates to the lack of data on perimenopause. We further show that the effects of positive cardiometabolic and lifestyle factors on brain health, as indexed with WMH volumes, generally do not change after menopause. Factors other than the menopausal status may be at play in explaining the difference in WMH burden between men and women in later life.

Patients with acute hemispheric stroke exhibit various visuospatial impairments. While many recover rapidly, others remain impaired. Better defining which symptoms characterize the acute and chronic phases and which brain areas and connections are implicated could help to improve diagnostic and rehabilitation tools and inform effective rehabilitation strategies. Here, we report a systematic anatomo-functional study of two populations of acute and chronic hemispheric stroke patients (cross-sectional design). Patients were examined by a series of neuropsychological tests assessing different post-stroke clinical manifestations in the visuospatial domain. We first performed a statistical factorial analysis of patients' behavioural performance across tests to break down symptoms into coherent profiles of co-varying deficits and determine whether any factors may be specific to each post-stroke phase. We then conducted voxel- and atlas-based lesion-symptom mapping, as well as disconnection-symptom mapping in the two populations. We found different patterns of behavioural impairment across groups, with acute symptoms mostly characterized by lateralized attentional deficits and chronic symptoms manifesting as constructional spatial impairments. Lesions to and/or disconnections of frontal and precentral gyri correlated with lateralized visuospatial symptoms in the acute but not chronic phase, whereas lesions to and/or disconnections of temporoparietal areas correlated with constructional deficits in the chronic phase. Our results indicate that constructional spatial deficits and damage/disconnection of dorsoventral higher-order visual areas most pervasively impair stroke patients in the long term. Such deficits might be overlooked or disregarded by rehabilitation strategies focusing on the (mainly acute) lateralized component of their visuospatial deficits and ignoring concomitant, more object-based deficits. This work may help design more specific diagnostic tests and guide future rehabilitation strategies, ultimately promoting better and more extensive recovery beyond lateralized deficits in attention and spatial awareness.

The spatiotemporal ordering of nigrostriatal iron deposition across different motor subtypes of Parkinson's disease (PD) remains poorly understand. This study explored the time course of nigrostriatal iron accumulation in 55 patients with postural instability and gait difficulty (PIGD) subtype and 53 patients with tremor-dominant (TD) subtype at early to late disease duration and 47 age-matched healthy controls (HC). Using quantitative susceptibility mapping, iron content was assessed in the substantia nigra (SN) and striatum. A spatial function method was employed to map the iron gradient along the principal axis of the subcortical structure. Nigrostriatal iron was compared among HC, PIGD/TD subgroup defined by disease duration [early, (<2 years); middle (2-6 years); late (>6 years)]. Associations with iron levels and motor symptoms were explored using partial correlation analysis. Nigrostriatal iron followed an inverted U-shaped progression, increasing initially and decreasing later in PIGD subtype. An S-shaped pattern was observed in TD subtype, increasing initially, decreasing later, then increasing again as disease progression. Iron distribution evolution of PD motor subtypes demonstrated opposite trends along medial-lateral axis (M-L) of the SN and anterior-posterior (A-P) axis of the putamen. Correlation analysis revealed that nigra iron content was positively associated with motor impairments, while caudate and putaminal iron level were negatively correlated with PIGD scores and Hoehn and Yahr scale in PIGD and TD subtype, respectively. These findings suggest that distinct nigrostriatal iron spatiotemporal pattern underlying different pathophysiology mechanism involved in these two PD motor subtypes. The opposite iron evolution trends along M-L axis of the SN and A-P axis of the putamen may provide a target for the development of new preventive or disease-modifying therapies.

High-frequency deep brain stimulation of the subthalamic nucleus is used to treat motor symptoms in patients with Parkinson's disease. There is evidence that low-frequency stimulation in the range of 4-10 Hz may improve cognitive functions. This study investigates whether low-frequency deep brain stimulation of the subthalamic nucleus in the beta band (20 Hz) frequency can improve response inhibition in patients with Parkinson's disease. In a double-blind crossover design, N = 17 participants with Parkinson's disease performed four neuropsychological experiments, while on their usual dopaminergic medication, under no, standard high-frequency and 20 Hz beta low-frequency deep brain stimulation. The experiments consisted of a response selection task (response execution), a flanker task (conflict monitoring), a Go-NoGo task (automatic inhibition) and a stop-change task (controlled inhibition). Reaction time and response accuracy were analysed using Bayesian mixed-effect models. Participants responded [m = 33.6 ms, Bayes factor (BF) = 129.6] slower and [m = 6.0%, BF > 1000] more accurately under low-frequency than high-frequency stimulation but not under no stimulation during the response selection task. In the flanker task, participants responded slower under low-frequency than high-frequency stimulation [m = 77.0 ms, BF > 1000] but not under no stimulation [m = 18.3 ms, BF = 0.1]. We found no performance differences by the stimulation condition of the congruency effect. In the Go-NoGo task, we found low-frequency stimulation slowed responses on uncertain Go trials compared to no stimulation [m = 136.8 ms, BF = 30.3] and high-frequency stimulation [m = 105.2 ms, BF = 2.5]. Additionally, participants committed fewer errors under low-frequency stimulation than under no and high-frequency stimulation, suggesting that 20 Hz subthalamic nucleus stimulation may improve automatic inhibition. Lastly, in the stop-change task, we found no performance modulation by low-frequency stimulation compared to no and high-frequency stimulation. Our results show that low-frequency beta stimulation may improve aspects of automatic response inhibition in patients with Parkinson's disease.

The quality of sleep and its cognitive benefits rely on the cyclic alternance of two distinct sleep stages associated (REM) or not (NREM) with rapid-eye-movements. The ability to predict shifts in sleep stages could help design future interventions in sleep medicine, but it remains unknown how robust the NREM-REM sleep architecture may be for a given individual over many successive nights. We sought to characterize the individual variability and test the predictability of healthy human sleep recorded longitudinally over unprecedented durations (weeks). Based on ultra-long-term sub-scalp electroencephalographic recordings from a newly available, minimally invasive device, we characterized sleep cycles in eight healthy subjects over a median of 30 consecutive days. We first decomposed EEG signals into five frequency bands (δ, θ, α, σ and β) using a multi-taper time-frequency transform. Second, we quantified variability in sleep spectral composition and predictability in sleep stage transitions based on unsupervised and supervised learning methods, respectively. Using dynamic time warping, we quantified the dissimilarity (D) between pairs of nights, showing that it was lower within (D = 2.5 ± 0.7) than across subjects (D = 4.1 ± 0.5, P < 0.001). Further, we extracted archetypal sleep patterns, which are most representative of an individual's NREM-REM spectral architecture. Based on the found interplay between δ and σ power bands modeled in a generalized linear model, we predicted transitions from NREM to REM two to four minutes in advance with high accuracy (area under the receiver operating characteristic curve = 0.88). Taken together, these results show that sleep is variable over consecutive nights in healthy subjects but that core dynamics in sleep oscillations are consistently shared across individuals. As a translational outlook, the predictability of certain sleep transitions affords the means to anticipate pathological symptoms specific of a given sleep stage.