Delineating the neural substrates of autobiographical memory impairment in Huntington's disease.

Emerging evidence suggests that autobiographical memory (ABM) is altered in Huntington's disease (HD). While these impairments are typically attributed to frontostriatal dysfunction, the neural substrates of ABM impairment in HD remain unexplored. To this end, we assessed ABM in 30 participants with genetically confirmed HD (18 premanifest, 12 manifest) and 24 age-matched healthy controls. Participants completed the Autobiographical Interview to assess free and probed ABM recall and underwent structural brain imaging. Whole-brain voxel-based morphometry (VBM) was used to explore voxel-wise associations between ABM performance and grey matter intensity (False Discovery Rate corrected at q = 0.05). Relative to controls, HD participants displayed significantly less detailed ABM retrieval across free and probed recall conditions, irrespective of disease stage. Recall performance did not differ significantly between manifest and premanifest HD groups. VBM analyses indicated that poorer ABM performance was associated with atrophy of a distributed cortico-subcortical network. Key regions implicated irrespective of ABM condition included the bilateral occipital cortex, left precuneus, right parahippocampal gyrus and right caudate nucleus. In addition, probed ABM recall was associated with the superior and inferior frontal gyri, frontal pole, right hippocampus, nucleus accumbens, paracingulate gyrus and cerebellum. Overall, our findings indicate that ABM impairments in HD reflect the progressive degeneration of a distributed cortico-subcortical brain network comprising medial temporal, frontal, striatal and posterior parietal cortices. Our findings advance our understanding of the neurocognitive profile of HD, providing an important foundation for future interventions to support memory function in this population.

Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields.

INTRODUCTION: While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. METHODS: We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. RESULTS: Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. CONCLUSIONS: Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

Patterns and prevalence of cognitive dysfunction in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, in which cognitive dysfunction is common, but poorly understood. This study aims to characterize the prevalence and patterns of cognitive dysfunction in SLE. METHOD: SLE patients (n = 95) and demographically matched healthy controls (n = 48) underwent cross-sectional cognitive testing using the 1-hr conventional neuropsychological test battery recommended by the American College of Rheumatology for use in SLE. We used standard deviations (SD) from the healthy control group to define impairment. For each cognitive test we compared SLE and control groups using independent samples t-tests (or alternatives when needed). We performed cluster analysis using a machine learning algorithm to look for patterns of cognitive dysfunction. RESULTS: The SLE group performed significantly worse than healthy controls on every cognitive test. The largest differences were in the domains of verbal fluency, working memory and attention, while fine motor and psychomotor speed were the least affected domains. As expected, the prevalence of cognitive dysfunction varied depending on the SD cut-off used, with 49% of participants being >1.5 SD below the healthy control mean in at least two cognitive domains. Heat mapping showed variability in the pattern of dysfunction between individual patients and cluster analysis confirmed the presence of two clusters of patients, which were those significantly impaired versus those having preserved cognition. CONCLUSIONS: Cognitive dysfunction is common in SLE but markedly heterogeneous across both cognitive domains and across the SLE group. Cluster analysis supports the use of a binary definition of cognitive dysfunction in SLE.

Fibromyalgia, mood disorders, cognitive test results, cognitive symptoms and quality of life in systemic lupus erythematosus.

OBJECTIVES: Cognitive dysfunction, and comorbidities such as mood disorder and fibromyalgia, are common in SLE. This study aims to explore the associations between fibromyalgia, mood disorders, cognitive symptoms and cognitive dysfunction in SLE patients, and their impact on quality of life. METHODS: We tested cognition in SLE patients and healthy controls, and evaluated cognitive symptoms, mood disorder, fibromyalgia, fatigue and quality of life using patient-reported outcome measures. We examined associations of these comorbidities with both patient-reported cognitive symptoms and cognitive test performance. RESULTS: High fibromyalgia symptom score and history of depression or anxiety were associated with cognitive dysfunction. There were no significant associations between current depression, anxiety symptoms or fatigue score and objective cognitive dysfunction. In contrast, mood disorder symptoms, history of mood disorder, fibromyalgia symptoms and fatigue all had significant associations with patient-reported cognitive symptoms. There were no significant associations between patient-reported cognitive symptoms and objective cognitive dysfunction. Objective cognitive dysfunction, patient-reported cognitive symptoms, history of mood disorder and fibromyalgia symptoms all had significant associations with poorer quality of life; fibromyalgia had the biggest impact. CONCLUSIONS: Cognitive symptoms are common in SLE, but there were no associations between cognitive symptoms and objective cognitive dysfunction. Depression, anxiety and fibromyalgia were more consistently associated with patient-reported cognitive symptoms than with objective cognitive dysfunction. These factors all have a significant impact on quality of life. Understanding the discrepancy between patient-reported cognitive symptoms and cognitive test performance is essential to advance care in this area of unmet need.

Hippocampal and striatal volumes correlate with spatial memory impairment in Huntington's disease.

Spatial memory impairments are observed in people with Huntington's disease (HD), however, the domain of spatial memory has received little focus when characterizing the cognitive phenotype of HD. Spatial memory is traditionally thought to be a hippocampal-dependent function, while the neuropathology of HD centers on the striatum. Alongside spatial memory deficits in HD, recent neurocognitive theories suggest that a larger brain network is involved, including the striatum. We examined the relationship between hippocampal and striatal volumes and spatial memory in 36 HD gene expansion carriers, including premanifest (n = 24) and early manifest HD (n = 12), and 32 matched healthy controls. We assessed spatial memory with Paired Associates Learning, Rey-Osterrieth Complex Figure Test, and the Virtual House task, which assesses three components of spatial memory: navigation, object location, and plan drawing. Caudate nucleus, putamen, and hippocampal volumes were manually segmented on T1-weighted MR images. As expected, caudate nucleus and putamen volumes were significantly smaller in the HD group compared to controls, with manifest HD having more severe atrophy than the premanifest HD group. Hippocampal volumes did not differ significantly between HD and control groups. Nonetheless, on average, the HD group performed significantly worse than controls across all spatial memory tasks. The spatial memory components of object location and recall of figural and topographical drawings were associated with striatal and hippocampal volumes in the HD cohort. We provide a case to include spatial memory impairments in the cognitive phenotype of HD, and extend the neurocognitive picture of HD beyond its primary pathology within the striatum.

Accuracy of automated amygdala MRI segmentation approaches in Huntington's disease in the IMAGE-HD cohort.

Smaller manually-segmented amygdala volumes have been associated with poorer motor and cognitive function in Huntington's disease (HD). Manual segmentation is the gold standard in terms of accuracy; however, automated methods may be necessary in large samples. Automated segmentation accuracy has not been determined for the amygdala in HD. We aimed to determine which of three automated approaches would most accurately segment amygdalae in HD: FreeSurfer, FIRST, and ANTS nonlinear registration followed by FIRST segmentation. T1-weighted images for the IMAGE-HD cohort including 35 presymptomatic HD (pre-HD), 36 symptomatic HD (symp-HD), and 34 healthy controls were segmented using FreeSurfer and FIRST. For the third approach, images were nonlinearly registered to an MNI template using ANTS, then segmented using FIRST. All automated methods overestimated amygdala volumes compared with manual segmentation. Dice overlap scores, indicating segmentation accuracy, were not significantly different between automated approaches. Manually segmented volumes were most statistically differentiable between groups, followed by those segmented by FreeSurfer, then ANTS/FIRST. FIRST-segmented volumes did not differ between groups. All automated methods produced a bias where volume overestimation was more severe for smaller amygdalae. This bias was subtle for FreeSurfer, but marked for FIRST, and moderate for ANTS/FIRST. Further, FreeSurfer introduced a hemispheric bias not evident with manual segmentation, producing larger right amygdalae by 8%. To assist choice of segmentation approach, we provide sample size estimation graphs based on sample size and other factors. If automated segmentation is employed in samples of the current size, FreeSurfer may effectively distinguish amygdala volume between controls and HD.

Discrete changes in the frequency and functions of autobiographical reminiscence in Huntington's disease.

Autobiographical memory is widely posited to serve self, social and directive functions. Recent evidence suggests marked autobiographical memory impairments in Huntington's disease (HD), however, no study to date has determined how the perceived functions of autobiographical reminiscence may be altered in HD. The current study aimed to assess the self-reported frequency and function of autobiographical reminiscence in HD. We assessed autobiographical reminiscence in late premanifest (n = 16) and early stage HD (n = 14), relative to healthy controls (n = 30). Participants completed the Thinking About Life Experiences Scale Revised (TALE-R), which measures three putative functions of autobiographical memory (self, social, directive). People with manifest HD reported talking less frequently about the past compared to controls. In contrast, no group differences were found in terms of thinking about the past. Manifest HD participants further reported using their autobiographical memories for social functions less frequently compared to controls. No other group differences were evident in terms of self or directive functions of autobiographical memory. These self-report findings complement recent reports of autobiographical memory disruption on performance-based tasks in HD. Future studies exploring how changes in autobiographical reminiscence impact a sense of self continuity in HD will be important in this regard.

Sleep fragmentation despite intact rest-activity patterns in premanifest Huntington's disease: An actigraphy study.

OBJECTIVE: Sleep research in Huntington's disease (HD) has primarily focused on manifest HD, with significantly less attention given to premanifest HD (Pre-HD). Therefore, we investigated sleep and rest-activity patterns in people with Pre-HD versus healthy controls (HC). METHODS: We conducted a cross-sectional study including 36 Pre-HD and 48 HC participants. Pre-HD participants were stratified into three groups according to their proximity to estimated diagnosis, using a cytosine-adenine-guanine (CAG) and current age-based predictive model: NEAR (<9 years to diagnosis), MID (9-15 years to diagnosis) and FAR (>15 years to diagnosis). Sleep and rest-activity patterns were assessed using wrist-worn actigraphy, a sleep diary, and sleep questionnaires. RESULTS: NEAR and MID groups experienced higher fragmentation index than HC and FAR groups. NEAR and MID groups also exhibited greater WASO than the FAR group. NEAR and MID groups showed lower intra-daily variability (IV) than HC and FAR groups, with the NEAR group also being more active in the most active 10 h (M10). Groups did not differ on subjective sleep measures, inter-daily stability (IS), sleep regularity index, relative amplitude, or amount of activity in the least active 5 h (L5). Considering all Pre-HD participants, fewer years to diagnosis, higher CAG-age-product (CAP) scores (a measure of cumulative exposure to the HD-causing gene mutation) and larger CAG repeat lengths correlated with higher WASO, fragmentation index, L5, IS, and lower sleep efficiency and IV. Higher CAP score correlated with higher M10. CONCLUSIONS: Despite intact rest-activity patterns and similar subjective sleep quality to HC, greater sleep fragmentation is a prominent and early feature in Pre-HD. Therefore, reducing sleep fragmentation may be a potential target for sleep intervention in HD. Longitudinal studies using larger samples are needed to assess sleep across the disease spectrum and its impact on clinical outcomes, like cognition.

Learning and memory-related brain activity dynamics are altered in systemic lupus erythematosus: a functional magnetic resonance imaging study.

BACKGROUND: Memory impairment is prevalent in systemic lupus erythematosus (SLE); however, the pathogenesis is unknown. METHODS: We studied 12 patients with SLE without clinically overt neuropsychiatric manifestations and 11 matched healthy controls, aiming to characterize neural correlates of memory impairment, using structural and functional magnetic resonance imaging (MRI). The paradigm consisted of three encoding and free-recall cycles, allowing characterization of dynamics along consecutive retrieval attempts. RESULTS: During learning, patients with SLE and healthy controls showed brain activity changes in two principal networks, the default mode network (DMN) and the task-positive network (TPN). Patients with SLE demonstrated significantly less deactivation in the DMN and greater activation in the TPN, reflecting greater recruitment of both networks. The anterior medial prefrontal cortex (amPFC) of the DMN emerged as the only region where brain activity dynamics were altered both over the learning process (p < 0.006), and within free-recall period attempts (p < 0.034). Patients showed significant positive correlations between learning efficiency and hippocampal activity, and greater hippocampal functional connectivity, with pronounced connectivity to DMN structures. CONCLUSIONS: Increased brain activation in patients with SLE during learning may reflect compensatory mechanisms to overcome memory impairment. Our findings localize this impairment to the amPFC, consistent with the behavioral pattern seen in SLE. Altered networking of the hippocampal subsystem of the DMN is consistent with hippocampal neuronal damage seen in SLE, and may reflect compensatory cortical reorganization to cope with dysfunction in these regions pivotal to mnemonic functions.

Sleep, Circadian Rhythms, and Cognitive Dysfunction in Huntington's Disease.

BACKGROUND: In healthy people, sleep and circadian disruption are linked to cognitive deficits. People with Huntington's disease (HD), who have compromised brain function and sleep and circadian disturbances, may be even more susceptible to these cognitive effects. OBJECTIVE: To conduct a comprehensive review and synthesis of the literature in HD on the associations of cognitive dysfunction with disturbed sleep and circadian rhythms. METHODS: We searched MEDLINE via OVID, CINAHL Plus, EMBASE via OVID, and PubMed in May 2023. The first author then screened by title and abstract and conducted a full review of remaining articles. RESULTS: Eight studies investigating the influence of sleep and/or circadian rhythms on cognitive function in HD were found. In manifest HD, poorer sleep was associated with worse cognitive function. For behavioral 24-hour (circadian) rhythms, two studies indicated that later wake times correlated with poorer cognitive function. No reported studies in HD examined altered physiological 24-hour (circadian) rhythms and cognitive impairment. CONCLUSION: Some associations exist between poor sleep and cognitive dysfunction in manifest HD, yet whether these associations are present before clinical diagnosis is unknown. Whether circadian disturbances relate to cognitive impairment in HD also remains undetermined. To inform sleep and circadian interventions aimed at improving cognitive symptoms in HD, future research should include a range of disease stages, control for external factors, and utilize robust cognitive batteries targeted to the aspects of cognitive function known to be adversely affected in HD.

A Randomized Controlled Trial of Probiotics Targeting Gut Dysbiosis in Huntington's Disease.

BACKGROUND: Gastrointestinal symptoms are clinical features of Huntington's disease (HD), which adversely affect people's quality of life. We recently reported the first evidence of gut dysbiosis in HD gene expansion carriers (HDGECs). Here, we report on a randomized controlled clinical trial of a 6-week probiotic intervention in HDGECs. OBJECTIVE: The primary objective was to determine whether probiotics improved gut microbiome composition in terms of richness, evenness, structure, and diversity of functional pathways and enzymes. Exploratory objectives were to determine whether probiotic supplementation improved cognition, mood, and gastrointestinal symptoms. METHODS: Forty-one HDGECs, including 19 early manifest and 22 premanifest HDGECs were compared with 36 matched-healthy controls (HCs). Participants were randomly assigned probiotics or placebo and provided fecal samples at baseline and 6-week follow-up, which were sequenced using 16S-V3-V4 rRNA to characterize the gut microbiome. Participants completed a battery of cognitive tests and self-report questionnaires measuring mood and gastrointestinal symptoms. RESULTS: HDGECs had altered gut microbiome diversity when compared to HCs, indicating gut dysbiosis. Probiotic intervention did not ameliorate gut dysbiosis or have any effect on cognition, mood, or gastrointestinal symptoms. Gut microbiome differences between HDGECs and HCs were unchanged across time points, suggesting consistency of gut microbiome differences within groups. CONCLUSION: Despite the lack of probiotic effects in this trial, the potential utility of the gut as a therapeutic target in HD should continue to be explored given the clinical symptomology, gut dysbiosis, and positive results from probiotics and other gut interventions in similar neurodegenerative diseases.

Clinical associations of cognitive dysfunction in systemic lupus erythematosus.

OBJECTIVE: Cognitive dysfunction in SLE is common, but clinical risk factors are poorly understood. This study aims to explore the associations of cognitive dysfunction in SLE with disease activity, organ damage, biomarkers and medications. METHODS: We performed cross-sectional cognitive assessment using a conventional neuropsychological test battery, with normative values derived from demographically matched healthy subjects. Endpoints included two binary definitions of cognitive dysfunction and seven individual cognitive domain scores. Clinical parameters included disease activity (SLEDAI-2K) and organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We performed regression analyses to determine associations between clinical parameters and cognitive endpoints. RESULTS: 89 patients with SLE were studied, with median age of 45 and disease duration of 15 years. Organ damage was significantly associated with severe cognitive dysfunction (OR 1.49, CI 1.01-2.22) and worse cognitive test performance in three of the seven individual cognitive domains. In contrast, no significant associations were found between SLEDAI-2K at the time of cognitive assessment and any cognitive endpoints on multivariate analysis. Higher time-adjusted mean SLEDAI-2K was associated with better verbal memory scores but had no significant associations with other cognitive endpoints. The presence of anti-dsDNA antibodies and high IFN gene signature were negatively associated with severe cognitive dysfunction; there were no significant associations with the other autoantibodies studied or any medications. Substance use was significantly associated with lower psychomotor speed. Only 8% of patients who had cognitive dysfunction on testing had been recognised by clinicians on their SDI score. CONCLUSIONS: In SLE, cognitive dysfunction was positively associated with organ damage, but not associated with disease activity, and serological activity and high IFN signature were negatively associated. Cognitive dysfunction was poorly captured by clinicians. These findings have implications for preventative strategies addressing cognitive dysfunction in SLE.

Cognitive dysfunction in systemic lupus erythematosus: how do we advance our understanding?

Despite the high reported prevalence and burden of cognitive dysfunction in systemic lupus erythematosus (SLE), there is poor understanding of its aetiology, clinical assessment, and management. In part, this lack of understanding is due to conceptual disorganisation in the available literature. In this Review, we address key knowledge gaps in the nomenclature, assessment, and interpretation of cognitive dysfunction in SLE. We apply basic principles of neuropsychology and incorporate lessons from other disease states to recommend principles that can help researchers to design studies in SLE. Better understanding of the trajectory of cognitive dysfunction in SLE will help to inform therapeutic trials, including the appropriate selection of outcome measures to capture clinically meaningful responses.

Evaluation of the Montreal Cognitive Assessment as a screening tool for cognitive dysfunction in SLE.

OBJECTIVES: Cognitive dysfunction in SLE is common and associated with significant morbidity but is currently underdetected. Early detection requires the use of screening tests, as formal diagnostic cognitive testing is time-consuming. This study aims to evaluate the Montreal Cognitive Assessment (MoCA) as a screening tool for cognitive dysfunction in SLE. METHODS: Patients with SLE (n=95) and demographically matched healthy control participants (n=48) underwent cognitive testing using the 1-hour neuropsychiatric test battery recommended by the American College of Rheumatology for use in SLE and the MoCA. We used regression analyses to determine associations between MoCA and cognitive test scores. We assessed several MoCA cut-offs for predicting cognitive impairment in terms of sensitivity, specificity, positive predictive value and negative predictive value. Receiver operating curve analyses were used to determine the diagnostic accuracy of the MoCA cut-off thresholds. RESULTS: We found a significant correlation between MoCA score and 9 of the 10 cognitive endpoints studied (all p<0.001). Receiver operating curve analysis suggested that a MoCA cut-off of <27 had highest diagnostic accuracy across the cognitive impairment definitions (area under the curve 0.76-0.78). Using a screening cut-off of <28, the MoCA had sensitivity of 83%-94% and specificity of 46%-59%, depending on the impairment definition used. CONCLUSIONS: The MoCA correlates strongly with cognitive test results in SLE and has sufficient sensitivity for use as a screening tool with a cut-off of <28 as the optimal threshold. This tool can be incorporated into clinical practice for screening for cognitive dysfunction in SLE.

Greater time in bed and less physical activity associate with poorer cognitive functioning performance in Huntington's disease.

Objective: This study aimed to investigate how sleep and physical activity habits related to cognitive functioning, in naturalistic settings, in early Huntington's disease (HD). Method: Forty-two participants with the expanded HD repeat (20 manifest, 22 premanifest) and 29 healthy controls wore Fitbit One sleep and activity monitors for 7 days and 7 nights. They used a smartphone application to complete daily sleep and activity diaries, sleep and mood inventories, and a brief battery of cognitive tests, which were completed on Day 8 of the study. All data were collected in naturalistic home and community settings. Results: Amongst participants with the expanded HD repeat, greater time spent in bed, measured by Fitbit, was associated with poorer accuracy and response speed on a test of visual memory, whereas lower levels of physical activity, measured by Fitbit, were associated with poorer accuracy on a test involving a working memory component. Neither time in bed nor physical activity is associated with a test of psychomotor speed. Groups were mostly similar across a range of Fitbit and self-report measures of sleep and physical activity, although the Manifest-HD group spent more time in bed than the Premanifest-HD and Healthy Control groups and had better self-reported sleep quality and more self-reported time spent sitting than the Healthy Control group and the Premanifest-HD group, respectively. Conclusions: Sleep timing and physical activity relate to cognitive functioning in HD and may be important targets for management in behavioral intervention studies aimed at improving cognition in HD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Feasibility and initial validation of 'HD-Mobile', a smartphone application for remote self-administration of performance-based cognitive measures in Huntington's disease.

OBJECTIVE: Smartphone-based cognitive assessment measures allow efficient, rapid, and convenient collection of cognitive datasets. Establishment of feasibility and validity is essential for the widespread use of this approach. We describe a novel smartphone application (HD-Mobile) that includes three performance-based cognitive tasks with four key outcome measures, for use with Huntington's disease (HD) samples. We describe known groups and concurrent validity, test-retest reliability, sensitivity, and feasibility properties of the tasks. METHODS: Forty-two HD CAG-expanded participants (20 manifest, 22 premanifest) and 28 healthy controls completed HD-Mobile cognitive tasks three times across an 8-day period, on days 1, 4, and 8. A subsample of participants had pen-and-paper cognitive task data available from their most recent assessment from their participation in a separate observational longitudinal study, Enroll-HD. RESULTS: Manifest-HD participants performed worse than healthy controls for three of four HD-Mobile cognitive measures, and worse than premanifest-HD participants for two of four measures. We found robust test-retest reliability for manifest-HD participants (ICC = 0.71-0.96) and with some exceptions, in premanifest-HD (ICC = 0.52-0.96) and healthy controls (0.54-0.96). Correlations between HD-Mobile and selected Enroll-HD cognitive tasks were mostly medium to strong (r = 0.36-0.68) as were correlations between HD-Mobile cognitive tasks and measures of expected disease progression and motor symptoms for the HD CAG-expanded participants (r = - 0.34 to - 0.54). CONCLUSIONS: Results indicated robust known-groups, test-retest, concurrent validity, and sensitivity of HD-Mobile cognitive tasks. The study demonstrates the feasibility and utility of HD-Mobile for conducting convenient, frequent, and potentially ongoing assessment of HD samples without the need for in-person assessment.

Functional MRI (fMRI) human mapping for indicating hippocampal content-specific responsivity and laterality.

OBJECTIVE: Presurgical memory functional MRI (fMRI) mapping for temporal lobe epilepsy surgery is important because of the excision of structures in the temporal lobe (e.g., hippocampus) that are relevant for intact memory. Although the American Academy of Neurology recommends the use of fMRI for presurgical mapping of epilepsy of verbal and nonverbal memory to predict memory outcome, there are still no specific recommendations about which tests to use. In the current study, we evaluate the potential for clinical utility of two established neuropsychological tests of memory adapted into the fMRI setting. METHOD: We used the Verbal Paired Associates (VPA) for assessment of verbal memory and the Object Learning and Location (OLL) task for assessment of visuospatial memory. To confirm that these tasks engage the hippocampus, we examined their neural underpinning and patterns of laterality in 20 healthy volunteers (mean age = 26.35). RESULTS: During fMRI of the VPA task of verbal memory, we found a strong left-lateralized posterior hippocampal activation. Remembering the location of objects in the OLL task of visuospatial memory elicited right-lateralized hippocampal activation. CONCLUSIONS: These findings demonstrate the utility of the VPA and OLL tests to delineate domain-specific activity and laterality and, as such, may provide supportive evidence to strengthen links between presurgical neuropsychological assessment and memory fMRI mapping for epilepsy surgery. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Gut dysbiosis in Huntington's disease: associations among gut microbiota, cognitive performance and clinical outcomes.

Huntington's disease is characterized by a triad of motor, cognitive and psychiatric impairments, as well as unintended weight loss. Although much of the research has focused on cognitive, motor and psychiatric symptoms, the extent of peripheral pathology and the relationship between these factors, and the core symptoms of Huntington's disease, are relatively unknown. Gut microbiota are key modulators of communication between the brain and gut, and alterations in microbiota composition (dysbiosis) can negatively affect cognition, behaviour and affective function, and may be implicated in disease progression. Furthermore, gut dysbiosis was recently reported in Huntington's disease transgenic mice. Our main objective was to characterize the gut microbiome in people with Huntington's disease and determine whether the composition of gut microbiota are significantly related to clinical indicators of disease progression. We compared 42 Huntington's disease gene expansion carriers, including 19 people who were diagnosed with Huntington's disease (Total Functional Capacity > 6) and 23 in the premanifest stage, with 36 age- and gender-matched healthy controls. Participants were characterized clinically using a battery of cognitive tests and using results from 16S V3 to V4 rRNA sequencing of faecal samples to characterize the gut microbiome. For gut microbiome measures, we found significant differences in the microbial communities (beta diversity) based on unweighted UniFrac distance (P = 0.001), as well as significantly lower alpha diversity (species richness and evenness) between our combined Huntington's disease gene expansion carrier group and healthy controls (P = 0.001). We also found major shifts in the microbial community structure at Phylum and Family levels, and identified functional pathways and enzymes affected in our Huntington's disease gene expansion carrier group. Within the Huntington's disease gene expansion carrier group, we also discovered associations among gut bacteria, cognitive performance and clinical outcomes. Overall, our findings suggest an altered gut microbiome in Huntington's disease gene expansion carriers. These results highlight the importance of gut biomarkers and raise interesting questions regarding the role of the gut in Huntington's disease, and whether it may be a potential target for future therapeutic intervention.

Structural and functional correlates of unilateral mesial temporal lobe spatial memory impairment.

The aim of this study was to explore the effects of preoperative and postoperative lateralized mesial temporal damage on three measures of spatial learning: navigation, object location and plan drawing, and to determine the relationship between volumetry of the hippocampus and memory performance. Fifteen patients with well-characterized unilateral hippocampal sclerosis, 15 patients who had undergone unilateral anterior temporal lobectomy (ATL), and a comparison group consisting of 15 patients with idiopathic generalized epilepsy and 25 neurologically healthy participants explored a novel virtual environment. Volumetric analyses of both hippocampi were conducted on unilateral hippocampal sclerosis and idiopathic generalized epilepsy patients' T(1)-weighted magnetic resonance imaging scans. Performance of temporal lobe epilepsy (TLE) patients (either unilateral hippocampal sclerosis or anterior temporal lobectomy) on the different spatial memory variables, namely navigation, object location and plan drawing, was significantly worse relative to the comparison groups (either idiopathic generalized epilepsy or controls). Patients with right TLE did not differ from patients with left TLE on any of the spatial memory measures. An index of absolute hippocampal asymmetry did not correlate with any of the spatial memory measures. Together, our lesion and volumetry findings suggest that the domain of spatial memory is systematically related to the integrity of both right and left mesial temporal lobe, and is unlikely to be a strongly lateralized function. From the standpoint of cerebral organization (lateralization), the notion of material-specificity, which postulates that all components of verbal and spatial memory are lateralized in their entirety to the left and right hemispheres, respectively, requires modification. Instead it would appear that the notion of task-specificity is a more accurate description of patterns of lateralization of spatial memory.

Spatial memory in Huntington's disease: A comparative review of human and animal data.

To improve the translational predictability of treatment strategies for Huntington's disease (HD), sensitive and analogous cognitive outcomes are needed across HD animal models and humans. Spatial memory measures are promising candidates because they are based on 'visual' or 'non-verbal' cognition, and are commonly tested in both animals and humans. Here, we consider the suitability of spatial memory for strengthening translational links between animals and humans in HD research and clinical trials. We describe findings of spatial memory impairments in human HD and mouse models, including which aspects of spatial memory are most affected and at which time points in disease progression. We also describe the neural systems that underlie spatial memory and link spatial memory impairments to HD neuropathology, focussing on striatal and hippocampal systems. We provide a critical analysis of the literature in terms of the suitability of spatial memory for bridging the translational gap between species. Finally, we discuss possible neural mechanisms that might explain the spatial memory impairments seen in HD, and their relevance to potential treatments.