Accelerated atrophy in dopaminergic targets and medial temporo-parietal regions precedes the onset of delusions in patients with Alzheimer's disease.

People with Alzheimer's disease (AD) and delusions have worse quality of life and prognosis. However, early markers of delusions have not been identified yet. The present study investigated whether there are any detectable differences in grey matter (GM) volume and cognitive changes in the year before symptom onset between patients with AD who did and did not develop delusions. Two matched samples of AD patients, 63 who did (PT-D) and 63 who did not develop delusions (PT-ND) over 1 year, were identified from the Alzheimer's Disease Neuroimaging Initiative database. The Neuropsychiatric Inventory (NPI) was used to assess the presence of delusions. Sixty-three additional matched healthy controls (HC) were selected. Repeated-measures ANCOVA models were used to investigate group-by-time effects on the volume of selected GM regions of interest and on cognitive performance. No neurocognitive differences were observed between patient groups prior to symptom onset. Greater episodic memory decline and GM loss in bilateral caudate nuclei, medio-temporal and midline cingulo-parietal regions were found in the PT-D compared with the PT-ND group. A pattern of faster GM loss in brain areas typically affected by AD and in cortical and subcortical targets of dopaminergic pathways, paralleled by worsening of episodic memory and behavioural symptoms, may explain the emergence of delusions in patients with AD.

The neural signatures of psychoses in Alzheimer's disease: a neuroimaging genetics approach.

Psychoses in Alzheimer's disease (AD) are associated with worse prognosis. Genetic vulnerability for schizophrenia (SCZ) may drive AD-related psychoses, yet its impact on brain constituents is still unknown. This study aimed to investigate the association between polygenic risk scores (PRSs) for SCZ and psychotic experiences (PE) and grey matter (GM) volume in patients with AD with (AD-PS) and without (AD-NP) psychosis. Clinical, genetic and T1-weighted MRI data for 800 participants were extracted from the ADNI database: 203 healthy controls, 121 AD-PS and 476 AD-NP. PRSs were calculated using a Bayesian approach and analysed at ten p-value thresholds. Standard voxel-based morphometry was used to process MRI data. Logistic regression models including both PRSs for SCZ and PE, and an AD-PRS were used to predict psychosis in AD. Associations between PRSs and GM volume were investigated in the whole sample and the three groups independently. Only the AD-PRS predicted psychosis in AD. Inconsistent associations between the SCZ-PRS and PE-PRS and GM volumes were found across groups. The SCZ-PRS was negatively associated with medio-temporal/subcortical volumes and positively with medial/orbitofrontal volumes in the AD-PS group. Only medio-temporal areas were more atrophic in the AD-PS group, while there was no significant correlation between psychosis severity and GM volume. Although not associated with psychoses, the SCZ-PRS was correlated with smaller medio-temporal and larger orbitofrontal volumes in AD-PS. Similar alterations have also been observed in SCZ patients. This finding suggest a possible disconnection between these regions associated with psychoses in more advanced AD.

The impact of social isolation due to the COVID-19 pandemic on patients with dementia and caregivers.

OBJECTIVE: Social distancing to limit COVID-19 transmission has led to extensive lifestyle changes, including for people with dementia (PWD). The aim of this study, therefore, was to assess the impact of lockdown on the mental health of PWD and their carers. METHODS: Forty-five carers of PWD completed a telephone interview during the baseline assessment of the SOLITUDE study to gather information on life conditions and changes in symptoms of PWD during lockdown. Associations between changes in symptoms of PWD and carers' concerns and mental health were investigated. RESULTS: About 44% of carers experienced anxiety and irritability and reported changes in behavioural and cognitive symptoms in PWD. These changes were associated with worse carers' mental health and concerns about faster disease progression (χ2 = 13.542, p < 0.001). CONCLUSION: COVID-19-related social isolation has had a negative impact on patients' and carers' mental health. Potential long-term neurocognitive consequences require further investigation.

White Matter Hyperintensity Load Modulates Brain Morphometry and Brain Connectivity in Healthy Adults: A Neuroplastic Mechanism?

White matter hyperintensities (WMHs) are acquired lesions that accumulate and disrupt neuron-to-neuron connectivity. We tested the associations between WMH load and (1) regional grey matter volumes and (2) functional connectivity of resting-state networks, in a sample of 51 healthy adults. Specifically, we focused on the positive associations (more damage, more volume/connectivity) to investigate a potential route of adaptive plasticity. WMHs were quantified with an automated procedure. Voxel-based morphometry was carried out to model grey matter. An independent component analysis was run to extract the anterior and posterior default-mode network, the salience network, the left and right frontoparietal networks, and the visual network. Each model was corrected for age, global levels of atrophy, and indices of brain and cognitive reserve. Positive associations were found with morphometry and functional connectivity of the anterior default-mode network and salience network. Within the anterior default-mode network, an association was found in the left mediotemporal-limbic complex. Within the salience network, an association was found in the right parietal cortex. The findings support the suggestion that, even in the absence of overt disease, the brain actuates a compensatory (neuroplastic) response to the accumulation of WMH, leading to increases in regional grey matter and modified functional connectivity.

Minority Stress and Psychosocial Influences on Cognitive Performance in Sexual Minority Older Adults.

Background and Objectives: Sexual minorities experience health inequalities, but little is known about differences in neurocognitive health between heterosexual and sexual minority older adults and potential risk factors. To investigate minority stress, depression, and marital status as risk factors for worse cognitive performance in sexual minority older adults. Research Design and Methods: A total of 336 sexual minorities and 5,561 heterosexual participants aged 50+, noninstitutionalized, and free from neurodegenerative diseases from Wave 6 of the English Longitudinal Study of Ageing were included. Cognitive performance (i.e., temporal orientation, episodic memory, and fluid intelligence) of sexual minority and heterosexual older adults was compared using general linear models including age, sex, and education as covariates. The differential impact of minority stress, depressive symptoms, and marital status on cognition in the 2 groups were also tested. Analyses were weighted for sampling probability and differential nonresponse. Results: Sexual minority participants were more likely to report minority stress and to be single but had better episodic memory than heterosexual participants. Depression and being single were associated with worse cognitive performance in both groups. However, minority stress was negatively associated (B = -2.116, p = .016) with fluid intelligence in the sexual minority group only. Discussion and Implications: Better memory in sexual minority participants and a negative effect of risk factors on cognition are in line with previous studies. However, this study provides the first evidence of a potential negative impact of minority stress on cognitive performance in sexual minorities. Further investigations are needed to assess minority stress more in detail and clarify its potential mechanisms of action on cognition in sexual minorities.

Associations between Neuropsychiatric Symptoms and Alzheimer's Disease Biomarkers in People with Mild Cognitive Impairment.

BACKGROUND: Neuropsychiatric symptoms (NPS) are associated with faster decline in mild cognitive impairment (MCI). This study aimed to investigate the association between NPS severity and Alzheimer's disease (AD) biomarkers, i.e., amyloid-ß (Aß), phosphorylated tau protein (p-tau) and hippocampal volume ratio (HR), to characterise in more detail MCI patients with a poor prognosis. METHODS: A total of 506 individuals with MCI and 99 cognitively unimpaired older adults were selected from the ADNI dataset. The patients were divided into three different groups based on their NPI-Q total scores: no NPS (n = 198), mild NPS (n = 160) and severe NPS (n = 148). Regression models were used to assess the association between the severity of NPS and each biomarker level and positivity status. RESULTS: Cerebrospinal fluid Aß levels were positively associated with older age and lower MMSE scores, while higher p-tau levels were associated with female sex and lower MMSE scores. Only patients with severe NPS had a lower HR (ß = -0.18, p = 0.050), i.e., more pronounced medio-temporal atrophy, than those without NPS. DISCUSSION: Only HR was associated with the presence of NPS, partially in line with previous evidence showing that severe NPS may be explained primarily by greater grey matter loss. Future longitudinal studies will be needed to ascertain the relevance of this finding.

The effect of physical activity on white matter integrity in aging and prodromal to mild Alzheimer's disease with vascular comorbidity.

Background: Physical activity is a modifiable lifestyle factor that has been previously associated with reduced vascular burden and reduced risk of dementia. Objectives: This study tested whether physical activity (i.e., being inactive vs. active) contributed to preservation of white matter microstructure in healthy aging controls and patients in prodromal to mild Alzheimer's disease with low/high vascular burden. Materials: A total of 213 participants were recruited from memory clinics. They were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Diffusion-weighted images were acquired for all participants and pre-processed based on a standard protocol. Methods: A factorial design using voxel-wise tract-based spatial statistics (TBSS) was adopted, with 5,000 permutations and threshold-free cluster enhancement (TFCE), to identify significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD), and radial diffusivity (RD). Results: Clusters of higher FA and lower AxD, MD, and RD values were found for physically active compared with inactive participants that were widespread covering mainly association and projection tracts but also some commissural tracts. A three-way Group × Physical Activity × Vascular Burden interaction effect was found for FA mostly in a variety of projection tracts with a right predominance, and some commissural and association tracts. Post hoc analyses revealed higher FA in patients with high vascular burden who were physically active compared with those patients with high vascular burden who were inactive mainly in projection and association/limbic tracts with a right predominance. Additionally, higher FA was observed in physically active patients with high vascular burden as compared with physically inactive controls with high vascular burden, mainly in bilateral projection fibers and cerebellar regions. Conclusion: Voxel-wise TBSS analysis revealed better preservation of white matter microstructure that was prominent in the high-risk group such as the patients with high vascular burden, specifically those who were physically active. The beneficial effects of physical activity on white matter microstructure were not observed in the controls.

A Multimodal Neuroimaging and Neuropsychological Study of Visual Hallucinations in Alzheimer's Disease.

BACKGROUND: Hallucinations in Alzheimer's disease (AD) have been linked to more severe cognitive and functional decline. However, research on visual hallucinations (VH), the most common type of hallucinations in AD, is limited. OBJECTIVE: To investigate the cognitive and cerebral macrostructural and metabolic features associated with VH in AD. METHODS: Twenty-four AD patients with VH, 24 with no VH (NVH), and 24 cognitively normal (CN) matched controls were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Differences in regional gray matter (GM) volumes and cognitive performance were investigated with whole brain voxel-based morphometry analyses of MRI structural brain scans, and analyses of neuropsychological tests. Glucose metabolic changes were explored in a sub-sample of patients who had FDG-PET scans available. RESULTS: More severe visuoconstructive and attentional deficits were found in AD VH compared with NVH. GM atrophy and hypometabolism were detected in occipital and temporal areas in VH patients in comparison with CN. On the other hand, NVH patients had atrophy and hypometabolism mainly in temporal areas. No differences in GM volume and glucose metabolism were found in the direct comparison between AD VH and NVH. CONCLUSION: In addition to the pattern of brain abnormalities typical of AD, occipital alterations were observed in patients with VH compared with CN. More severe visuoconstructive and attentional deficits were found in AD VH when directly compared with NVH, and might contribute to the emergence of VH in AD.

Macrostructural and Microstructural White Matter Alterations Are Associated with Apathy across the Clinical Alzheimer's Disease Spectrum.

Apathy is the commonest neuropsychiatric symptom in Alzheimer's disease (AD). Previous findings suggest that apathy is caused by a communication breakdown between functional neural networks involved in motivational-affective processing. This study investigated the relationship between white matter (WM) damage and apathy in AD. Sixty-one patients with apathy (AP-PT) and 61 without apathy (NA-PT) were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and matched for cognitive status, age and education. Sixty-one cognitively unimpaired (CU) participants were also included as controls. Data on cognitive performance, cerebrospinal fluid biomarkers, brain/WM hyperintensity volumes and diffusion tensor imaging indices were compared across groups. No neurocognitive differences were found between patient groups, but the AP-PT group had more severe neuropsychiatric symptoms. Compared with CU participants, only apathetic patients had deficits on the Clock Drawing Test. AP-PT had increased WM damage, both macrostructurally, i.e., larger WM hyperintensity volume, and microstructurally, i.e., increased radial/axial diffusivity and reduced fractional anisotropy in the fornix, cingulum, anterior thalamic radiations and superior longitudinal and uncinate fasciculi. AP-PT showed signs of extensive WM damage, especially in associative tracts in the frontal lobes, fornix and cingulum. Disruption in structural connectivity might affect crucial functional inter-network communication, resulting in motivational deficits and worse cognitive decline.

Divergent patterns of cognitive deficits and structural brain alterations between older adults in mixed-sex and same-sex relationships.

Background: Sexual minority (SM) older adults experience mental health disparities. Psychiatric disorders and neuropsychiatric symptoms (NPS) are risk factors for cognitive decline. Although older people in same-sex (SSR) compared to mixed-sex relationships (MSR) perform more poorly on cognitive screening tests, prior studies found no differences in rates of dementia diagnosis or neuropsychological profiles. We sought to explore the role of NPS on neurocognitive outcomes for SM populations. We compared cognitive performance and structural brain parameters of older adults in SSR and MSR. Methods: Data were originally collected at Alzheimer's Disease Research Centers (ADRCs). Inclusion criteria were: age of 55+ years, a study partner identified as a spouse/partner, and availability of T1-MRI brain volumes/thickness. Participants were labeled as either SSR or MSR based on their/their co-participant's reported sex. We identified 1,073 participants (1,037 MSR-555 cognitively unimpaired [CU]; 36 SSR-23 CU) with structural MRI data, Mini-Mental State Exam (MMSE), and Neuropsychiatric Inventory Questionnaire (NPI-Q) scores. A subset of the overall sample completed comprehensive neuropsychological assessment (n = 939; 908 MSR-494 CU; 31 SSR-22 CU). Covariates included in statistical models were age, sex, education, total intracranial volume, and apolipoprotein E genotype. Results: Multivariate general linear models showed significant diagnosis-by-relationship interaction effects on the left parahippocampal gyrus volume. After stratification by relationship group, only cognitively impaired (CI) MSR had significantly smaller left parahippocampal volumes than MSR-CU. The SSR group showed better episodic memory performance. Severity of neuropsychiatric symptoms was negatively associated with volume/thickness of bilateral fronto-temporal areas and with MMSE scores, predominantly in the MSR group. Conclusion: In our study, MSR participants presented with a more compromised cognitive profile than SSR participants. MSR-CI participants showed significantly smaller left medio-temporal volumes, a neural signature of AD. Neuropsychiatric symptoms predicted smaller fronto-temporal volumes in the MSR more consistently than in the SSR group. These findings may be due to unexplored protective factors against cognitive decline in SM elders. Indeed, social support has been proposed as a protective factor warranting future investigation.

The Impact of Social Isolation Due to COVID-19 on Symptom Progression in People With Dementia: Findings of the SOLITUDE Study.

Background: People with dementia (PWD) are vulnerable to abrupt changes to daily routines. The lockdown enforced on the 23rd of March 2020 in the UK to contain the expansion of the COVID-19 pandemic limited opportunities for PWD to access healthcare services and socialise. The SOLITUDE study explored the potential long-term effects of lockdown on PWD's symptoms and carers' burden. Methods: Forty-five carers and 36 PWD completed a telephone-based assessment at recruitment (T0) and after 3 (T1) and 6 months (T2). PWD completed measures validated for telephonic evaluations of cognition and depression. Carers completed questionnaires on their burden and on PWD's health and answered a customised interview on symptom changes observed in the initial months of lockdown. Longitudinal changes were investigated for all outcome variables with repeated-measures models. Additional post hoc multiple regression analyses were carried out to investigate whether several objective factors (i.e., demographics and time under social restrictions) and carer-reported symptom changes observed following lockdown before T0 were associated with all outcomes at T0. Results: No significant changes were observed in any outcomes over the 6 months of observations. However, post hoc analyses showed that the length of social isolation before T0 was negatively correlated with episodic and semantic memory performance at T0. Carers reporting worsening of neuropsychiatric symptoms and faster disease progression in PWD also reported higher burden. Moreover, carer-reported worsening of cognitive symptoms was associated with poorer semantic memory at T0. Conclusion: PWD's symptoms and carers' burden remained stable over 6 months of observation. However, the amount of time spent under social restrictions before T0 appears to have had a significant detrimental impact on cognitive performance of patients. In fact, carer-reported cognitive decline during social isolation was consistent with the finding of poorer semantic memory, a domain sensitive to progression in Alzheimer's disease. Therefore, the initial stricter period of social isolation had greater detrimental impact on patients and their carers, followed then by a plateau. Future interventions may be designed to maintain an optimal level of social and cognitive engagement for PWD in challenging times, to prevent abrupt worsening of symptoms and associated detrimental consequences on patients' carers.

Functional Neural Architecture Supporting Highly Superior Autobiographical Memory.

Background: The neural mechanisms of highly superior autobiographical memory (HSAM) are poorly understood. To shed light on the functional magnetic resonance imaging (fMRI)-informed neurobiology of this condition, in this study we characterize for the first time the neurofunctional architecture of a 20-year-old individual (B.B.) with HSAM and no concurrent neurological/psychiatric or other clinical conditions. Materials and Methods: Relying on t-test inferential models comparing a single observation with a control group, we processed B.B.'s resting-state fMRI signal and compared it with the neurofunctional architecture of 16 young adults with normal autobiographical memory. Specifically, we analyzed large-scale brain networks, region-to-region functional connectivity, and connectivity indices informed by graph theory. Results: B.B. showed higher expression of large-scale and region-to-region connectivity, larger segregation of the pallidum and enhanced centrality of the temporal pole, orbitofrontal cortex and cerebellar lobule IX. Conclusion: These findings indicate that HSAM is associated with increased expression of neural pathways that support memory encoding, retrieval, and elaboration, but also with reduced expression of patterns typically involved in information control and metacognition, the use of which would be minimized thanks to automatic and accurate memory processing.

Heterogeneity in Regional Damage Detected by Neuroimaging and Neuropathological Studies in Older Adults With COVID-19: A Cognitive-Neuroscience Systematic Review to Inform the Long-Term Impact of the Virus on Neurocognitive Trajectories.

Background: Other than its direct impact on cardiopulmonary health, Coronavirus Disease 2019 (COVID-19) infection affects additional body systems, especially in older adults. Several studies have reported acute neurological symptoms that present at onset or develop during hospitalisation, with associated neural injuries. Whilst the acute neurological phase is widely documented, the long-term consequences of COVID-19 infection on neurocognitive functioning remain unknown. Although an evidence-based framework describing the disease chronic phase is premature, it is important to lay the foundations for future data-driven models. This systematic review aimed at summarising the literature on neuroimaging and neuropathological findings in older over-60 patients with COVID-19 following a cognitive neuroscientific perspective, to clarify the most vulnerable brain areas and speculate on the possible cognitive consequences. Methods: PubMed and Web of Science databases were searched to identify relevant manuscripts published between 1st March 2020 and 31th December 2020. Outputs were screened and selected by two assessors. Relevant studies not detected by literature search were added manually. Results: Ninety studies, mainly single cases and case series, were included. Several neuroimaging and neuropathological findings in older patients with COVID-19 emerged from these studies, with cerebrovascular damage having a prominent role. Abnormalities (hyperintensities, hypoperfusion, inflammation, and cellular damage) were reported in most brain areas. The most consistent cross-aetiology findings were in white matter, brainstem and fronto-temporal areas. Viral DNA was detected mainly in olfactory, orbitofrontal and brainstem areas. Conclusion: Studies on COVID-19 related neural damage are rich and diverse, but limited to description of hospitalised patients with fatal outcome (i.e., in neuropathological studies) or severe symptoms (i.e., in neuroimaging studies). The damage seen in this population indicates acute and largely irreversible dysfunction to neural regions involved in major functional networks that support normal cognitive and behavioural functioning. It is still unknown whether the long-term impact of the virus will be limited to chronic evolution of acute events, whether sub-clinical pathological processes will be exacerbated or whether novel mechanisms will emerge. Based on current literature, future theoretical frameworks describing the long-term impact of COVID-19 infection on mental abilities will have to factor in major trends of aetiological and topographic heterogeneity.

A network-based cognitive training induces cognitive improvements and neuroplastic changes in patients with relapsing-remitting multiple sclerosis: an exploratory case-control study.

Cognitive impairments are commonly observed in patients with multiple sclerosis and are associated with lower levels of quality of life. No consensus has been reached on how to tackle effectively cognitive decline in this clinical population non-pharmacologically. This exploratory case-control study aims to investigate the effectiveness of a hypothesis-based cognitive training designed to target multiple domains by promoting the synchronous co-activation of different brain areas and thereby improve cognition and induce changes in functional connectivity in patients with relapsing-remitting multiple sclerosis. Forty-five patients (36 females and 9 males, mean age 44.62 ± 8.80 years) with clinically stable relapsing-remitting multiple sclerosis were assigned to either a standard cognitive training or to control groups (sham training and non-active control). The standard training included twenty sessions of computerized exercises involving various cognitive functions supported by distinct brain networks. The sham training was a modified version of the standard training that comprised the same exercises and number of sessions but with increased processing speed load. The non-active control group received no cognitive training. All patients underwent comprehensive neuropsychological and magnetic resonance imaging assessments at baseline and after 5 weeks. Cognitive and resting-state magnetic resonance imaging data were analyzed using repeated measures models. At reassessment, the standard training group showed significant cognitive improvements compared to both control groups in memory tasks not specifically targeted by the training: the Buschke Selective Reminding Test and the Semantic Fluency test. The standard training group showed reductions in functional connectivity of the salience network, in the anterior cingulate cortex, associated with improvements on the Buschke Selective Reminding Test. No changes were observed in the sham training group. These findings suggest that multi-domain training that stimulates multiple brain areas synchronously may improve cognition in people with relapsing-remitting multiple sclerosis if sufficient time to process training material is allowed. The associated reduction in functional connectivity of the salience network suggests that training-induced neuroplastic functional reorganization may be the mechanism supporting performance gains. This study was approved by the Regional Ethics Committee of Yorkshire and Humber (approval No. 12/YH/0474) on November 20, 2013.

Modulatory effects of cognitive exertion on regional functional connectivity of the salience network in women with ME/CFS: A pilot study.

BACKGROUND: A common symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM). Various brain abnormalities have been observed in patients with ME/CFS, especially in insular and limbic areas, but their link with ME/CFS symptoms is still unclear. This pilot study aimed at investigating the association between PEM in ME/CFS and changes in functional connectivity (FC) of two main networks: the salience network (SN) and the default-mode network (DMN). METHODS: A total of 16 women, 6 with and 10 without ME/CFS, underwent clinical and MRI assessment before and after cognitive exertion. Resting-state FC maps of 7 seeds (3 for the SN and 4 for the DMN) and clinical measures of fatigue, pain and cognition were analysed with repeated-measure models. FC-symptom change associations were also investigated. RESULTS: Exertion induced increases in fatigue and pain in patients with ME/CFS compared to the control group, while no changes were found in cognitive performance. At baseline, patients showed altered FC between some DMN seeds and frontal areas and stronger FC between all SN seeds and left temporal areas and the medulla. Significantly higher FC increases in patients than in controls were found only between the right insular seed and frontal and subcortical areas; these increases correlated with worsening of symptoms. CONCLUSIONS: Cognitive exertion can induce worsening of ME/CFS-related symptoms. These changes were here associated with strengthening of FC of the right insula with areas involved in reward processing and cognitive control.

A Comparison of Neurocognitive Decline in Older Adults in Same-Sex and Opposite-Sex Relationships.

BACKGROUND: Individuals from sexual minorities experience health inequalities that have detrimental impacts on their health, especially in the elderly, by exacerbating care needs and symptoms of chronic conditions such as Alzheimer's disease (AD). Neurocognitive decline due to AD in the sexual minority population remains under-investigated. However, being in a relationship may mitigate the risk of experiencing cognitive impairment. OBJECTIVE: The aim of this study was to investigate whether cognitive decline and brain atrophy may differ in people from sexual minorities. METHODS: Clinical data for this study were selected from the National Alzheimer's Coordinating Center's Uniform Data Set and structural MRI data collected across 14 Alzheimer's Disease Centers. Eighty participants including 20 patients with AD and 20 healthy controls (HC) in same-sex relationships were identified and matched to groups of participants (20 AD and 20 HC) in opposite-sex relationships. The effects of diagnosis and relationship were investigated on all measures. RESULTS: No diagnosis-by-relationship interactions were found on any variable. However, post hoc analyses revealed that the opposite-sex group had grey matter atrophy mainly in medio-temporal areas. In the same-sex group, atrophy also extended to pre-frontal and cingulate areas. The severity of neuropsychiatric symptoms correlated with volume of pre-frontal and insular/temporal areas only in the same-sex group. CONCLUSION: Neurocognitive decline due to AD may express similarly across individuals, independently of relationship type, thus suggesting a protective role of relational status. However, the same-sex group appeared to be more likely to experience at least one neuropsychiatric symptom and to have atrophy extending to fronto-limbic areas.

The Impact of COVID-19 Infection and Enforced Prolonged Social Isolation on Neuropsychiatric Symptoms in Older Adults With and Without Dementia: A Review.

Background: The sudden and drastic changes due to the Coronavirus Disease 19 (COVID-19) pandemic have impacted people's physical and mental health. Clinically-vulnerable older people are more susceptible to severe effects either directly by the COVID-19 infection or indirectly due to stringent social isolation measures. Social isolation and loneliness negatively impact mental health in older adults and may predispose to cognitive decline. People with cognitive impairments may also be at high risk of worsening cognitive and mental health due to the current pandemic. This review provides a summary of the recent literature on the consequences of COVID-19, due to either viral infection or social isolation, on neuropsychiatric symptoms in older adults with and without dementia. Methods: A search was conducted in PubMed and Web of Science to identify all relevant papers published up to the 7th July 2020. Two independent assessors screened and selected the papers suitable for inclusion. Additional suitable papers not detected by literature search were manually added. Results: Fifteen articles were included: 8 focussed on the psychiatric symptoms caused by the COVID-19 infection and 7 investigated the impact of social isolation on older adults' neuropsychiatric symptoms. Four studies included older adults without dementia and 11 included patients with cognitive impairment mainly due to Alzheimer's disease. All studies found that different neuropsychiatric symptoms emerged and/or worsened in older adults with and without dementia. These changes were observed as the consequence of both COVID-19 infection and of the enforced prolonged conditions of social isolation. Cases were reported of viral infection manifesting with delirium at onset in the absence of other symptoms. Delirium, agitation and apathy were the symptoms most commonly detected, especially in people with dementia. Conclusion: The available evidence suggests that the COVID-19 pandemic has a wide negative impact on the mental well-being of older adults with and without dementia. Viral infection and the consequent social isolation to limit its spreading have a range of neuropsychiatric consequences. Larger and more robustly designed studies are needed to clarify such effects and to assess the long-term implications for the mental health of older adults, and to test possible mitigating strategies.

The Association between Polygenic Hazard and Markers of Alzheimer's Disease Following Stratification for APOE Genotype.

BACKGROUND: Research indicates that polygenic indices of risk of Alzheimer's disease are linked to clinical profiles. OBJECTIVE: Given the "genetic centrality" of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers. METHODS: A polygenic hazard score (PHS) was extracted from 784 non-demented participants recruited in the Alzheimer's Disease Neuroimaging Initiative and stratified by APOE ε4 status. Datasets were split into sub-cohorts defined by clinical (unimpaired/MCI) and amyloid status (Aß+/Aß-). Linear models were devised in each sub-cohort and for each APOE-ε4 status to test the association between PHS and memory, executive functioning and grey-matter volumetric maps. RESULTS: PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aß+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 Aß+ participants. CONCLUSION: The link between polygenic hazard and neurocognitive variables varies depending on APOE-ε4 allele status. This suggests that clinical phenotypes might be influenced by complex genetic interactions.

Right fronto-parietal white matter disruption contributes to speech impairments in amyotrophic lateral sclerosis.

INTRODUCTION: Non-linguistic properties of speech are widely heterogeneous and require complex neurological integration. The association between white matter integrity and the severity of dysarthria was investigated in a group of patients diagnosed with amyotrophic lateral sclerosis (ALS). METHODS: Thirty-six patients diagnosed with amyotrophic lateral sclerosis completed a magnetic resonance imaging protocol inclusive of diffusion-weighted images. A clinical assessment of pneumo-phono-articulatory abilities was conducted for each patient, and a composite score of residual speech capacity was calculated. Tract-Based Spatial Statistics was carried out to model the potential association between residual speech capacity and microstructural properties of white matter (fractional anisotropy, mean and radial diffusivity). RESULTS: A significant negative association was found between residual speech capacity and mean diffusivity in a large white matter cluster located in frontal, parietal and right temporal regions. These subcortical areas were characterised by pathological microstructural disruption, as revealed by post hoc analyses. CONCLUSIONS: Non-linguistic aspects of speech are associated with microstructural integrity of frontal, parietal and right temporal white matter in amyotrophic lateral sclerosis. Such mapping is consistent with the centres responsible of volitional control of speech and sensory feedback during non-linguistic speech production.

Understanding the effect of cognitive/brain reserve and depression on regional atrophy in early Alzheimer's disease.

Introduction: Depression in patients with mild cognitive impairment (MCI) and dementia of the Alzheimer's type (AD) is associated with worse prognosis. Indeed, depressed MCI patients have worse cognitive performance and greater loss of gray-matter volume in several brain areas. To date, knowledge of the factors that can mitigate this detrimental effect is still limited. The aim of the present study was to understand in what way cognitive reserve/brain reserve and depression interact and are linked to regional atrophy in early stage AD. Methods: Depression was evaluated with the Patient Health Questionnaire-9 in 90 patients with early AD, and a cutoff of ≥ 5 was used to separate depressed (n = 44) from non-depressed (n = 46) patients. Each group was further stratified into high/low cognitive reserve/brain reserve. Cognitive reserve was calculated using years of education as proxy, while normalized parenchymal volumes were used to estimate brain reserve. Voxel-based morphometry was carried out to extract and analyze gray-matter maps. 2 × 2 ANCOVAs were run to test the effect of the reserve-by-depression interaction on gray matter. Age and hippocampal ratio were used as covariates. Composite indices of major cognitive domains were also analyzed with comparable models. Results: No reserve-by-depression interaction was found in the analytical models of gray matter. Depression was associated with less gray matter volume in the cerebellum and parahippocampal gyrus. The brain reserve-by-depression interaction was a significant predictor of executive functioning. Among those with high brain reserve, depressed patients had poorer executive skills. No significant results were found in association with cognitive reserve. Conclusion: These findings suggest that brain reserve may modulate the association between neurodegeneration and depression in patients with MCI and dementia of the AD type, influencing in particular executive functioning.