BACKGROUND:The prodromal phase of Dementia with Lewy bodies (DLB) remains unexplored and poorly defined. This systematic review scrutinised studies on the earliest cognitive DLB deficits, focusing on the most useful neuropsychological tests. METHODS:From an initial pool of 2307 articles, 37 articles met inclusion criteria including either a prodromal DLB population or DLB cohorts comprehensive of individuals in prodromal or Mild Cognitive Impairment (MCI) due to Lewy Bodies pathology. These studies included comparisons with healthy controls, MCI due to Alzheimer's Disease (MCI-AD), or other aetiologies, and patients with established dementia. RESULTS:Mild impairments were found in attention, executive functions, visual perception, and working memory in prodromal DLB patients. Prodromal DLB exhibited worse performance in memory and language than healthy controls, while showing better memory but worse performance in visual perception, attention, and executive tasks than MCI-AD. Comparisons in some articles with MCI of other aetiologies confirmed the distinctiveness for prodromal DLB of this pattern of impairment. The most used tests to detect prodromal DLB included the Frontal Assessment Battery (FAB), Digit Symbol Substitution Test (DSST), Stroop test, AX continuous performance test (AX-CPT), digit span backward, Rey-Osterrieth Complex Figure copy, pareidolia test, and Visual Object and Space Perception battery (VOSP). CONCLUSIONS:Prodromal DLB can be detected using test batteries focused on specific cognitive domains and facilitating early diagnosis. It is possible to standardise a targeted test battery centred on specific visuoperceptual and attention domains for early detection of subtle cognitive decline due to Lewy body pathology.

Category Fluency (CF) “item-level” scoring methodologies identify neurocognitive processes that are distinct from those of standard quantitative scoring. One of these accounts for words’ serial recall order (SRO) and calculates the correlation between SRO and item-level complexity to operationalise the tendency to name increasingly complex words. We hypothesised this tendency would be altered in individuals with amnestic mild cognitive impairment (aMCI), to reflect lexical-semantic organisational decline resulting from potential functional alterations of perirhinal cortex. We expected aMCI individuals to show higher correlational indices than people with no objective cognitive decline (NOCD) due to these trends being more influenced by word count than overall complexity.Sixty aMCI and 54 NOCD individuals, recruited by the TREDEM initiative and representative of the North-East Italian population were administered a 1-min “animals” CF. Four complexity features were scored: frequency, age-of-acquisition, typicality and graphemic length. Individual z-converted correlation coefficients were calculated between SRO and complexity. The two groups were then compared via uncorrected t-tests, age- and education-corrected ANCOVAs, and further ANCOVAs also correcting for quantitative CF scores.aMCI individuals named fewer words, and words of lower and more variable complexity. They also showed a significantly stronger “SRO-graphemic length” correlation. This emerged from the uncorrected models and from the first set of ANCOVAs.Significant differences in lexical-semantic organisation exist in aMCI. Length is a diagnostically relevant feature of Italian words generated as part of CF. In line with cross-linguistic generalisability of findings, potential mechanisms differentiating phonological and orthographic length in languages with transparent/opaque orthographies are discussed.

Functional gradients offer a novel, synthetic and interpretable view of functional connectivity. By integrating gradients, graph theory, morpho-volumetric indices, amyloid status, and regional tau burden, we aim to understand how cognitive decline relates to functional and structural brain changes. We analyzed 279 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database with available functional, structural, and proteomic data at baseline and at 2-year follow-up, alongside detailed assessments of verbal memory abilities (encoding, retrieval and recall). Results at baseline revealed distinct patterns based on amyloid status and clinical severity. In individuals with positive amyloid status, increased functional dispersion of the Default Mode Network (DMN) correlated with poorer memory, while in individuals with negative status higher dispersion was associated with better performance. Notably, middle temporal regions exhibited connectivity profiles opposite to other DMN areas. We also observed that regions where gradients’ dispersion predicted impaired memory performance showed preserved structural integrity but had a more widespread connectivity profile. Baseline dispersion predicted future memory decline, showing consistent patterns across positive and negative amyloid groups—higher dispersion was linked to faster memory decline, except in tau-rich regions like the temporal cortex, where it was advantageous. Furthermore, higher dispersion was associated with future tau buildup and morphological alterations. This study extends a previous investigation and evaluates the utility of a multimodal framework in tracking disrupted DMN activity as an early marker of reduced coherence in communication among brain regions, possibly having a predictive value for future progression of cognitive decline.

Background: Sexual minorities experience several health disparities. However, risk/protective factors relevant to cognitive health of sexual minority older adults (SMOAs) have not been fully investigated. The aim of this study was to quantify the impact of several psychosocial factors on both subjective and objective cognitive health in SMOAs. Methods: Thirty-nine cognitively unimpaired SMOAs and 30 heterosexual older adults (HOAs) completed an online survey to provide information on psychosocial risks (i.e., depression, anxiety, general stress), subjective cognitive decline (SCD), beliefs about their own memory and dementia worries. SMOAs also completed questionnaires on minority stress and outness. Twenty-seven SMOAs and 24 HOAs underwent a comprehensive neuropsychological assessment. General linear models were used to assess the relationship between psychosocial risks and cognitive health and interactions between sexual orientation and risk factors. Associations between minority stress, outness and cognitive health were assessed in SMOAs only. Results: SMOAs reported worse mental and subjective cognitive health than HOAs, but similar cognitive performance. Worse depression explained more negative beliefs about memory in SMOAs than HOAs. Anxiety and general stress were associated with worse attention/processing speed performance in SMOAs only. Minority stress was associated with higher risk of SCD for language and more negative beliefs about memory, while higher outness levels were associated with better short-term memory. Conclusions: Psychosocial risks affect cognitive health more severely in SMOAs than HOAs. Minority stress affects subjective cognitive health of SMOAs, while outness may provide cognitive resilience. Further investigations are needed to devise prevention strategies aimed at preserving cognitive health in SMOAs.

IntroductionPatients with Dementia with Lewy Bodies (DLB) typically experience attentional deficits. Understanding these deficits and the underlying neural correlates is crucial as sustained attention supports higher level cognitive functions. The objective of this study was to investigate the patterns of brain connectivity during a functional magnetic resonance imaging (fMRI) sustained attention task in a DLB group compared with healthy controls (HC).MethodsIn this study, 30 DLB patients and 25 HC underwent a comprehensive neuropsychological assessment and a brain 3T MRI protocol that included a high-resolution structural sequence (T1-w 3D MPRAGE) and a task-based fMRI study using an auditory Psychomotor Vigilance Task (PVT).ResultsDLB patients performed worse in neuropsychological tests mainly related to the visuospatial domain and had poorer performance than HC on sustained attention (i.e., PVT) in terms of lapses and longer response times. Moreover, during the PVT, the DLB group exhibited significantly lower activation in the precuneus, intracalcarine cortex, angular gyrus and cuneus, regions implicated in sustained attention.DiscussionOverall, the identification of a distinct pattern of brain activity related to attention impairment in DLB patients offers opportunities for the development of tailored cognitive stimulation treatments.

Iron overload has been implicated in the pathology of several neurodegenerative diseases, and quantitative susceptibility mapping (QSM), an MRI-based technique, has identified abnormal iron overload in alpha-synucleinopathies. However, there is a limited understanding of the significance of changes in magnetic susceptibility, assessed by QSM, in patients with Dementia with Lewy Bodies (DLB). In this study, 39 DLB patients (58-88 years) and 30 cognitively unimpaired older adults (OA) (56-86 years) underwent an advanced MRI protocol that included T1w and QSM sequences, and a comprehensive neuropsychological evaluation. This study investigated (1) differences in whole-brain magnetic susceptibility and brain volumes between DLB patients and OA; (2) associations between regional changes in magnetic susceptibility and brain volumes, symptom duration, and cognitive functioning; (3) whether regional changes in magnetic susceptibility could differentiate DLB phenotypes based on earlier symptoms. DLB patients showed higher magnetic susceptibility values than OA in the bilateral substantia nigra, globus pallidus, thalamus, brainstem, and hippocampus, as well as in posterior cortical regions. No significant associations were observed between QSM susceptibility values and brain volumes, symptom duration, or cognitive functions. Using classificatory algorithms, different DLB phenotypes were identified based on iron accumulation values in the basal ganglia, thalamus, brainstem, and frontal cortical regions. Our findings suggest that QSM, assessing in vivo changes in brain iron accumulation, could serve as a useful noninvasive diagnostic biomarker in DLB patients. Longitudinal studies, including the prodromal phase of DLB, are needed to understand the interplay between brain volumetric loss, iron accumulation, and clinical manifestations.

Psychotic symptoms may manifest in Alzheimer’s disease (AD), especially in advanced disease stages and in patients with higher polygenic risk scores for schizophrenia (SCZ-PRS). Such genetic risk seems also to influence grey matter volume (GMV) alterations in patients with psychosis. Since multiple neurotransmitter systems, namely dopamine (DA) and serotonin (5-HT), have been implicated in psychosis, the aim of this study was to investigate whether a SCZ-PRS may explain variance in the association between GMV and the cerebral distribution of DA and 5-HT. Eight-hundred ADNI participants with genetic data were selected for this study: 203 cognitively unimpaired (CU) and 597 people with AD. Patient were divided into psychotic (PT-PS, n = 121) and non-psychotic (PT-NP, n = 476) based on available NPI-Q data. A SCZ-PRS was calculated for each participant using a Bayesian approach. T1-weighted MRI scans were pre-processed with SMP12 and JuSpace to extract Fisher’s z-transformed individual correlation coefficients between GMV and PET atlases for DA and 5-HT receptors/transporters. General linear models were used to test the association between the SCZ-PRS and GMV-neurotransmitter correlation coefficients (p < 0.05). Analyses were replicated in a sub-sample of amyloid-positive participants. The SCZ-PRS was negatively associated with correlations coefficients between GMV and the D2 dopaminergic receptor (D2r) in the whole sample (β = -0.016, p = 0.023) and in the PT-PS group (β = -0.037, p = 0.030). However, the latter association was significant only when analyses were restricted to amyloid-positive participants (Figure 1). In the PT-NP group, the SCZ-PRS was negatively associated with correlations coefficients between GMV and two 5-HT receptors (5-HT 1b : β = -0.014, p = 0.027; 5-HT 2a : β = -0.013, p = 0.038). No between-group differences in SCZ-PRSs were found. The SCZ-PRS was differentially associated with GMV alterations linked to either DA, in PT-PS, or 5-HT, in PT-NP, that are both neurotransmitters previously implicated in psychotic symptoms. However, the influence of SCZ-PRS on DA-related GMV loss appears to be primarily relevant to psychotic manifestations in AD. These findings suggest that future innovative pharmacological interventions targeting the DA system may be beneficial to treat psychosis in AD.

BACKGROUND:Socio-cognitive assessment in neurocognitive disorders (NCDs) is rare in clinical practice and no consensus exists as to a uniform operationalization of socio-cognitive measures for NCDs in memory clinics. The SIGNATURE initiative aims to optimize the use of socio-cognitive measures in memory clinics, defining expert recommendations. We report consortium guidelines for the use of socio-cognitive measures in NCDs based on available evidence from the literature and the current state of practices in memory clinics. METHODS:Using a Delphi consensus method supported by a literature review and the results of an international survey, 22 specialists defined recommendations for the context of use, relevance in NCD diagnosis, priorities for future research and facilitators/obstacles of socio-cognitive assessment in major and mild NCDs. RESULTS:Overall, panelists recommended social cognition testing in routine diagnostic assessment to evaluate both socio-cognitive and socio-behavioral alterations. A set of clinical, methodological, implementation and external factors facilitating or hampering the use of socio-cognitive tasks was identified. CONCLUSIONS:This is the first focused endeavor to favor the implementation of socio-cognitive assessment, which is required by DSM-5 but seldom performed despite clear evidence of its clinical relevance for diagnosis and care. Our results provide an initial set of recommendations, refinable through the future actions of the SIGNATURE initiative. Future collaborative clinical research projects should overcome current limitations and foster the use of ecological and cross-culturally validated measures in clinics.

Blood-based biomarkers are becoming emerging tools, easily detectable and minimally invasive, to reveal neurodegeneration and neuroinflammation in Alzheimer’s disease (AD). However, a comprehensive and up-to-date overview of the association between blood-based biomarkers and brain parameters as measured by MRI is not available. The aim of this review is to fill this gap and clarify the relationship between the main peripheral blood-based protein biomarkers (i.e., Aβ, p-tau, t-tau, NfL and GFAP) and brain parameters derived from MRI in the AD continuum. A literature search was carried out searching the PubMed and Web of Science databases for articles published up to May 2023. Articles were excluded according to the following criteria: no data on protein biomarkers; no data on the association between biomarkers and MRI data; articles not presenting novel data; articles that included only cognitively unimpaired older adults or patients with other neurological conditions; animal studies; molecular imaging studies; non-peer reviewed articles; non-English language articles; case reports. A total of 33 articles were included in this systematic review. The findings revealed the following: hippocampal volume was positively correlated with Aβ42 and Aβ42/Aβ40 and negatively with Aβ40 plasma levels; p-tau181 and p-tau217 concentrations were negatively correlated with temporal grey matter volume and cortical thickness; NfL levels were negatively correlated with white matter microstructural integrity, whereas GFAP levels were positively correlated with myo-inositol values in the posterior cingulate cortex/precuneus. Moreover, higher plasma GFAP levels were also negatively associated with hippocampal atrophy, lower cortical thickness, and smaller white matter volumes in temporal and parietal regions. Our systematic review showed strong associations between the main blood-based protein biomarkers and MRI markers of AD, highlighting a high degree of concordance between these measurements. This suggests a possible advantage in combining multiple AD-related markers to improve accuracy of early diagnosis, prognosis, progression monitoring and treatment response. Acknowledgement : This study is supported by funding obtained under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 - Project code PE0000006, CUP D93C22000930002, “A multiscale integrated approach to the study of the nervous system in health and disease” (MNESYS).

Acetylcholinesterase inhibitors are used to delay cognitive decline due to Alzheimer's disease (AD) by preventing breakdown of acetylcholine. Such treatment appears to be associated with cerebral changes, although the mechanism of action has not been clarified yet. This study aimed at assessing rivastigmine-induced changes in acetylcholine-related functional connectivity (FC) and cognitive performance in patients with prodromal to mild AD. Thirty-two patients with prodromal to mild AD recruited consecutively from a memory clinic were randomly assigned either to a 12-week rivastigmine patch treatment (ADt; n  = 16) or to an untreated control group (ADu; n  = 16). Participants underwent comprehensive neuropsychological and MRI assessments at baseline (T0) and after 12 weeks (T1). Functional MRI scans were pre-processed with the REACT pipeline to extract whole-brain FC maps weighted by the expected distribution of the vesicular acetylcholine transporter, the α4β2 nicotinic and the M1 muscarinic receptors using publicly available atlases. Between-group differences in T0-to-T1changes in cognitive performance and neurotransmitter-related FC were investigated. A regression model was used to assess the association between longitudinal changes (T1-T0) in cognitive performance and FC in the ADt group. At T0, the ADt group had worse visual long-term memory and higher α4β2-related FC in frontal and occipito-cerebellar cortices compared with the ADu group. Compared with the ADu group, the ADt group showed a greater longitudinal reduction in frontal α4β2-related FC and a greater improvement in visual memory. Changes in α4β2-related FC were significantly associated with memory improvements. Rivastigmine treatment induced FC changes in frontal and occipito-cerebellar areas in patients with prodromal to mild AD that were associated with long-term memory performance improvements over 12 weeks. These rivastigmine-induced effects on resting-state brain activity and the mediating role of the α4β2 nicotinic receptor for acetylcholine are in line with previous findings. Neurotransmitter-related FC can be an MRI biomarker sensitive to test mechanisms of actions and to track neuroplastic changes induced by pharmacological treatments targeting specific neurotransmitter systems in people with AD.

This national expert-based Delphi-consensus aims at formulating recommendations on the management of dementia care in Italy. This effort seems important and timely given in light of a new scenario arising from a new biological definition of Alzheimer’s disease (AD) and the availability of disease-modifying treatments (DMTs). the Steering Committee of the Italian Neurological Society for dementia (SINdem) created appropriate statements. Invited SINdem experts were requested to vote on the statements according to a modified three-round Delphi method. Only those statements reaching Grade A (full agreement ≥ 75

Early alterations in the ventral tegmental area, a major brainstem dopaminergic nucleus, may be a marker of Alzheimer’ disease (AD). However, how dopamine (DA) may influence neurofunctional and cognitive decline due to AD remains elusive. The aim of this study was to investigate alterations in resting-state functional connectivity (FC) associated with DA distribution in the brain along the AD continuum. Eighty-six older adults with mild cognitive impairment (MCI), 58 with mild dementia due to AD and 76 cognitively unimpaired (CU) participants of the multicentre VPH-DARE@IT project were included. Participants underwent comprehensive clinical, neuropsychological and MRI assessments Functional MRI data were pre-processed by using the REACT pipeline to obtain FC maps informed by DA receptor and transporter PET/SPECT atlas for the whole brain and for the nigrostriatal and mesocorticolimbic pathways. Whole-brain FC maps informed by acetylcholine (ACh) were also extracted for comparison. A cognitive composite score (Cog-CS) was calculated as the average of neuropsychological test z-scores. Between-group differences in neurotransmitter-informed FC were assessed using ANCOVA models in SMP12. Moreover, the association between FC maps and both Cog-CS and episodic memory scores was investigated in the whole sample. Age, education, sex, total intracranial volume and recruitment site were included as covariates. The AD group showed mesocorticolimbic DA-related FC decline in the bilateral precuneus, and increase in the thalamus, while the MCI group showed nigrostriatal FC decline in the left superior temporal gyrus. ACh-related FC decline was observed in both MCI and AD, compared with CU, in fronto-parietal and temporal areas. The Cog-CS was positively associated with ACh-related FC only in posterior cingulate, temporal and cerebellar areas. Episodic memory performance was correlated positively with ACh- and DA-related FC in occipito-parietal areas and negatively with DA-related FC in thalamic and fronto-temporal areas. FC alterations associated with both Ach and DA may be sensitive to cognitive decline due to AD. These findings, first of this kind, may offer useful insights to test recently proposed hypotheses on the involvement of these neuromodulatory systems in driving AD-related neuropathological changes as well as to investigate the mechanisms of action of novel treatments.

Frontotemporal lobar degeneration (FTLD) includes heterogenous diseases: behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasias (PPA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We applied neuroanatomical normative modelling to quantify individual atrophy patterns and heterogeneity within and between FTLD forms. We included 160 participants across FTLDNI and 4RTNI studies: controls (n = 15), bvFTD (n = 22), nfvPPA (n = 14), svPPA (n = 21), CBS (n = 43) and PSP (n = 45). Using cortical thickness and subcortical volumes from 3T MRIs, we applied normative modelling with a large healthy reference dataset (n = 58,836), further accounting for age, sex, and scanner. Outlier regions (z < – 1.96) were used to compute total outlier counts (tOC) and Hamming distances, capturing individual atrophy patterns and inter-subject dissimilarity. bvFTD, svPPA, CBS and PSP showed significantly higher cortical tOC than controls, with all groups showing higher subcortical tOC than controls, especially svPPA and PSP. bvFTD, svPPA, CBS and PSP had significantly higher cortical Hamming distance scores than controls, with higher scores in bvFTD and svPPA than nfvPPA and PSP. svPPA and PSP had significantly higher subcortical scores than controls and CBS. Greater disease severity (measured using the Clinical Dementia Rating—CDR for PSP and CBS, and the CDR® plus NACC-FTLD global scores for FTD variants) was associated with increased tOC and dissimilarity, highlighting the link between clinical progression and neuroanatomical heterogeneity. The pronounced heterogeneity within and between FTLD subtypes (particularly in bvFTD) increases with disease progression and may reflect distinct underlying pathologies. This supports the development of subtype-specific biomarkers and emphasize the need for personalized diagnostic and therapeutic strategies.

Cognitive decline in Alzheimer’s disease (AD) continuum is knowingly associated with degenerative neurobiological features; however, reliable markers for the early detection of the preclinical stages of AD are not fully established. The main goal of this study was to track ongoing brain neurodegeneration across the AD continuum by combining neuropsychological data, brain MRI features, and plasmatic - brain-derived circulating cell-free DNA (b-cfDNA) biomarkers. A total of 91 participants were included in this study including 28 healthy controls (HC) (mean age 66.4±9.2), 21 participants with Subjective Cognitive Decline (SCD) (mean age 70.4±8.5), 18 participants with Mild Cognitive Impairment (MCI) (mean age 72.3±7.1) and 24 patients with AD dementia (mean age 71.5±8.3). All participants underwent a neuropsychological evaluation, a brain MRI and a blood sample test to quantify the levels of brain-derived cfDNA in plasma. ANCOVAs were used to test differences across participants. In addition, the median value of b-cfDNA levels was set as a threshold to categorize participants into b-cfDNA-positive or negative. Pearson’s correlations were carried out between all variables. Results were corrected for multiple comparisons and statistical significance was set at p<0.05. Several regions in frontal, temporal and inferior parietal lobes showed progressively lower volumes going from HC to AD dementia. Although no statistical differences between mean b-cfDNA levels were observed among groups, we found a trend of increased values in SCD and MCI participants. In addition, volumes of specific temporal regions differed significantly between b-cfDNA-positive and b-cfDNA-negative participants. Moreover, b-cfDNA values correlated with semantic fluency scores in the AD dementia group (p = 0.038) and with the Stroop test scores in the HC group (p = 0.007). These results suggest that active neurodegeneration in the early phases of AD can be associated with a release of b-cfDNA in plasma. Thus, this blood-based biomarker might reveal early neurodegenerative processes even in the pre-clinical dementia stage, when the neuropsychological and MRI changes are very subtle and difficult to detect at the individual level. Acknowledgement : This study is supported by funding obtained under the National Recovery and Resilience Plan (NRRP), Mission 4 Component 2 Investment 1.3 -Project code PE0000006, CUP D93C22000930002, MNESYS

Background/Objectives: Studies have shown that higher polygenic risk scores (PRSs) for Alzheimer’s disease (AD) are associated with smaller volumes in temporal brain regions typically affected by this disease. These effects have also been found in cognitively unimpaired (CU) older adults. This study aimed to investigate the relationship between PRSs and brain volumes in specific areas associated with early AD. Methods: 342 participants were selected from the Alzheimer’s Disease Neuroimaging Initiative and stratified into three groups: 114 amyloid-positive atrophic (A+N+), 114 amyloid-negative non-atrophic (A−N−), and 114 amyloid-positive non-atrophic (A+N−) people. Linear regressions were performed within each group to investigate associations between PRSs and regional grey matter volumes. Analyses were also repeated after stratifying groups by APOE status and clinical diagnosis. Two sensitivity analyses were run to investigate the impact of APOE and amyloid status and concordance across biomarkers. Multiplicity was controlled for using the Benjamini–Hochberg false discovery rate (FDR) approach. Results: Negative associations were observed between PRSs and volumes of the left amygdala and hippocampus in A+N+, right hippocampus in A+N−, and right posterior cingulate cortex in A−N− participants. Associations were found especially in A−N− participants, both ε4 allele carriers and non-carriers, and mostly confirmed in sensitivity analyses. Associations emerged only in CU and AD participants, but not in people with MCI. None of these findings survived correction for FDR. Conclusions: These findings highlight the potential of PRSs as novel biological indicators for a deeper characterisation of AD-related neural alterations.

Sporadic Alzheimer's disease (AD) accounts for >90% of AD cases, of which 70% are thought to be due to a combination of several risk genes. Investigating polygenic risk scores (PRS) that examine many genes simultaneously may increase understanding of gene-gene interactions and their contribution to AD-related changes in brain structure. The aim of this study was to investigate associations between PRS for AD and regional grey matter volume. Data from 738 ADNI participants were examined. Two sets of PRSs were constructed, PRSwithAPOE vs. PRSwithoutAPOE, using 3 thresholds (Threshold 1: 172 SNPs including APOE vs. 121 SNPs without APOE; Threshold 2: 1561 SNPs with APOE vs. 1465 without APOE; Threshold 3: 455028 SNPs with APOE vs. 454638 SNPs without APOE). MatLab and Statistical Parametric Mapping 12 were used to process T1-weighted brain images and to extract volumes for 114 regions of interest. Multiple hierarchical linear regression models that removed the effect of demographic and clinical confounding variables showed that: (1) at whole-group level, all PRSwithAPOE thresholds were associated with bilateral hippocampi and amygdalae volumes, R>L; (2) when stratified by diagnostic group, PRSwithAPOE Threshold 1 & 3 were associated with R hippocampus volume in cognitively unimpaired (CU) participants, PRSwithAPOE Threshold 3 was associated with the volume of the R subcallosal area in MCI, and PRSwithAPOE Thresholds 1 & 2 were associated with the volume of the L entorhinal area in AD; (3) when stratified by amyloid status, all PRSwithAPOE thresholds were associated with the volumes of bilateral hippocampi and amygdalae, R>L, and R middle occipital gyrus for amyloid positive participants. No other associations survived corrections for multiple comparisons (false discovery rate). PRS for AD is associated with regional grey matter volume that is characteristic of AD and is influenced by either the combination of several risk genes plus APOE SNPs or APOE SNPs alone. Association between PRSwithAPOE and volume of the L entorhinal area may distinguish AD patients from MCI/CU. Therefore, PRS may be a useful contributor to AD diagnosis.

Minor visual phenomena (MVP), such as visual illusions, pareidolias, feeling of presence, and passage hallucinations, are often experienced by patients with Lewy Body Disease (LBD), in addition to complex visual hallucinations (VH), even in the early stages of the disease. This systematic review aimed to provide an up-to-date literature review of the occurrence and prevalence of MVP in LBD and to assess their potential associations both with VH and visuoperceptual and visuospatial deficits. A systematic literature search was carried out in PubMed, Web of Science, APA PsycInfo, Scopus, and Cochrane Library, and a total of 44 articles were included. The included studies showed significant variability in the occurrence of MVP in the LBD population and in the assessment methods used, such as standardized scales (e.g., the noise pareidolia test), semi-structured interviews (e.g., the North-East Visual Hallucinations Interview), and clinical descriptions. Similarly to VH, MVP appears to be highly specific to LBD, helping in differential diagnosis from Alzheimer’s Disease. The overall relationship between MVP, VH, and visuoperceptual/visuospatial deficits remains unclear. Some studies found that MVP (especially pareidolic responses and presence of hallucinations) was positively correlated with VH, yet it is challenging to determine whether MVP can be considered a precursor of future VH development. Negative associations were reported between MVP (especially pareidolias) and visuoperceptual/visuospatial abilities. However, it is not clear whether these deficits serve as independent, exclusive factors in MVP occurrence or if they interact with VH as a contributing component. Gaining insight into the occurrence of these phenomena could prove beneficial for differential diagnosis, prognosis, and prediction of treatment outcomes in patients with LBD.

Background/Objectives: Sexual minority older adults (SMOAs) report greater subjective cognitive decline (SCD) than heterosexual older adults (HOAs). This study aimed to compare the impact of multiple psycho-social risk factors on objective and subjective cognitive decline in HOAs and SMOAs. Methods: Two samples of self-identified HOAs and SMOAs were selected from the English Longitudinal Study of Ageing. Reliable change indices for episodic and semantic memory were created to assess cognitive decline. SCD was self-reported for memory and general cognition. Depressive symptoms, loneliness, marital status and socio-economic status were investigated as risk factors. Results: No between-group differences were found in cognitive decline. Higher depression was associated with greater SCD risk and worse semantic memory decline. The latter effect was stronger in SMOAs. The findings were largely replicated in the sensitivity analysis. Conclusions: Poor mental health may represent the strongest driver of cognitive decline in SMOAs and to a greater extent than in HOAs.

Abstract Alzheimer’s disease (AD) may be associated with early dopamine (DA) dysfunction. However, its effects on neurofunctional alterations in the neurotransmission pathways remain elusive. In this study, PET atlases and functional MRI data for 86 older adults with mild cognitive impairment (AD-MCI), 58 with mild AD dementia and 76 cognitively unimpaired (CU) were combined to investigate connectivity alterations associated with the dopaminergic and cholinergic (ACh) systems. A cross-sectional design was used to compare neurotransmitter-related functional connectivity across groups and associations between functional connectivity and cognitive performance. The findings show that the AD-dementia group showed a decline in mesocorticolimbic DA-related connectivity in the precuneus but heightened connectivity in the thalamus, whereas the AD-MCI group showed a decline in nigrostriatal connectivity in the left temporal areas. ACh-related connectivity decline was observed in both AD-MCI and AD-dementia primarily in the temporo-parietal areas. Episodic memory scores correlated positively with ACh- and DA-related connectivity in the temporo-parietal cortex and negatively with DA-related FC in the fronto-thalamic areas. This study shows that connectivity alterations in ACh and DA functional pathways parallel cognitive decline in AD and might be a clinically relevant marker in early AD.

BACKGROUND:Sexual minorities (i.e. people who identify as non-heterosexual) show several health disparities. However, risk/protective factors relevant to cognitive health of sexual minority older adults (SMOAs) have not been fully investigated. The aim of this study was to quantify the impact of several psycho-social factors on subjective and objective cognitive health in SMOAs. METHOD:Thirty-nine cognitively unimpaired SMOAs (age = 64.1±10.0; M = 74.4%) and 30 heterosexual older adults (HOAs; age = 65.6±9.7; M = 40.0%) completed an online survey to provide information on psycho-social risks (i.e., depression, anxiety, general stress), subjective cognitive decline (SCD), beliefs about their memory and dementia worries. SMOAs also completed questionnaires on minority stress and outness. Twenty-seven SMOAs and 24 HOAs underwent a comprehensive neuropsychological battery. General linear models were used to assess the relationship between psycho-social risk factors and cognitive health and the interactions between sexual orientation and risk factors. Minority stress and outness were also investigated as risk/protective factors for cognitive health in SMOAs only. RESULT:Compared with HOAs, SMOAs reported worse mental and subjective cognitive health (i.e. SCD for memory, negative memory beliefs and dementia worries), but similar cognitive performance. Worse depression/anxiety were associated with more dementia worries in both groups, while anxiety was associated with worse performance on the Trail Making Test in SMOAs only (Figure 1). Moreover, worse minority stress was associated with higher risk of SCD for language (OR = 6.79, p =  0.048) and more negative memory beliefs (b = 0.41, p =  0.012), while being more out about one's own sexual orientation was associated with better short-term memory performance (b = 0.54, p =  0.004). CONCLUSION:This is the first targeted study highlighting that SMOAs experience more detrimental effects of anxiety than HOAs on attentional functions. Minority stress primarily affects subjective cognitive health of SMOAs, while outness appears to provide resilience against cognitive decline. Further investigations are needed to ascertain longitudinal cognitive changes and to devise potential prevention strategies aimed at preserving cognitive health in SMOAs.