Riccardo Manca

Biallelic intronic repeat expansions in the replication factor C subunit 1 (RFC1) gene are a common cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome and other late-onset ataxias. Recent evidence suggests a broader phenotypic spectrum. This systematic review and meta-analysis evaluated the prevalence and features of motor neuron, extrapyramidal, and cognitive involvement in RFC1 disease. We systematically searched PubMed, Scopus, and Web of Science for studies reporting motor neuron, extrapyramidal, or cognitive involvement in RFC1 disease from inception to March 2025. Eligible sources comprised research articles and case reports/series on genetically confirmed cases. Extracted data included publication details, study design, location, and individual participant data (IPD) covering demographics, signs, and symptoms. When needed, IPD were obtained from corresponding authors. Random-effects models were used to estimate pooled prevalences (95% CIs). Univariable mixed-effects logistic regression accounted for clustering within studies, with multivariable models including variables with p < 0.10 in univariate analyses. Of 729 articles, 37 were included in the systematic review and 36 (874 patients) in the proportion meta-analyses. For IPD meta-analysis, 30 cohorts provided data on 312 patients (mean age 66.91 ± 10.76 years; median disease duration 12 [interquartile range 7–18] years; 51.5% male). Upper and lower motor neuron signs were present in 18% (95% CI 6%–34%) and 11% (95% CI 2%–24%). Patients with the ACAGG pentanucleotide repeat expansion (biallelic or compound heterozygous with an AAGGG expansion) had higher odds of muscle atrophy (OR 17.90, p 0.001) and weakness (OR 11.69, p 0.001); men had an increased likelihood of muscle atrophy (OR 2.71, p = 0.038). The pooled prevalence of parkinsonism and cognitive impairment was 8% (95% CI 1%–18%) and 31% (95% CI 13%–53%), with prominent executive-attention deficits. Cognitive decline was more likely with longer disease duration (OR 1.04, p = 0.047) and in biallelic AAGGG carriers vs ACAGG (ACAGG_exp: OR 0.13, p = 0.041). Motor neuron, extrapyramidal, and cognitive involvement may extend the phenotypic spectrum of RFC1 disease. Still, their true prevalence remains uncertain due to heterogeneity across studies, with potential overestimation from publication bias favoring atypical cases and underestimation when subtle signs are not systematically investigated. Larger multicenter cohorts with standardized assessments are needed to clarify their clinical relevance.

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.

Socio-cognitive assessment in neurocognitive disorders (NCDs) is rare in clinical practice and no consensus exists as to a uniform operationalization of so

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.

Alzheimer’s disease (AD) pathology has been recently shown to accumulate in multiple brainstem nuclei in pre-cortical disease stages. However, the impact of neurotransmission alterations on brain atrophy and their genetic correlates in AD remain unexplored. This study investigated (1) associations between grey matter (GM) loss and uptake values of PET/SPECT ligands tracing concentration of multiple neurotransmitter receptors/transporters and pathways; (2) the impact of AD polygenic risk scores (AD-PRSs) on such associations along the AD continuum. T1-weighted MRI scans, genetic and clinical data were selected for 800 ADNI participants: 203 cognitively unimpaired older adults (CU), 442 with mild cognitive impairment (MCI) and 155 with AD. JuSpace was used to calculate correlations between GM volume (GMV) and the concentration of several neurotransmitters. Two PRSs, with (AD-PRS) and without APOE (AD-PRS_noAPOE), were investigated as predictors of the strength of correlation between GMV and neurotransmitters in general linear models. In both patient groups, atrophy was negatively associated with serotoninergic and dopaminergic receptors/transporters. In the whole sample, both PRSs were associated with the strength of correlation between GMV and different serotonin receptors and fluorodopa uptake. The pattern of associations was replicated in participants with evidence of amyloid pathology. GM loss in AD may be particularly affected by the alterations in serotoninergic and in presynaptic dopaminergic activity that are known to influence functioning of medio-temporal and frontal cortices. Such alterations appear to be driven by higher AD-PRS values. Investigating further neurotransmitter-related neural alterations may help clarifying neuropathological changes in pre-clinical AD and response to treatments.

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.

Background: Sexual minority older adults (SMOAs) report subjective cognitive decline (SCD) more than heterosexual older adults (HOAs). Inconsistent findings have emerged about the risk of cognitive decline in SMOAs. This study aimed to compare the impact of multiple psycho‐social risk factors on both objectively assessed and subjectively reported cognitive decline between HOAs and SMOAs.Method: Two samples of self‐identified HOAs (n = 4180) and SMOAs (n = 92) who completed Waves 8 and 9 of the English Longitudinal Study of Ageing were selected. Reliable change indices for episodic and semantic memory were created to assess longitudinal cognitive changes. SCD was self‐assessed for both memory and general cognition. Mental and cardiovascular health, marital status, loneliness, and socio‐economic status (SES) were investigated as risk factors for cognitive decline. The effect of each risk factor and their interaction effects with sexual orientation on memory changes and SCD were tested, respectively, with general linear and logistic regression models. Age, education, and sex were included as covariates. A sensitivity analysis was carried out in a sub‐sample (n = 92, per group) matched for demographics.Result: Cognitive changes and rates of SCD were similar between SMOAs and HOAs. All risk factors, apart from marital status, were associated SCD risk, while only SES was associated with decline in episodic memory (β = .01, p = .038). A SES×sexual orientation interaction was found for semantic memory (β = ‐.06, p = .042); among those in the lowest quintile, SMOAs had better semantic memory preservation over time than HOAs. A sensitivity analysis found among those in the highest quintile, SMOAs had worse semantic memory decline than HOAs.Conclusion: SCD was associated with a multitude of risk factors, in line with previous evidence of SCD as a heterogeneous construct. This was similar between SMOAs and HOAs. Longitudinal changes in semantic memory were, instead, differentially impacted by SES in the groups. Sensitivity analysis confirmed a potential lack of protective effect in SMOAs, although the groups did not differ for SES. These findings may be interpreted within the framework of material deprivation, which is more likely among SMOAs and may contribute to their cognitive decline more severely than in HOAs.

Background: Tau protein tangles have been recently shown to accumulate in multiple brainstem nuclei in pre‐cortical Alzheimer’s disease (AD) stages. The impact of neurotransmission alterations on brain atrophy and their genetic correlates in AD remain unexplored. Therefore, the aims of this study were: 1) to investigate associations between grey matter (GM) loss across the AD continuum and the distribution of multiple neurotransmitter receptors/transporters; 2) to investigate the impact of polygenic risk scores for AD (PRSs) on such associations.Method: T1‐weighted MRI scans, genetic and clinical data were selected for 800 ADNI participants (age = 74.1±7.6; M = 55.3%) including 203 cognitively unimpaired older adults (CU), 442 with mild cognitive impairment (MCI) and 155 with AD. GM atrophy was investigated in MCI and AD groups, compared with CU. JuSpace was used to calculate correlations between GM atrophy and the distribution of several neurotransmitters. Two PRSs, with (AD‐PRS) and without APOE (AD‐PRS_noAPOE) were calculated using a Bayesian approach and investigated as predictors of the strength of correlation between GM volume (GMV) and neurotransmitters in general linear models.Result: GM atrophy was primarily in medio‐temporal areas in MCI, while was widespread in AD participants. In both groups, atrophy was negatively associated with serotoninergic and dopaminergic receptors/transporters. In the whole sample, AD‐PRS and AD‐PRS_noAPOE were negatively associated with the strength of correlation between GMV and 2 serotonin receptors (5‐HT1a and 5‐HT4). AD‐PRS was also associated with GMV‐FDOPA (negatively) and with GMV‐5‐HT1b (positively) correlation coefficients. In amyloid positive participants, AD‐PRS was associated with GMV‐5‐HT1b (b = 0.012, p < 0.001) and AD‐PRS_noAPOE with GMV‐5‐HT4 (b = ‐0.013, p < 0.001) correlation strength only.Conclusion: GM loss due to AD may be particularly affected by the alterations in inhibitory serotoninergic and in presynaptic dopaminergic activity, that are known to affect acetylcholine function and memory decline. Such alterations appear to be driven by polygenic risk for AD, with potential specific effects dependent on APOE genotype and amyloid status. Investigating further the impact of AD‐PRS on various neurotransmitter‐related neural alterations may help clarifying neuropathological changes in pre‐clinical AD and support early detection of people at risk of dementia.

Background: 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.Method: 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.Result: 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.Conclusion: 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.

Blood-based biomarkers are minimally invasive tools to detect the pathological changes of Alzheimer’s Disease (AD). This meta-analysis aims to investigate the use of blood-derived p-tau isoforms (181, 217, 231) to predict conversion from mild cognitive impairment (MCI) to AD dementia (ADD). Studies involving MCI patients with data on blood p-tau isoforms at baseline and clinical diagnosis at follow-up (≥1 year) were included. Twelve studies on p-tau 181 (4340 MCI, conversion rate 20.6%), four on p-tau 217 (913 MCI, conversion rate 33.4%), and one on p-tau 231 (135 MCI, conversion rate 33%) were included. For p-tau 181, the pooled area under the receiver operating characteristic curve (AUC) was 0.73 (95% CI = 0.68–0.78), and for p-tau 217 was 0.85 (95% CI = 0.75–0.91). Plasma levels of p-tau 181 had good discriminatory power to identify MCI patients who will convert to ADD. Although only four studies on p-tau 217 have been included in the meta-analysis, in the last year the predictive power of p-tau 217 is emerging as superior to that of other isoforms. However, given the high heterogeneity detected in the p-tau 217 studies included in this meta-analysis, additional supportive evidence is needed. Insufficient results were available for p-tau 231. These findings support the prognostic utility of p-tau 181 and p-tau 217 measured in blood to predict progression to ADD in MCI and encourage its future implementation in clinical practice.