Huntington’s disease (HD) is characterized by heterogeneous rates of clinical progression, complicating patient monitoring and clinical trial design. Although speech and language alterations are increasingly recognized as part of the HD cognitive phenotype, their value as short-term prognostic biomarkers of clinically meaningful disease progression and neurodegeneration remains unestablished. In this prospective 12-month longitudinal study, we investigated whether objectively quantified spontaneous speech and language measures predict short-term clinically meaningful progression and relate to biomarkers of neurodegeneration in HD. Eighty-six participants (42 manifest HD, 24 premanifest gene carriers, and 20 healthy controls) underwent baseline spontaneous speech assessment, structural MRI, and plasma neurofilament light chain (NfL) quantification. Clinically meaningful worsening was defined using validated minimal clinically important difference thresholds in the composite Unified Huntington’s Disease Rating Scale (cUHDRS). Spontaneous speech and language measures progressively deteriorated across disease stages and were associated with reduced cortico-subcortical gray matter volume in distributed associative and integrative regions. In manifest HD, logistic regression analyses revealed that baseline language integrity independently predicted clinically meaningful worsening at 12 months (OR = 3.840, 95

BACKGROUND:Huntington's disease (HD) is the most frequent autosomal dominant neurodegenerative disorder, which is caused by a CAG repeat expansion in the HTT gene. Despite its well-defined genetic origin, there is currently no cure, and reliable biomarkers for disease progression and pathophysiology remain limited. Mutant huntingtin protein accumulates in endosomal compartments, disrupting endosomal trafficking and potentially affecting the biogenesis, release, and cargo of exosomes-extracellular vesicles (EVs) derived from the endosomal pathway. However, the role of exosomes in HD pathogenesis and their potential as biomarkers has been underexplored. In this work, we investigated whether the levels and content of small EV subpopulations, including exosomes, are altered in the brains of HD patients. METHODS:We analyzed two distinct subpopulations of small EVs from the striatum and cortex of postmortem HD brains at early and advanced neuropathological stages, as well as from age-matched controls. EVs were isolated by differential ultracentrifugation and high-resolution iodixanol density gradient centrifugation, and analyzed by Western blotting, electron microscopy, NTA, and proteomics using mass spectrometry. EV secretion was also analyzed in primary fibroblasts derived from HD patients and healthy controls. RESULTS:Mass spectrometry data revealed HD-associated alterations in EV protein content, particularly proteins related to the endosomal system. Our data also indicate that the level of ectosomes increased in the HD cortex, whereas exosomes were reduced in the HD striatum compared to controls. In terms of EV content, EVs from HD brains showed increased levels of Annexin A2 and decreased levels of Alix, a key component of the endosomal sorting complex required for transport (ESCRT). Alix depletion in EVs mirrored a progressive reduction of Alix in brain tissue, correlating with disease severity based on Vonsattel staging. In vitro, HD fibroblasts secreted EVs with reduced Alix content, despite no significant difference in cellular Alix levels compared to controls. CONCLUSIONS:These findings highlight disease-specific changes in EV populations and cargo in HD, and identify Alix as a potential neuropathological marker. This study advances our understanding of the role of brain-derived EVs in HD and underscores their potential utility in biomarker discovery.

Cognitive impairment is a core feature of Huntington’s disease (HD), yet no disease-modifying or symptomatic interventions have demonstrated efficacy in addressing these deficits. Non-pharmacological interventions, particularly cognitive training (CT), are promising options for maintaining neural plasticity, enhancing cognition, and improving emotional well-being. This 24-week, single-center, randomized, single-blind study evaluated the safety and efficacy of two cognitive rehabilitation strategies in early-to-middle-stage HD patients. Participants were randomized into a computerized cognitive training (CT; n = 13) intervention or a music therapy (MT; n = 16) intervention. A standard of care (SoC; n = 15) group with no active intervention was also involved. Weekly 45-min sessions were conducted. Baseline and endpoint assessments included measures of global cognition, functional, motor, and neuropsychiatric assessments, along with structural and functional neuroimaging. Both CT and MT groups demonstrated significant improvements in primary and secondary cognitive endpoints, including global cognition an composite measures of disease severity. Regression analysis identified longitudinal cognitive score changes as independent predictors of the rate of atrophy in the caudate, putamen, and inferior frontal gyrus. Functional connectivity analysis showed distinct intervention-related effects: CT group exhibited increased connectivity between the central executive and sensorymotor networks, while MT group reduced aberrant connectivity between the central executive and the default-mode network. This is the first randomized-controlled trial to evaluate two cognitive rehabilitation strategies in HD using multimodal neuroimaging. Both interventions were effective in improving cognition and modulating structural and functional brain changes in regions critical to HD. Trial Registration ClinicalTrials.gov (ID: NCT05769972).

ABSTRACTContextRetinal microperimetry (MPR) is a non‐invasive method that measures retinal light sensitivity (RS) and gaze fixation stability (GFS). MPR has been described as a marker of cognitive impairment in people with Type 2 diabetes, but it has never been assessed in people with Type 1 diabetes (T1D). Our group described subclinical cognitive alterations, structural brain differences, and increased levels of light chain neurofilament (NfL) in people with T1D and impaired awareness of hypoglycaemia.ObjectiveTo measure RS and GFS using MPR in individuals with T1D and evaluate its correlation with neuropsychological assessment, plasma NfL levels and CGM‐derived glucometric parameters. Secondary objectives: to evaluate the possible differences of RS and GFS in people with T1D depending on hypoglycaemia awareness.Design, Setting and ParticipantsPilot observational study, people with T1D without clinical cognitive impairment, moderate–severe retinopathy or glaucoma. MPR was performed with MAIA3.ResultsA total of 30 subjects were studied: 40% women, age 58 ± 11 years; T1D duration 31 ± 9 years, mild retinopathy 33%. RS was 27.5 dB (26.1–28.3) and GFS(%) 97.6% (93.5%–99.5%). We found a correlation between RS and memory alteration tests (p = 0.016) and between GFS(%) and a composite of attention and executive neuropsychological tests (p = 0.025). An inverse correlation between GFS and time below range was found. No correlation was found with NfL.ConclusionThis first exploratory study in people with T1D supports the potential utility of MPR as a screening tool for subclinical neurocognitive alterations in this population.

Background:Cognitive decline is a core feature of Huntington's disease (HD), often preceding motor symptoms and progressing with disease severity. While several neuropsychological tests track cognitive changes, few studies have examined the biological correlates of brief screening tools adapted for HD. Objectives:This study investigates the neuroanatomical and fluid biomarker correlates of performance on the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), aiming to validate it as a clinically and biologically grounded tool for cognitive assessment in HD. Methods:Fifty-two symptomatic gene-expansion carriers (CAG >39) underwent cognitive (PD-CRS), motor (UHDRS), and behavioral (PBA) assessments. Plasma neurofilament light chain (NfL) levels were measured via Simoa as a marker of neurodegeneration. Voxel-based morphometry (VBM) was used to identify gray matter volume (GMV) correlates of PD-CRS scores. Linear regressions evaluated relationships among PD-CRS, GMV, and NfL, including subdomain-level and stage-stratified analyses based on HD-ISS classification. Results:PD-CRS scores were significantly associated with GMV in frontostriatal, paralimbic, parietal, and occipital regions. NfL levels correlated with both cognitive scores and GMV in key regions, supporting their value as biomarkers of neurodegeneration. Subdomain analyses revealed region-specific associations (e.g., visuospatial tasks with posterior cortices, fluency with striatum). Perseveration, motor severity, and education predicted PD-CRS performance (adjusted R2 = 0.799). PD-CRS remained the strongest GMV predictor (adjusted R2 = 0.519), particularly in later disease stages. Conclussions:The PD-CRS reflects biologically meaningful aspects of cognitive dysfunction in HD, with robust associations to structural and molecular disease markers. These findings support its use as a practical and sensitive tool for clinical and research applications.

BACKGROUND:Huntington's disease (HD) is primarily associated with executive dysfunction, but episodic memory impairment is also present. Traditionally, these memory deficits have been attributed to retrieval difficulties linked to fronto-striatal dysfunction, rather than to disruptions in encoding or consolidation processes. However, the specific nature and diversity of memory impairments in HD remain underexplored. OBJECTIVE:To characterize the profile of episodic memory impairment in HD, identify distinct cognitive phenotypes, and examine their clinical, neuroanatomical, and biomarker correlates. METHODS:We assessed episodic memory in HD patients and healthy controls using the Free and Cued Selective Reminding Test (FCSRT), complemented by Item-Specific Deficit Approach (ISDA) indices to quantify encoding, consolidation, and retrieval deficits. Structural MRI was used to identify gray matter volume correlates, and plasma neurofilament light chain (NfL) was measured as a marker of neuroaxonal injury. RESULTS:Compared to controls, HD patients showed marked impairments in free recall with preserved cued recall, suggesting predominant retrieval deficits. However, nearly one-third of patients exhibited global impairments across all FCSRT components, mainly driven by consolidation deficits consistent with medial temporal lobe dysfunction. This subgroup also showed worse cognitive and functional performance and significant atrophy in the hippocampus, entorhinal cortex, and parahippocampal gyrus. CONCLUSION:Episodic memory dysfunction in HD is heterogeneous and includes both retrieval-related and consolidation-driven profiles. These profiles reflect distinct neurodegenerative patterns, emphasizing the importance of cognitive subtyping for improving clinical characterization and biomarker development in HD.

ABSTRACT Objective Huntington's disease (HD) speech/language disorders have typically been attributed to motor and executive impairment due to striatal dysfunction. In‐depth study of linguistic skills and the role of extrastriatal structures in HD is scarce. This study aimed to explore the profile of language compromise in HD and identify the structural neuroimaging correlates. Methods Language and structural correlates were assessed using the Mini Linguistic State Examination (MLSE) in 81 participants (20 HD‐ISS 0‐1, 40 HD‐ISS 2‐3 and 21 controls). Clinical and global cognition measures were also obtained. Imaging data included computed gray matter volume (GMV) and cortical thickness (CTh) values extracted from a general linear model with the MLSE. Correlation analyses were performed with the language components of the MLSE. Multivariate regression analyses were used to explore the predictive ability of the language components on GMV and CTh loss. Results HD individuals showed impaired MLSE performance (84.5 ± 12.8), particularly in syntax, motor speech, and to a lesser extent, semantics and phonology. Significant associations were found between linguistic performance and the structural integrity of nodes within the temporo‐parietal, fronto‐parietal, and fronto‐striatal lexical‐semantic and syntactic networks. Correlation analyses linked motor speech and syntax with predominantly left fronto‐striatal GMV and CTh clusters, while semantics had a bilateral fronto‐parietal topography. Multivariate regression analyses showed language domains as independent contributing factors of GMV and CTh loss in classical language‐related regions. Interpretation Language impairment is an integral part of the HD cognitive phenotype, with severity associated with structural disintegration in extensive cortico‐subcortical territories involved in language production and processing.

AbstractObjectiveThe clinical phenotype of Huntington's disease (HD) can be very heterogeneous between patients, even when they share equivalent CAG repeat length, age, or disease burden. This heterogeneity is especially evident in terms of the cognitive profile and related brain changes. To shed light on the mechanisms participating in this heterogeneity, the present study delves into the association between Tau pathology and more severe cognitive phenotypes and brain damage in HD.MethodsWe used a comprehensive neuropsychological examination to characterize the cognitive phenotype of a sample of 30 participants with early‐to‐middle HD for which we also obtained 3 T structural magnetic resonance image (MRI) and cerebrospinal fluid (CSF). We quantified CSF levels of neurofilament light chain (NfL), total Tau (tTau), and phosphorylated Tau‐231 (pTau‐231). Thanks to the cognitive characterization carried out, we subsequently explored the relationship between different levels of biomarkers, the cognitive phenotype, and brain integrity.ResultsThe results confirmed that more severe forms of cognitive deterioration in HD extend beyond executive dysfunction and affect processes with clear posterior‐cortical dependence. This phenotype was in turn associated with higher CSF levels of tTau and pTau‐231 and to a more pronounced pattern of posterior‐cortical atrophy in specific brain regions closely linked to the cognitive processes affected by Tau.InterpretationOur findings reinforce the association between Tau pathology, cognition, and neurodegeneration in HD, emphasizing the need to explore the role of Tau in the cognitive heterogeneity of the disease.

OBJECTIVE:Cognitive impairment in Parkinson's disease (PD) can show a very heterogeneous trajectory among patients. Here, we explored the mechanisms involved in the expression and prediction of different cognitive phenotypes over 4 years. METHODS:In 2 independent cohorts (total n = 475), we performed a cluster analysis to identify trajectories of cognitive progression. Baseline and longitudinal level II neuropsychological assessments were conducted, and baseline structural magnetic resonance imaging, resting electroencephalogram and neurofilament light chain plasma quantification were carried out. Linear mixed-effects models were used to study longitudinal changes. Risk of mild cognitive impairment and dementia were estimated using multivariable hazard regression. Spectral power density from the electroencephalogram at baseline and source localization were computed. RESULTS:Two cognitive trajectories were identified. Cluster 1 presented stability (PD-Stable) over time, whereas cluster 2 showed progressive cognitive decline (PD-Progressors). The PD-Progressors group showed an increased risk for evolving to PD mild cognitive impairment (HR 2.09; 95% CI 1.11-3.95) and a marked risk for dementia (HR 4.87; 95% CI 1.34-17.76), associated with progressive worsening in posterior-cortical-dependent cognitive processes. Both clusters showed equivalent clinical and sociodemographic characteristics, structural magnetic resonance imaging, and neurofilament light chain levels at baseline. Conversely, the PD-Progressors group showed a fronto-temporo-occipital and parietal slow-wave power density increase, that was in turn related to worsening at 2 and 4 years of follow-up in different cognitive measures. INTERPRETATION:In the absence of differences in baseline cognitive function and typical markers of neurodegeneration, the further development of an aggressive cognitive decline in PD is associated with increased slow-wave power density and with a different profile of worsening in several posterior-cortical-dependent tasks. ANN NEUROL 2024;96:981-993.

Hypomimia is a frequent manifestation in Parkinson's disease (PD) that can affect interpersonal relationships and quality of life. Recent studies have suggested that hypomimia is not only related to motor dysfunction but also to impairment in emotional processing networks. Therefore, we hypothesized that the severity of hypomimia could be associated with performance on a task aimed at assessing facial emotion recognition. In this study, we explored the association between hypomimia, recognition of facial expressions of basic emotions using the Ekman 60 Faces Test (EF), and brain correlates of both hypomimia and performance on the EF. A total of 94 subjects underwent clinical assessments (neurological and neuropsychological examinations), and 56 of them participated in the neuroimaging study. We found significant correlation between hypomimia, EF Disgust ( r = −0.242, p = 0.022) and EF Happiness ( r = −0.264, p = 0.012); an independent reduction in Cortical Thickness (Cth) in the postcentral gyrus, insula, middle and superior temporal gyri, supramarginal gyrus, banks of the superior temporal sulcus, bilateral fusiform gyri, entorhinal cortex, parahippocampal gyrus, inferior and superior parietal cortex, and right cuneus and precuneus; and multiple correlations between negative emotions such as EF Disgust or EF Anger and a reduced Cth in fronto-temporo-parietal regions. In conclusion, these results suggest that the association between hypomimia and emotion recognition deficits in individuals with PD might be mediated by shared circuits, supporting the concept that hypomimia is not only the result of the dysfunction of motor circuits, but also of higher cognitive functions.

Individuals with pre‐manifest and early symptomatic Huntington's disease (HD) have shown deficits in solving arithmetic word‐problems. However, the neural correlates of these deficits in HD are poorly understood. We explored the structural (gray‐matter volume; GMV) and metabolic (18F‐FDG PET; SUVr) brain correlates of arithmetic performance using the recently developed HD‐word problem arithmetic task (HD‐WPA) in seventeen preHD and sixteen HD individuals. Symptomatic participants showed significantly lower scores in the HD‐WPA than preHD participants. Lower performance in the HD‐WPA was associated with reduced GMV in subcortical, medial frontal, and several posterior‐cortical clusters in HD participants. No significant GMV loss was found in preHD participants. 18F‐FDG data revealed a widespread pattern of hypometabolism in association with lower arithmetic performance in all participants. In preHD participants, this pattern was restricted to the ventrolateral and orbital prefrontal cortex, the insula, and the precentral gyrus. In HD participants, the pattern extended to several parietal–temporal regions. Word‐problem solving arithmetic deficits in HD is subserved by a pattern of asynchronous metabolic and structural compromise across the cerebral cortex as a function of disease stage. In preHD individuals, arithmetic deficits were associated with prefrontal alterations, whereas in symptomatic HD patients, more severe arithmetic deficits are associated with the compromise of several frontal‐subcortical and temporo‐parietal regions. Our results support the hypothesis that cognitive deficits in HD are not exclusively dominated by frontal‐striatal dysfunctions but also involve fronto‐temporal and parieto‐occipital damage.

BackgroundInsulin-like growth factor 1 (IGF-1) seems to be involved in the neural circuits associated with social cognition and brain structure. ObjectivesTo investigate the association of IGF-1 levels with social cognition and brain structure in Huntington's disease (HD). MethodsWe evaluated social cognition using the Ekman test in 22 HD patients and 19 matched controls. Brain structure was assessed using standard volume-based voxel-based morphometry and surface-based cortical thickness pipeline. We analyzed the association of IGF-1 levels with social cognition and brain structure using adjusted regression analysis. ResultsSocial cognition was worse in HD patients (P < 0.001), on antidopaminergic drugs (P = 0.02), and with lower IGF-1 levels (P = 0.04). In neuroimaging analyses, lower IGF-1 levels were associated with social cognition impairment and atrophy mainly in frontotemporal regions (P < 0.05 corrected). ConclusionsIn HD, abnormal IGF-1 function seems to be associated with brain atrophy leading to clinical deficits in social cognition.