Presence hallucination in Parkinson’s disease (PD) is shown to arise from errors in sensorimotor integration and frontotemporal disconnection.

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

Background: Cognitive impairment in Parkinson's disease (PD) is a well‐established non‐motor complication that significantly affects the quality of life and well‐being of both patients and care partners. To optimally detect mild cognitive impairment or dementia, extensive neuropsychological assessment is essential. A wide range of cognitive tests and clinical outcome assessments have been used in clinical settings, often without regard to their clinimetric quality.Methods: We performed a literature review of tests assessing attention/working memory and executive domains in PD (tests on other domains are included in an accompanying review). The selected tests were evaluated for their clinimetric properties and categorized by a panel of experts as “recommended,” “recommended with caveats,” “suggested,” or “listed” according to the International Parkinson and Movement Disorder Society Clinical Outcome Assessment Scientific Evaluation Committee guidelines.Results: A total of 30 tests were reviewed. Eight tests were “recommended,” including four tests assessing attention/working memory abilities (WAIS‐IV Digit Span, Coding and Symbol Search subtests, and Trail Making Test) and four tests assessing executive abilities (WAIS‐IV Similarities, Wisconsin Card Sorting Test, Fluency Tests, and Stroop Color‐Word Test). These tests demonstrated good to excellent levels of reliability and validity, have normative datasets, and are sensitive to change. Eight other tests were “recommended with caveats”, eleven were “suggested,” and three were “listed.”Conclusions: The recommended tests for attention/working memory and executive functioning in PD can guide PD cognitive assessment. Other tests were identified as potentially useful; however, caution is advised due to their clinimetric limitations. Further validation studies are required for these tests. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND AND PURPOSE: Huntington disease is a devastating genetic neurodegenerative disorder for which no effective treatment is yet available. Although progressive striatal atrophy is its pathologic hallmark, concomitant cortical deterioration is assumed to occur, but it is poorly characterized. Our objective was to study the loss of cortical integrity and its association with clinical indicators throughout the course of the disease. MATERIALS AND METHODS: Using a cohort of 39 patients with Huntington disease and 25 controls with available MR imaging (T1WI and DTI), we compared cortical atrophy and intracortical diffusivity across disease stages. Intracortical diffusivity is a DTI-derived metric that has recently been suggested to detect incipient neuronal death because water can diffuse more freely in cortical regions with reduced neural density. RESULTS: We observed progressive thinning and increasing diffusivity within the cerebral cortex of patients with Huntington disease (P < .05, corrected for multiple comparisons). Most important, in the absence of pronounced atrophy, widespread increased diffusivity was already present in individuals with premanifest Huntington disease, correlating, in turn, with clinical and disease-specific progression markers. CONCLUSIONS: Intracortical diffusivity may be more sensitive than cortical thinning for tracking early neurodegeneration in Huntington disease. Moreover, our findings provide further evidence of an early cortical compromise in Huntington disease, which contributes to our understanding of its clinical phenotype and could have important therapeutic implications.

Despite the advances in the understanding of Huntington's disease (HD), there is a need for molecular biomarkers to categorize mutation carriers during the preclinical stage of the disease preceding functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological processes. Here, using an optimized method for plasma extracellular vesicles (EVs) purification and an exhaustive analysis pipeline of sRNA sequencing data, we show that EV‐sRNAs are downregulated early in mutation carriers and that this deregulation is associated with premanifest cognitive performance. Seven candidate sRNAs (tRF‐Glu‐CTC, tRF‐Gly‐GCC, miR‐451a, miR‐21‐5p, miR‐26a‐5p, miR‐27a‐3p and let7a‐5p) were validated in additional subjects, showing a significant diagnostic accuracy at premanifest stages. Of these, miR‐21‐5p was significantly decreased over time in a longitudinal study; and miR‐21‐5p and miR‐26a‐5p levels correlated with cognitive changes in the premanifest cohort. In summary, the present results suggest that deregulated plasma EV‐sRNAs define an early biosignature in mutation carriers with specific species highlighting the progression and cognitive changes occurring at the premanifest stage.