People with severe mental illnesses (SMIs), including schizophrenia spectrum disorders (SSD), major depressive disorder (MDD), and bipolar disorder (BD), experience elevated rates of physical comorbidity and premature mortality. Dementia and ischemic stroke contribute substantially to this burden, yet age-specific patterns of these associations remain poorly characterized. To bridge this gap, we conducted a population-based cross-sectional study using the PADRIS-PRESTO cohort, integrating primary and specialized care records from the Catalan public health system (Spain). Adults with a lifetime SMI diagnosis were compared with controls without any psychiatric condition. Weighted age-stratified prevalence was calculated and logistic regression models estimated age-specific odds ratios (ORs) with 95% confidence intervals (CIs), adjusting for socioeconomic status and medical comorbidity burden. Among 694,086 participants, 176,870 had an SMI diagnosis. Dementia prevalence was 3.49% (range, 0.33% at ages 20-29 to 39.51% at 90-99 years) in SMIs and 0.36% (0.02%-17.7%) in controls. Ischemic stroke prevalence was 5.3% (0.22%-16.4%) in SMIs and 2.75% (0.08%-14.67%) in controls. The ORs between SMI and dementia were significant across all age groups, with the strongest association observed at younger ages (OR = 23.21, 95% CIs = 13.74-39.19 at 30-39 years). Elevated ORs for stroke persisted up to 70-79 years, peaking at 40-49 years (OR = 2.99, 95% CIs = 2.63-3.41). Patterns were consistent across SMI subtypes. These findings highlight the need for earlier and more systematic neurological and cardiometabolic screening and management within psychiatric care and support policies that recognize SMIs as risk factors for vascular diseases and dementia.

Phenylketonuria (PKU) is a rare metabolic disorder caused by a deficiency in the enzyme phenylalanine hydroxylase, leading to the accumulation of phenylalanine (Phe). Raised Phe levels can result in neurocognitive deficits, intellectual disabilities, and behavioral or psychiatric disorders. To conduct a systematic review of human studies on metabolites identified through metabolomics in individuals with PKU, compared to healthy controls, and to provide insights into their biological significance. A total of 26 human studies analyzing metabolites in urine and blood met the inclusion criteria. In total, 544 metabolites that differed between patients with PKU and healthy controls were identified through different metabolomic techniques (LC-MS, GC-MS, NMR). Differences were primarily observed in blood samples, which accounted for 95

Alterations in sleep-wake patterns are well-recognized features of overt alpha-synucleinopathies. However, their presence in prodromal stages, characterized by isolated Rapid-Eye-Movement (REM) sleep behavior disorder, remains controversial, and their association with clinical symptoms and imaging risk factors has been underexplored. In this study, we used seven-day ambulatory circadian monitoring to characterize circadian and sleep-wake disturbances in a well-characterized sample of forty-two patients with video-polysomnography-confirmed isolated REM sleep behavior disorder and 23 healthy controls. We investigated the associations between circadian disturbances and non-motor clinical symptoms, assessed in a comprehensive neuropsychological protocol, alongside imaging proxies of glymphatic system functioning, namely the Diffusion Tensor Imaging Along the Perivascular Spaces index, and the volume of perivascular spaces and choroid plexuses. Moreover, we assessed the associations between circadian alterations and striatal dopaminergic uptake in the most affected putamen, a well-established risk factor for conversion to alpha-synucleinopathies, as assessed with presynaptic dopaminergic imaging. Patients with isolated REM sleep behavior disorder exhibited reduced diurnal physical activity, along with reduced amplitude and increased fragmentation of the sleep probability and motor activity rhythms. Circadian alterations correlated with greater neuropsychiatric symptoms and reduced psychomotor and mental speed. Patients with isolated REM sleep behavior disorder exhibited a decreased Diffusion Tensor Imaging Along the Perivascular Spaces and larger volume of perivascular spaces, but only the former was associated with sleep impairment. Decreased putaminal dopaminergic uptake was associated with rest-activity rhythm fragmentation. These results show that circadian alterations are observed in early stages of neurodegeneration and are associated with clinical and imaging risk markers of conversion to alpha-synucleinopathies, posing them as possible targets for intervention in prodromal disease stages.

BACKGROUND:Isolated rapid-eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviors in REM sleep and is considered as a prodromal symptom of alpha-synucleinopathies. Resting-state functional magnetic resonance imaging (rsfMRI) studies have unveiled altered functional connectivity (rsFC) in patients with iRBD. However, the associations between intra- and inter-network rsFC with clinical symptoms and neuropsychological functioning in iRBD remain unclear. OBJECTIVE:To characterize intra- and inter-network rsFC in iRBD patients using a data-driven approach and to assess its associations with clinical features and cognitive functioning. METHODS:Forty-two patients with iRBD and 45 healthy controls (HC) underwent rsfMRI and comprehensive neuropsychological testing. Resting-state networks were characterized using independent component analyses. Group differences in intra- and inter-network rsFC and their associations with clinical and neuropsychological data were studied. A threshold of corrected P < 0.05 was used in all the analyses. RESULTS:iRBD patients displayed lower intra-network rsFC within basal ganglia, visual, sensorimotor, and cerebellar networks, relative to HC. Mean rsFC strength within the basal ganglia network positively correlated with processing speed and negatively with the non-motor symptoms in iRBD patients. Reduced inter-network rsFC between sensorimotor and visual medial networks was observed in iRBD patients, which was associated with global cognitive status. CONCLUSIONS:iRBD is characterized by both reductions in intra-network rsFC in cortical and subcortical networks and inter-network dysconnectivity between sensorimotor and visual networks. Abnormalities in intra- and inter-network rsFC are associated with cognitive performance and non-motor symptoms, suggesting the utility of both rsFC measures as imaging markers in prodromal alpha-synucleinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

It has been estimated that ∼4% of individuals infected with SARS-CoV-2 will be diagnosed with post-COVID condition. Previous studies have evidenced the presence of cognitive dysfunction and structural brain changes in infected individuals; however, the relationship between structural changes and cognitive alterations in post-COVID condition is still not clear. Consequently, the aim of this work is to study structural brain alterations in post-COVID condition patients after almost 2 years of infection and their likely relationship with patients' cognitive impairment. Additionally, the association with blood biomarkers and clinical variables was also explored. One hundred and twenty-eight individuals with post-COVID condition and 37 non-infected healthy controls from the Nautilus Project (ClinicalTrials.gov IDs: NCT05307549 and NCT05307575) underwent structural brain magnetic resonance imaging and a comprehensive neuropsychological assessment. A subsample of 66 post-COVID participants also underwent blood extraction to obtain levels of blood biomarkers. Cortical thickness and subcortical volumes were obtained and analysed using FreeSurfer (v7.1). FMRIB Software Library software (v6.0.4) was used to perform grey matter voxel-based analysis and to study microstructural white matter integrity. Patients with post-COVID performed significantly worse in working and verbal memory, processing speed, verbal fluency and executive functions, compared to healthy controls. Moreover, patients with post-COVID showed increased cortical thickness in the right superior frontal and the right rostral middle frontal gyri that negatively correlated with working memory performance. Diffusion tensor imaging data showed lower fractional anisotropy in patients in the right superior longitudinal fasciculus, the splenium and genu of the corpus callosum, the right uncinate fasciculus and the forceps major, that negatively correlated with subjective memory failures. No differences in blood biomarkers were found. Once patients were classified according to their cognitive status, post-COVID clinically cognitively altered presented increased cortical thickness compared to those classified as non-cognitively altered. In conclusion, our study showed that grey and white matter brain changes are relevant in this condition after almost 2 years of infection and partly explain long-term cognitive sequelae. These findings underscore the critical importance of monitoring this at-risk population over time.

In the present study we aimed to assess the cognition of post-COVID condition (PCC) participants regarding their sleep quality, and to analyse different possible moderators of this effect, such as quality of life (European Quality of Life-5 Dimensions, EQ-5D), fatigue (Chadler Fatigue Questionnaire, CFQ), cognitive reserve (Cognitive Reserve Questionnaire, CRC), and subjective cognitive complaints (Memory Failures of Everyday Questionnaire, MFE-30). We included 373 individuals with PCC and 126 healthy controls (HCs) from the NAUTILUS Project (NCT05307549 and NCT05307575) that were assessed with a comprehensive neuropsychological battery and different questionnaires. We included 373 individuals with PCC and 126 healthy controls (HCs) from the NAUTILUS Project (NCT05307549 and NCT05307575) that were assessed with a comprehensive neuropsychological battery and different questionnaires. We found that PCC participants with poor sleep quality have a 4.3% greater risk of having immediate verbal memory deficits the greater the MFE-30 score (Odd Ratio (OR) 1,043; Confidence Interval (CI) 1,023-1,063). Also, they multiply their risk of having immediate verbal memory disorders by 2.4 when the EQ-5D is low (OR 0,33; CI 0,145-0,748), and they have less risk of having delayed visual memory deficits the greater the CRC (OR 0,963; CI 0,929-0,999). With processing speed performance, PCC participants and poor sleep quality have a 6.7% greater risk of having deficits the greater the MFE (OR 1,059; CI 1,024-1,096) and the risk of slowing processing speed triples the lower the EQ-5D (OR 0,021; CI 0,003-0,141). These results indicate that poor subjective sleep quality plays a role as a potential trigger for cognitive deficits. Therapeutic strategies to maximize sleep quality would be reducing not only sleep disturbances, but perhaps also cognitive impairment in PCC participants.

In the current study, we aimed (i) to evaluate sleep quality via wrist actigraphy monitoring of nonhospitalized and hospitalized post-COVID-19 condition (PCC) participants; (ii) to correlate actigraphy measures with subjective measures of sleep quality, such as the Pittsburgh Sleep Quality Index (PSQI); and (iii) to investigate whether total sleep time or sleep efficiency could affect PCC cognitive performance. We included 49 individuals with PCC from the NAUTILUS Project (NCT05307549 and NCT05307575) who were monitored for 1 week via actigraphy and who were also assessed with a comprehensive neuropsychological battery and the PSQI. We found that there were significant differences between nonhospitalized PCCs and hospitalized PCCs in the number of awakenings. We also found a correlation between the total sleep time of both measures (actigraphy and PSQI), but we did not observe correlations between objective and subjective parameters of latency and sleep efficiency. Regarding cognition and actigraphy measures, there was a trend of statistical significance in the performance of immediate visual memory, attention span and social cognition according to sleep efficiency. In conclusion, results indicate that although the PSQI provides clinically relevant indicators of sleep, there are divergent results between self-reported and objective sleep measures (actigraphy). Furthermore, we found a tendency toward statistical significance in cognitive performance in PCC participants according to their sleep efficiency which could indicate that is more important for cognitive function of post-COVID-19 patients than total sleep time.

Cortical mean diffusivity (cMD), a marker of cortical microstructural changes in neurodegenerative disorders, remains unexplored in isolated REM sleep behavior disorder (iRBD), a prodromal stage of Lewy body (LB) diseases. Its relationship with cortical thickness (CTh), clinical features, and neuropsychological performance is also unknown. We assessed cMD and CTh in thirty-six patients with iRBD at high risk of conversion and 29 healthy controls (HC), examining associations with clinical and cognitive measures. Effect sizes were calculated using Cohen’s d. Patients with iRBD showed increased cMD in rostral and caudal cortical regions compared to HC (d > 0.5). Cortical thinning was restricted to caudal areas. Higher cMD correlated with longer iRBD duration, later onset, MDS-UPDRS III, apathy, and poorer performance on Grooved Pegboard and Symbol-Digit Modality Tests. These findings suggest that cMD may be more sensitive than CTh and serve as a valuable imaging biomarker for detecting early cortical changes in prodromal LB diseases.

Altered white matter (WM) is consistently reported in patients with phenylketonuria (PKU). However, the knowledge about WM microstructural integrity in early-treated adults with classical PKU and its relationship with cognition and metabolic parameters is inconclusive. This study aims to explore the cerebral WM microstructural alterations in adult patients with early-treated classical PKU and their association with blood phenylalanine (Phe) levels and neuropsychological performance using whole-brain diffusion tensor imaging (DTI). Twenty-nine patients with early-treated classical PKU (mean age = 30.86, SD = 7.74) and 31 healthy controls (mean age = 32.45, SD = 9.40) underwent neuropsychological assessment and MRI. Phe dry blood spot (DBS-Phe) samples, along with venous Phe levels, were collected from the PKU sample to calculate the index of dietary control (IDC). Tract-based spatial statistics (TBSS) of the mean diffusivity (MD), and fractional anisotropy (FA), were carried out with FSL v6.0.4 to assess between-group differences and to explore associations with both cognitive and clinical data. Patients exhibited a widespread white matter tract involvement, with lower MD and higher FA values compared to controls. The most affected tracts were the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus for MD, and the anterior corona radiata, uncinate fasciculus and forceps minor for FA. MD negatively correlated with IDC and venous Phe levels, whereas FA negatively correlated with full-scale intelligence quotient (FSIQ) (p-value ≤0.05 FWE-corrected). Microstructural WM alterations were present in adults with early-treated classical PKU, and these abnormalities were related to global intelligence and metabolic control markers. Although our results suggest the importance of proper disease management, further studies are needed to determine its long-term relevance.

After COVID-19 infection, some patients develop a post-COVID condition (PCC) that is popularly referred to as long COVID. Among its symptoms is persistent cognitive dysfunction that is potentially linked to altered brain functional connectivity (FC). While research has explored functional reorganization in patients with PCC, the intra- and inter- network connectivity and its relationship with cognitive status and clinical outcomes remain unclear. In this study, we recruited 121 individuals with PCC (67 with, and 54 without, cognitive impairment), 20 months after infection, along with 37 non-infected healthy controls from the NAUTILUS Project (ClinicalTrials.gov IDs: NCT05307549 and NCT05307575). Participants underwent resting-state functional magnetic resonance imaging and comprehensive neuropsychological assessment. Resting-state networks were characterized using independent component analyses, dual regression and network modelling for individual FC characterization. Group differences in intra- and inter-network FC, and their associations with clinical and neuropsychological data, were studied. Significance was set at a corrected p-value of < 0.05. Patients with PCC showed increased intra-network FC in 10 cognitively relevant networks, including the default mode, salience, executive control, auditory and basal ganglia networks, correlating positively with general cognition (Montreal Cognitive Assessment scores), time since infection, fatigue and subjective memory failures. Increased inter-network FC between default mode and sensorimotor networks was also observed. Increases in FC may reflect an inefficient compensatory mechanism in patients with PCC, associated with fatigue, subjective memory complaints and persistence of PCC.

Glymphatic alterations may underlie neurodegeneration in alpha-synucleinopathies. Reduced Diffusion-Tensor Imaging ALong the Perivascular Space (DTI-ALPS), a proxy of perivascular glymphatic activity, has been scarcely studied in isolated REM sleep behaviour disorder (iRBD), a prodromal synucleinopathy stage. Furthermore, its associations with clinical symptoms and brain structural abnormalities remain unexplored. We assessed the DTI-ALPS in sixty-two patients with iRBD and twenty-three healthy controls (HC), exploring its associations with clinical symptoms, cortical thickness and brain volumetric data. iRBD patients exhibited a lower DTI-ALPS and poorer odor identification, semantic fluency and processing speed relative to HC. The DTI-ALPS positively correlated with cognitive performance, olfactory function and amygdalar, hippocampal, brainstem and diencephalic volumes, and negatively with age in iRBD. Perivascular glymphatic activity is compromised in iRBD and is associated with brain atrophy and clinical risk factors of progression to alpha-synucleinopathies, supporting the potential of the DTI-ALPS index as an early imaging neurodegeneration marker.

Objectives: In the present study, we aimed (i) to describe the personality traits of a cohort of post-COVID-19 condition (PCC) patients compared with a healthy control (HC) group, (ii) to evaluate the relationship between sleep quality and personality traits, and (iii) to investigate whether this relationship differs according to disease severity. Methods: We included 599 participants from the Nautilus Project (ClincalTrials.gov IDs: NCT05307549 and NCT05307575) with an age range from 20 to 65 years old. Of 599 participants, 280 were nonhospitalized (mild PCC), 87 were hospitalized (hospitalized PCC), 98 were in the PCC-ICU, and 134 were in the HC group. We assessed sleep quality with the Pittsburgh Sleep Quality Index (PSQI) and personality traits with the NEO Five-Factor Inventory (NEO FFI). Results: We found that mild-PCC patients had higher scores of neuroticism than HCs (p < 0.001) and ICU-PCC patients did (p = 0.020). The higher the neuroticism score was, the higher the total PSQI score (B 0.162; p < 0.001), the worse the sleep latency (B 0.049; p < 0.001), the greater the degree of sleep disturbance (B 0.060; p < 0.001), the greater the use of sleeping medication (B 0.035; p = 0.033), and the greater the incidence of daytime disturbances (B 0.065; p < 0.001) among the PCC patients. High neuroticism is also an indicator of worse sleep quality in mild-PCC (t = 3.269; p 0.001) and hospitalized-PCC (t = 6.401; p < 0.001) patients and HCs (t = 4.876; p < 0.001) but not in ICU-PCC patients. Conclusions: Although neuroticism affected sleep quality in both the PCC patients and HCs, the clinical implications and magnitude of the relationship were more significant in the PCC group. Specific and multidimensional interventions are needed to treat sleep problems in this population, and the influence of their personality traits should be considered.

AbstractBackgroundContinued dietary treatment since early diagnosis through newborn screening programs usually prevents brain-related complications in phenylketonuria (PKU). However, subtle neurocognitive and brain alterations may be observed in some adult patients despite early treatment. Nevertheless, neuropsychological and neuroimaging studies in the field remain scarce.ObjectivesThis work aimed to determine possible neuropsychological and structural brain alterations in treated adult patients with PKU.MethodsThirty-five patients with PKU and 22 healthy controls (HC) underwent neuropsychological assessment and T1-weighted magnetic resonance imaging on a 3 T scanner.FreeSurfer(v.7.1) was used to obtain volumetric measures and SPSS (v27.0.1.0) was used to analyze sociodemographic, neuropsychological, volumetric, and clinical data (p < 0.05).ResultsAdult patients with PKU showed significantly lower performance than HC in Full Scale IQ (t = 2.67;p = .010) from the WAIS-IV. The PKU group also showed significantly lower volumes than HC in the pallidum (U = 224.000;p = .008), hippocampus (U = 243.000;p = .020), amygdala (U = 200.000;p = .002), and brainstem (t = 3.17;p = .006) as well as in total cerebral white matter volume (U = 175.000;p = .001). Blood phenylalanine (Phe) levels in PKU patients were negatively correlated with the pallidum (r = -0.417;p = .013) and brainstem (r = -0.455,p = .006) volumes.ConclusionsAdult patients with early-treated PKU showed significantly lower global intelligence than HC. Moreover, these patients showed reduced global white matter volume as well as reductions in the volume of several subcortical grey matter structures, which might be related to the existence of underlying neurodevelopmental alterations. Higher blood Phe levels were also negatively correlated with pallidum and brainstem, suggesting a higher vulnerability of these structures to Phe toxicity.

The risk factors for post-COVID-19 cognitive impairment have been poorly described. This study aimed to identify the sociodemographic, clinical, and lifestyle characteristics that characterize a group of post-COVID-19 condition (PCC) participants with neuropsychological impairment. The study sample included 426 participants with PCC who underwent a neurobehavioral evaluation. We selected seven mental speed processing and executive function variables to obtain a data-driven partition. Clustering algorithms were applied, including K-means, bisecting K-means, and Gaussian mixture models. Different machine learning algorithms were then used to obtain a classifier able to separate the two clusters according to the demographic, clinical, emotional, and lifestyle variables, including logistic regression with least absolute shrinkage and selection operator (LASSO) (L1) and Ridge (L2) regularization, support vector machines (linear/quadratic/radial basis function kernels), and decision tree ensembles (random forest/gradient boosting trees). All clustering quality measures were in agreement in detecting only two clusters in the data based solely on cognitive performance. A model with four variables (cognitive reserve, depressive symptoms, obesity, and change in work situation) obtained with logistic regression with LASSO regularization was able to classify between good and poor cognitive performers with an accuracy and a weighted averaged precision of 72%, a recall of 73%, and an area under the curve of 0.72. PCC individuals with a lower cognitive reserve, more depressive symptoms, obesity, and a change in employment status were at greater risk for poor performance on tasks requiring mental processing speed and executive function. Study registration : www.ClinicalTrials.gov , identifier NCT05307575.

Sex differences permeate many aspects of dementia with Lewy bodies (DLB), yet sex differences in patterns of neurodegeneration in DLB remain largely unexplored. Here, we test whether grey matter networks differ between sexes in DLB and compare these findings to sex differences in healthy controls. In this cross-sectional study, we analysed clinical and neuroimaging data of patients with DLB and cognitively healthy controls matched for age and sex. Grey matter networks were constructed by pairwise correlations between 58 regional volumes after correction for age, intracranial volume, and centre. Network properties were compared between sexes and diagnostic groups. Additional analyses were conducted on w-scored data to identify DLB-specific sex differences. Data from 119 (68.7 ± 8.4 years) men and 45 women (69.9 ± 9.1 years) with DLB, and 164 healthy controls were included in this study. Networks of men had a lower nodal strength compared to women. In comparison to healthy women, the grey matter networks of healthy men showed a higher global efficiency, modularity, and fewer modules. None of the network measures showed significant sex differences in DLB. Comparing DLB patients with healthy controls revealed global differences in women and more local differences in men. Modular analyses showed a more distinct demarcation between cortical and subcortical regions in men compared with women. While topologies of grey matter networks differed between sexes in healthy controls, those sex differences were diluted in DLB patients. These findings suggest a disease-driven convergence of neurodegenerative patterns in women and men with DLB, which may inform precision medicine in DLB.

Background/Objectives: Studies using optical coherence tomography angiography (OCTA) have revealed that individuals recovering from COVID-19 have a reduced retinal vascular density (VD) and larger foveal avascular zones (FAZs) than healthy individuals, with more severe cases showing greater reductions. We aimed to examine aspects of the retinal microvascularization in patients with post-COVID-19 condition (PCC) classified by COVID-19 severity and how these aspects relate to cognitive performance. Methods: This observational cross-sectional study included 104 PCC participants from the NAUTILUS Project, divided into severe (n = 59) and mild (n = 45) COVID-19 groups. Participants underwent cognitive assessments and OCTA to measure VD and perfusion density (PD) in the superficial capillary plexus (SVP) and FAZ. Analysis of covariance and partial Pearson and Spearman correlations were used to study intergroup differences and the relationships between cognitive and OCTA variables. Results: Severe PCC participants had significantly lower central (p = 0.03) and total (p = 0.03) VD, lower central (p = 0.02) PD measurements, and larger FAZ areas (p = 0.02) and perimeters (p = 0.02) than mild cases. Severe cases showed more cognitive impairment, particularly in speed processing (p = 0.003) and executive functions (p = 0.03). Lower central VD, lower central PD, and larger FAZ areas and perimeters were associated with worse executive function performance in the entire PCC sample and in the mild COVID-19 group. Conclusions: Retinal microvascular alterations, characterized by reduced VD and PD in the SVP and larger FAZ areas, were associated with cognitive impairments in PCC individuals. These findings suggest that severe COVID-19 leads to long-lasting microvascular damage, impacting retinal and cognitive health.

Clinical, cognitive, and atrophy characteristics depending on sex have been previously reported in Parkinson’s disease (PD). However, though sex differences in cortical gray matter measures in early drug naïve patients have been described, little is known about differences in cortical thickness (CTh) as the disease advances. Our multi-site sample comprised 211 non-demented PD patients (64.45% males; mean age 65.58 ± 8.44 years old; mean disease duration 6.42 ± 5.11 years) and 86 healthy controls (50% males; mean age 65.49 ± 9.33 years old) with available T1-weighted 3 T MRI data from four international research centers. Sex differences in regional mean CTh estimations were analyzed using generalized linear models. The relation of CTh in regions showing sex differences with age, disease duration, and age of onset was examined through multiple linear regression. PD males showed thinner cortex than PD females in six frontal (bilateral caudal middle frontal, bilateral superior frontal, left precentral and right pars orbitalis), three parietal (bilateral inferior parietal and left supramarginal), and one limbic region (right posterior cingulate). In PD males, lower CTh values in nine out of ten regions were associated with longer disease duration and older age, whereas in PD females, lower CTh was associated with older age but with longer disease duration only in one region. Overall, male patients show a more widespread pattern of reduced CTh compared with female patients. Disease duration seems more relevant to explain reduced CTh in male patients, suggesting worse prognostic over time. Further studies should explore sex-specific cortical atrophy trajectories using large longitudinal multi-site data.

Parkinson's disease (PD) is clinically heterogeneous, which suggests the existence of subtypes; however, there has been no consensus regarding their characteristics. This study included 633 PD individuals across distinct cohorts: unmedicated de novo PD, medicated PD, mild-moderate PD, and a cohort based on diagnostic work-up in clinical practice. Additionally, 233 controls were included. Clustering based on cortical and subcortical gray matter measures was conducted with and without adjusting for global atrophy in the entire PD sample and validated within each cohort. Subtypes were characterized using baseline and longitudinal demographic and clinical data. Unadjusted results identified three clusters showing a gradient of neurodegeneration and symptom severity across the entire sample and the individual cohorts. When adjusting for global atrophy eight clusters were identified in the entire sample, lacking consistency in individual cohorts. This study identified atrophy-based subtypes in PD, emphasizing the significant impact of global atrophy on subtype number, patterns, and interpretation in cross-sectional analyses.