Background Cerebrospinal fluid (CSF) α-synuclein seed amplification assay (SAA) has emerged as a diagnostic biomarker for Parkinson's disease (PD) and has been linked to differences in disease severity and progression. However, whether SAA status predicts responsiveness to levodopa remains unknown. We investigated the longitudinal association between SAA status, levodopa responsiveness, dopaminergic denervation, and motor complications in sporadic PD. Methods In this longitudinal analysis, PD participants from the Parkinson's Progression Markers Initiative (PPMI) cohort with CSF SAA testing who initiated levodopa treatment were included. SAA- and SAA+ patients were matched on sex, age, and disease duration at treatment initiation. Motor severity was assessed using MDS-UPDRS Part III, with proportional and absolute responsiveness derived from ON and OFF medication states. Motor complications were assessed using MDS-UPDRS Part IV, and dopaminergic dysfunction was quantified using caudate DAT-SPECT. Linear mixed-effects models examined longitudinal differences as a function of SAA status. Findings In this analysis, 40 SAA- patients were compared to 183 matched SAA+ patients. SAA+ patients showed a slower rate of ON-state motor progression than SAA- patients (0.87 vs 3.47 points/year; p = 0.01). Consistently, proportional levodopa responsiveness increased over time in SAA+ patients while declining in SAA- patients (p = 0.036). These differences were accompanied by lower caudate DAT binding at treatment initiation in SAA- patients (p = 0.002) and faster dopaminergic decline over time (p = 0.008). Although SAA+ patients had fewer motor complications at treatment initiation, their progression was similar. Interpretation CSF α-synuclein SAA status is associated with divergent levodopa response in PD, with SAA+ patients showing sustained and progressively greater motor benefit, while SAA- patients show declining responsiveness. Faster dopaminergic denervation in SAA- patients may underlie this difference. SAA status captures clinically relevant heterogeneity that may inform patient stratification and therapeutic decision-making. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement HA reports grants from Fonds de Recherche du Quebec - Sante (FRQS) and Parkinson Canada. RM reports a grant from FRQS. MD reports grants from the Canadian Institute of Health Research (CIHR), Future Leaders Brain Canada, and the Natural Sciences and Engineering Research Council of Canada (NSERC). AS reports grants paid to their institution from the Michael J. Fox Foundation, NIH-National Institute on Aging (NIA), NIH-National Institute of Neurological Disorders and Stroke (NINDS), and Roche; consulting fees from Aveum Therapeutics, Theravance, Cerevance, Mitsubishi, Boehringer Ingelheim, BioVie, Eli Lilly, and CND Life Sciences; and participation on data safety monitoring boards for the Huntington Study Group, Massachusetts General Hospital, Eli Lilly, Prilenia, Roche, and Cerevance. AD reports grants from CIHR. YZ reports grants from CIHR, ALS Canada - Brain Canada, and NSERC. SMF declares no competing interests. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used in the preparation of this manuscript were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (https://www.ppmi-info.org/access-data-specimens/download-data). All the information and data used in this study are publicly available for free and can be requested on the PPMI website (https://www.ppmi-info.org). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used in the preparation of this manuscript were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (https://www.ppmi-info.org/access-data-specimens/download-data). All the information and data used in this study are publicly available for free and can be requested on the PPMI website (https://www.ppmi-info.org).

The brain's extraordinary energy demands are met by a suite of metabolic pathways that selectively appropriate glucose across development, yet how this metabolic strategy changes across the lifespan and whether it is conserved across species remains incompletely understood. We previously mapped five core energy metabolism pathways across the human cortex and lifespan, revealing a fundamental dichotomy between anabolic and energy-producing pathway expression: the pentose phosphate pathway, which contributes to biomass, peaks prenatally, while glycolysis, the TCA cycle, and oxidative phosphorylation rise postnatally. Here, we extend the analysis to the rhesus macaque and show that the prenatal-to-postnatal transition is similar across the two species. Using the MitoCarta3.0 annotation framework, we further identify two consistent mitochondria-specific programs: a progressive decline in mitochondrial genome maintenance pathways, and a postnatal rise in mitochondrial energy production and substrate utilization, replicated across human and macaque. Extending to mouse, rat, and chicken, we find this shifting metabolic strategy is a conserved feature of vertebrate brain development. Finally, we map the cortical expression of mitochondria-localized pathway genes in the adult human cortex, finding that the anabolic-oxidative dichotomy follows in the mature brain. Together, these findings provide a comparative transcriptomic framework for studying brain energy metabolism across the lifespan.

BACKGROUND:Historically, Alzheimer's disease (AD) and Parkinson's disease (PD) have been investigated as 2 distinct disorders of the brain. However, a few similarities in neuropathology and clinical symptoms have been documented over the years. Traditional single-gene centric studies, such as differential gene expression analyses, have struggled to unravel the molecular basis for the observed pathological links between AD and PD. RESULTS:We tailor a latent factor framework to analyze synchronous gene co-expression changes in AD or PD at sub-cell-type resolution. Utilizing large, single-nucleus transcriptomics datasets in AD (70,634 nuclei) and PD (340,902 nuclei) from postmortem human brains, we systematically extract and juxtapose disease-critical molecular signatures in the brain. Our transcriptomic analysis reveals shared molecular programs between AD and PD that localize to specific glial and neuronal cell types. In neurons, convergent gene groups in AD and PD relate to cytoskeletal dynamics and mitochondrial stress mechanisms. In microglia, overlapping gene modules implicate T cell activation mechanisms and synapse pruning pathways. In parallel, AD- and PD-associated gene groups in astrocytes are involved in heavy metal processing; oligodendrocytes highlight convergent dysregulation in myelin synthesis. Additionally, our analysis reveals apolipoprotein E gene (an AD risk gene), and the synuclein alpha gene (a PD risk gene) to have disease predictive roles in both AD- and PD-associated gene modules. CONCLUSION:Our multi-module sub-cell-type approach offers novel insights into the molecular basis of shared neuropathology in AD and PD.

In Alzheimer's disease (AD), tau pathology accumulates gradually throughout the brain, with clinical decline reflecting tau progression. A comprehensive understanding of, first, whether tau propagation is predominantly governed by connectome-based diffusion, regional vulnerability, or an interplay of both, and second, which types of brain connectivity or regional factors best explain tau propagation, remains crucial for advancing our understanding of AD progression. Here, we apply multi-scale, biologically informed disease progression simulations to human data, to disentangle the influence of local mechanisms on global tau progression patterns in AD. We find that whether tau reaches a brain region (presence) and how much tau accumulates there (load) are governed by different mechanisms. Tau presence patterns are highly consistent across the population, and can be largely explained through synaptic spread through white-matter networks and excitatory-inhibitory dynamics. Meanwhile tau load differs across people, and is driven by a combination of synaptic spread and intrinsic or extrinsic regional properties, including regional β-amyloid load, MAPT gene expression and regional blood flow. Finally, while distinct tau patterns in the population could each be explained by established AD mechanisms, our models highlight a role of distinct brain networks (parietal networks in MTL-sparing AD tau subtype) and neurotransmitter systems (cholinergic system in posterior subtype). Together, this work suggests that network dynamics likely determine the sequence of regional tau progression, while individual-specific tissue-vulnerability factors influence regional tau load.

BACKGROUND:Dementia with Lewy bodies shares clinical and pathological features with both Parkinson's disease and Alzheimer's disease, but the local biological factors that render specific cortical regions vulnerable to atrophy remain poorly defined. In particular, it is unclear whether cortical thinning in dementia with Lewy bodies reflects generic neurodegenerative mechanisms, processes shared with Parkinson's disease and Alzheimer's disease, or dementia with Lewy bodies-specific molecular and network susceptibilities. METHODS:A total of 89 patients with dementia with Lewy bodies and 89 matched controls underwent T1-weighted brain MRI. Scans were processed to generate surface-based cortical thickness maps. Regional cortical thickness estimates, after slice-by-slice manual correction, were mapped to gene expression data from healthy postmortem human brains to identify transcriptomic signatures associated with decreased thickness in dementia with Lewy bodies. We assessed whether genes whose expression was increased with regional thinning converged onto established Parkinson's disease- and Alzheimer's disease-related pathways and identified genes uniquely implicated in dementia with Lewy bodies. Spatial annotation mapping was then used to test whether patterns of cortical thinning overlapped with in vivo neurotransmitter system distributions and whether the observed thickness pattern was constrained by large-scale structural connectivity, consistent with a network-based propagation process. RESULTS:Cortical thinning predominated in regions that, in the healthy brain, show higher expression of genes involved in mitochondrial function and synaptic transmission. The transcriptomic profile associated with thinning significantly overlapped with genes belonging to Parkinson's disease and Alzheimer's disease pathways, supporting shared pathogenic mechanisms across Lewy body- and Alzheimer-type neurodegeneration. However, 90 genes associated with cortical thinning did not overlap with Parkinson's disease or Alzheimer's disease pathways and were enriched for GABAergic signalling. Spatial mapping analyses showed that regions with greatest thickness reductions colocalized with GABAA, serotoninergic 5-HT1A, 5-HT1B, 5-HT4, and dopaminergic D2 receptor distributions, and that the thickness pattern followed structural connectivity. CONCLUSIONS:MRI-derived cortical thickness changes in dementia with Lewy bodies reflect selective molecular and network vulnerabilities rather than a non-specific degenerative process. Mitochondrial and synaptic genes, together with a distinct GABAergic association and connectivity constraints, delineate mechanisms explaining why some cortical territories are more affected in dementia with Lewy bodies.

Purpose of reviewParkinsonian syndromes are a heterogeneous group of neurodegenerative diseases that pose challenges in early diagnosis, differentiation, and pathophysiological understanding. The objective of this review is to summarize recent contributions of computational models combined with neuroimaging data to the differential diagnosis of Parkinsonian syndromes, disease subtyping, and understanding of disease processes.Recent findingsUsing machine learning algorithms trained with MRI features, diagnostic accuracies above 90% have been achieved for distinguishing patients with Parkinson’s disease from healthy controls and for the differential diagnosis of Parkinsonian syndromes. Computational models, such as hierarchical cluster analysis and Subtype and Stage Inference (SuStaIn), have enabled the identification of distinct disease subtypes within Parkinson’s disease based on imaging-derived brain features. Network models based on structural and functional connectomes have revealed that disease spread in Parkinson’s disease is primarily driven by global connectivity. Additionally, local brain characteristics such as gene expression, cellular composition, and neuroreceptor profiles may contribute to selective vulnerabilities.SummaryComputational approaches enhance the diagnosis of Parkinsonian syndromes, particularly in the early stages, and refine the characterization of disease subtypes, benefiting clinicians, especially in non-expert centers. Such applications hold significant potential for enabling more personalized management and selecting appropriate candidates for clinical trials. Furthermore, a deeper understanding of pathophysiology supports the development of disease-specific therapies.

ABSTRACT Background Degeneration in the cholinergic nucleus basalis of Meynert (nbM) is thought to contribute to early cognitive deficits in Parkinson’s disease (PD). However, it is unknown whether this relationship is confounded by the parallel degeneration of the substantia nigra (SN) and the locus coeruleus (LC), and whether this relationship is unique to PD. Methods We conducted a cross-sectional analysis in 112 PD patients (disease duration <10 years) and 46 controls who underwent standard neuropsychological testing, diffusion-weighted and neuromelanin magnetic resonance imaging. Mean diffusivity (MD) of the nbM and neuromelanin signal of the SN and LC were used as proxy measures of neurodegeneration. Results nbM MD did not differ between PD patients and controls (β=0.05, 95% CI [−0.27, 0.37], p =.771), a finding that was replicated using other MRI metrics. Higher nbM MD in PD patients was associated with worse executive function (β=−0.22, 95% CI [−0.39, −0.05], p FDR =.027), controlling for degeneration in the SN and LC. An association with attention did not survive multiple comparisons correction (β=−0.22, 95% CI [−0.41, −0.02], p FDR =.112), and there was no association with memory (β=0.08, 95% CI [−0.15, 0.30], p FDR =.572). When considering both groups jointly, the relationship between increased nbM MD and worse executive function was stronger in PD than controls (β nbM * Group =−0.30, 95% CI [−0.54, −0.06], p FDR =.036). Conclusion Our findings suggest that in early-stage PD, nbM microstructural changes may account for unique variance in executive dysfunction in PD, independent of the effects of LC degeneration, and with a stronger association in PD than controls. KEY MESSAGES What is already known on this topic Although cognitive deficits may stem, at least in part, from degeneration of cholinergic neurons in the nucleus basalis of Meynert (nbM), it is unknown whether this relationship is confounded by the parallel degeneration of the substantia nigra (SN) and the locus coeruleus (LC), and whether this relationship is unique to PD. What this study adds The novelty of our approach is that we considered the effects of the nbM, SN, and LC jointly rather than in isolation. We found that in early-stage PD, loss of nbM microstructural integrity was associated with executive dysfunction in PD, independent of the association of LC and executive dysfunction. How this study might affect research, practice, or policy These findings have important clinical implications because they suggest that the effects of degeneration in the cholinergic and noradrenergic system are at least partially independent and therefore could be targeted separately for remediating cognitive impairments.

Aquaporin-4 (AQP4) water channels support the glymphatic system, a brain-wide pathway that clears cerebral waste products. Despite its importance, the whole-brain organization of this system in humans remains underexplored. Here we use AQP4 gene expression as a molecular anchor to reconstruct a whole-brain glymphatic-related topography and link it to vascular physiology, edema, and neurodegenerative vulnerability. We find that AQP4 expression is highly organized across the brain, peaking in subcortical, ventral, and periventricular territories, consistent with a clearance axis near cerebrospinal fluid reservoirs and perivascular interfaces. Linking AQP4 expression to vascular organization, we find that AQP4-enriched regions show lower normative blood perfusion and lower vein density, suggesting that this axis is not simply explained by vascular supply or large-vessel anatomy. Turning to neurodegeneration, we find that atrophy patterns across multiple neurodegenerative diseases co-localize with AQP4 expression---most strongly for tau and TDP-43 proteinopathies---and high-atrophy regions lie close to AQP4 hotspots in both anatomical space and structural connectome space. Furthermore, incorporating normative PET markers of neuroinflammation typically strengthens the spatial alignment between AQP4 expression and disease atrophy, suggesting that inflammatory tone and glymphatic-related architecture jointly shape vulnerability. Finally, we show that peritumoral edema is most frequent in AQP4-enriched regions and is further shaped by regional inflammatory tone. Collectively, this work highlights a whole-brain glymphatic organization that relates to diverse aspects of brain physiology and vulnerability.

Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them with disorder-specific, microarchitectural, neurotransmitter-level, and connectome measures. Positive and negative schizotypy were associated with distinct cortical signatures, of predominantly thinner frontal and thicker paralimbic cortical areas, respectively. These cortical signatures of positive and negative schizotypy were differentially linked to brain-wide cortical patterns of schizophrenia-spectrum (clinical high-risk for psychosis, schizophrenia) and neurodevelopmental conditions (ADHD, autism spectrum disorder and 22q11.2 deletion syndrome). Additionally, the positive and negative schizotypy-related cortical profiles mapped onto different local attributes of gene expression, cortical myelination, D1, and histamine receptor distributions. Network models further showed that positive and negative schizotypy cortical signatures were spatially associated with cortical hubs, suggesting that highly interconnected regions are more vulnerable to the morphological differences associated with both schizotypy dimensions. Finally, predominantly sensorimotor-to-association and paralimbic areas emerged as epicenters with connectivity profiles significantly linked to the schizotypy-related cortical patterns. Collectively, this study identified cortical signatures of positive and negative schizotypy traits that are embedded along multiple scales of cortical organization and neuropsychiatric pathologies. Our work yields novel insights into how neurobiology and brain architecture may guide neuroanatomical vulnerability and resilience to psychopathology in the general population.

BACKGROUND:Alzheimer's disease (AD) co-pathology contributes to dementia in PD, but its role in earlier cognitive impairment remains uncertain. OBJECTIVE:To determine if p-tau217, a biomarker of early AD, is associated with cognitive impairment in PD. METHODS:Plasma p-tau217 levels in 167 PD patients without dementia and 63 controls were related to performance on standard neuropsychological testing, and to cognitive impairment as defined by a MoCA score <26 and by self-report. Plasma GFAP, NfL and APOE ε4 carrier status were also examined. RESULTS:No significant differences in p-tau217, GFAP and NfL level were observed between groups (pFDR > 0.08). Higher p-tau217 was associated with worse visuospatial function and greater self-reported cognitive impairment, but these associations did not survive correction (pFDR > 0.08). There was no association with cognitive impairment (pFDR > 0.08). CONCLUSION:These results suggest that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Objective To examine changes in the neural valuation of high- versus low-calorie stimuli following bariatric surgery and determine whether these changes relate to weight loss at 24 months. Methods Adults undergoing bariatric surgery completed fMRI scans before surgery and at 4, 12 and 24 months post-surgery while performing the Becker-DeGroot-Marschak auction task to assess willingness- to-pay (WTP) for food stimuli. Linear mixed-effect models tested longitudinal changes in WTP-related blood oxygen level-dependent (BOLD) associations and their interactions with total weight loss at 24 months. Results WTP for high-calorie foods decreased significantly after surgery, WTP of low-calorie foods remained stable. At 4 months, WTP-BOLD associations for high- versus low-calorie stimuli were enhanced within the frontoparietal control network and right lateral orbitofrontal cortex relative to pre surgery. These early postoperative changes did not correlate with 24-month weight loss. Instead, greater 24-month weight loss correlated with both pre-surgical and long-term changes (24 months versus pre-surgery) in WTP-BOLD associations within the precuneus, inferior parietal cortex and visual cortex. Conclusion Bariatric surgery induces early reductions in the valuation of high-calorie foods, potentially through enhanced cognitive control and aversive processing. However, long-term weight-loss success appears more strongly related to trait-like neural differences in self-referential and attentional processing.

Neuropeptides are functionally diverse signaling molecules in the brain, regulating a wide range of basal bodily and cognitive processes. Despite their importance, the distribution and function of neuropeptides in the human brain remains underexplored. Here we comprehensively map the organization of human whole-brain neuropeptide receptors across multiple levels of description, including molecular and cellular embedding, mesoscale connectivity and macroscale cognitive specialization. Using gene transcription as a proxy, we reconstruct a topographical cortical and subcortical atlas of 38 neuropeptide receptors across 14 different neuropeptide families. We find that most neuropeptide receptors are highly expressed either in the cortex or subcortex, delineating an anatomical cortical-subcortical gradient. Mapping neuropeptide receptors onto hypothalamic nuclei, we demonstrate that neuropeptide receptor gene expression recapitulates fundamental anatomical divisions in the hypothalamus. Neuropeptides preferentially colocalize with metabotropic neurotransmitters, suggesting a system-wide correspondence between slow-acting molecular signaling mechanisms. To investigate the behavioral consequences of distributed neuropeptide systems, we apply meta-analytical decoding to neuropeptide maps and show a spectrum of functions, from sensory-cognitive to reward and bodily functions. Finally, using evolutionary analysis we find extended positive selection for neuropeptides in early mammals, suggesting that refinement of neuropeptides coincides with the emergence of neocortex and higher cognitive function. Collectively, these results show that neuropeptide receptors are highly organized across the human brain and closely intertwined with multiple features of brain structure and function.

BACKGROUND:Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathy such as Parkinson's disease (PD). Brain cholinergic alterations have been reported in these diseases, but direct comparisons of terminal density between iRBD and clinically manifest PD have not yet been performed. OBJECTIVES:To assess brain cholinergic terminal density in iRBD using positron emission tomography (PET) with [18F]-fluoroethoxybenzovesamicol (FEOBV), and to compare findings with both healthy controls and patients with PD. METHODS:Forty-six participants (16 with polysomnography-confirmed iRBD, 12 with PD, and 18 controls) underwent high-resolution PET neuroimaging with FEOBV. Voxel-wise analyses and effect size mapping were conducted to compare the groups, using standardized uptake value ratios (SUVRs). Correlations were performed between whole-cortex SUVR and clinical measures. RESULTS:Compared to controls, both the iRBD and PD groups exhibited significant cortical cholinergic denervation of similar magnitudes (11-12 %). Effect size mapping revealed very large losses (Cohen's ds < -1.5) in the posterior cortex in both patient groups, predominantly occipital-parietal in iRBD and occipital-temporal in PD. In iRBD, lower cortical uptake was associated with poorer performance on executive and visuospatial tests. Moreover, in iRBD but not in PD, there was a trend toward higher FEOBV uptake in subcortical areas, including brainstem regions. CONCLUSIONS:Cholinergic denervation in iRBD is comparable in extent to that in PD, with subtle topographic distinctions, and correlates with cognitive deficits.

Substance use disorders (SUD) are chronic conditions with devastating effects on brain health, functioning, and survival. In this study, we compared brain morphometry of 2,782 individuals with SUD to 1,951 controls and assessed the topographic overlap of these differences with brain connectivity and receptor architecture. Across SUD, we identified a morphometric signature involving frontal, parietal, temporal and limbic systems that overlapped with cortical hub regions and harbored cortical and subcortical disease epicenters. Findings were highly consistent across six substances and numerous robustness and generalizability analyses. Transdiagnostic comparisons showed high spatial overlap of SUD epicenters with those of schizophrenia and bipolar disorder, suggesting shared network-constrained cortical differences. Finally, multivariate mapping revealed that SUD brain differences aligned with two neurotransmitter axes contrasting cannabinoid-opioid and dopaminergic systems. These findings indicate that addiction-related brain differences are shaped by connectome and neurotransmitter architecture, positioning brain network and neurochemical organization as key principles of SUD-related brain alterations.

Type 2 diabetes (T2D) is associated with cognitive impairment, but it remains unclear whether this reflects primary effects of metabolic dysfunction or secondary consequences of comorbid conditions, as most studies have focused on older adults. To address this, we examined the relationship between prediabetes and cognition in youth with overweight/obesity in a 2-year longitudinal study (n=67 at baseline; n=42 at follow-up). Participants underwent comprehensive cognitive testing, metabolic phenotyping, and structural and functional neuroimaging. At baseline, youth with prediabetes exhibited lower IQ and poorer performance in executive function, psychomotor speed, and visuospatial processing compared to those with normal glucose control, independent of adiposity. Across the full sample, reduced peripheral insulin sensitivity was associated with slower processing speed and altered central insulin sensitivity in the intraparietal sulcus. Longitudinally, cognitive differences between groups were stable over 2 years and were not explained by changes in adiposity or glucose tolerance. In contrast, expected developmental reductions in cortical surface area were observed only in youth with normal glucose control. These findings demonstrate that prediabetes in youth is associated with a broad and stable neurocognitive disadvantage that is independent of adiposity and not readily reversible with short-term changes in metabolic status. The early emergence and persistence of these differences suggest that altered neurocognitive function may be a feature of metabolic risk prior to overt disease onset. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by R01 DK114169 awarded to D.M.S and S.C. from the National Institute of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB Human Investigation Committee of Yale University gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes De-identified data may be accessed on a case-by-case basis by contacting the corresponding author.

The brain and body undergo coordinated changes throughout the life span, yet studies of aging have traditionally examined these systems as separate entities. Here we ask how brain health relates to aging and peripheral biomarkers of metabolic and vascular function, including body mass index, blood pressure, and blood biochemistry. We use multivariate pattern learning to identify generalizable patterns of covariance between multi-modal neuroimaging data (structural, functional, diffusion, and arterial spin labeling MRI), demographic, and physiological markers in two large-scale deeply phenotyped datasets: the Human Connectome Project-Aging and UK Biobank. This data-driven approach isolates two principal axes of brain-body associations in both biological sexes. The first axis is driven by the dominant contribution of age. Across multiple brain measures, aging is associated with loss of brain structural integrity and cerebral vascular dysfunction. The second axis is driven by metabolic features, characterized by low high-density lipoprotein cholesterol, elevated body mass index, blood pressure, glycosylated hemoglobin, insulin, glucose, and alanine aminotransferase that predominantly converge on reduced cerebral perfusion. Importantly, the aging and the metabolic axes are independent of each other, meaning that age and metabolic dysfunction have separable influences on the brain. Finally, we show that deviations from a healthy metabolic profile are linked to cognitive deficits, particularly in females. Our study contributes to development of comprehensive translatable biomarkers for brain health assessment, and highlights the importance of metabolic health as a determinant of brain health in aging population.

Abstract Background Neuromelanin-MRI enables in vivo assessment of the substantia nigra (SN) and locus coeruleus (LC) in individuals with Parkinson’s disease (PD), yet longitudinal studies rely on cross-sectional processing that may introduce measurement variability and confound estimates of change over time. Objectives In this paper, a longitudinal neuromelanin-MRI processing framework is presented that is designed and validated to improve measurement stability and reduce processing-related variability across repeated scans. Methods Imaging and clinical data from the Quebec Parkinson Network were analyzed in 268 participants (199 PD, 69 controls), including a longitudinal subset of 74 participants (49 PD, 25 controls) scanned approximately one year apart. Validation experiments evaluated slice-by-slice intensity normalization for slice dependent intensity variation, bias field correction for LC signal asymmetry, and the effects of longitudinal registration on measurement stability and PD-control discrimination. Results Slice-by-slice intensity normalization significantly reduced brainstem intensity variability by 3.6%. A systematic leftward signal asymmetry was observed in the LC and persisted following N4 bias field correction, suggesting a scanner-related effect not captured by conventional bias field modeling. Longitudinal registration reduced annualized change variability by 25-36% for SN CR and 27-34% for LC CR metrics in controls, indicating improved within-subject measurement stability. Residual variability was also reduced for contrast-based metrics by up to 28%. Longitudinal registration generally produced larger PD-control effect sizes at baseline and follow-up, particularly for SN volume metrics. However, no significant method × group × time interactions were observed, indicating that estimated longitudinal trajectories did not differ significantly between longitudinal and conventional cross-sectional processing. Conclusions Longitudinal registration reduced technical variability and improved the precision of NM-MRI measurements. Although it did not significantly enhance detection of longitudinal PD-control differences over the follow-up interval examined here, it provides a more robust framework for longitudinal NM-MRI studies and may improve sensitivity to subtler biological effects in future investigations.

Pathogenic LRRK2 gene variants are a major genetic risk factor for both familial and sporadic Parkinson’s dissease (PD), opening an unattended window into disease mechanisms and potential therapies. Investigating the influence of pathogenic variants in LRRK2 gene on brain structure is a crucial step toward enabling early diagnosis and personalized treatment. Yet, despite its significance, the ways in which LRRK2 genotype affects brain structure remain largely unexplored. Work in this domain is plagued by small sample sizes and differences in cohort composition, which can obscure genuine distinctions among clinical subgroups. In this study, we overcome such important limitations by combining explicit modeling of population background variation and pattern matching. Specifically, we leverage a cohort of 603 participants (including 370 with a PD diagnosis) to examine MRI-detectable cortical atrophy patterns associated with the LRRK2 pathogenic variants in people with PD and carriers without Parkinson’s symptoms. LRRK2 PD patients exhibit milder cortical thinning compared to sporadic PD, with notable preservation in temporal and occipital regions, suggesting a distinct pattern of neurodegeneration. Non-manifesting LRRK2 carriers show no significant cortical atrophy, indicating no structural signs of subclinical PD. We further analyze the relationship between aggregated alpha-synuclein in cerebrospinal fluid and atrophy. We find that those with evidence of aggregated alpha-synuclein experienced pronounced neurodegeneration and increased cortical thinning, possibly defining another aggressive PD subtype. Our findings highlight genetic avenues for distinguishing PD subtypes, which could lead to more targeted treatment approaches and a more complete understanding of Parkinson’s disease progression. Parkinson’s disease is a brain disorder that affects movement, thinking, and daily functioning. While most cases have no clear cause, some people carry rare changes in a gene called LRRK2. Another important factor is a brain protein called alpha-synuclein, which can build up in harmful ways. In this study, we used brain scans from a large international project to understand how these genetic and protein markers relate to brain changes. We found that people with LRRK2 mutations had less brain damage than those with typical Parkinson’s disease, even when they had similar symptoms. This suggests that some people may have natural protection in the brain. Our findings could help doctors better understand different forms of Parkinson’s and guide more personalized treatments in the future. Kopal et al. analyze MRI data from a Parkinson’s Disease cohort to assess how LRRK2 gene variants shape brain structure. They find that LRRK2-associated Parkinson’s Disease shows a milder and anatomically distinct pattern of neurodegeneration compared to non LRRK2-associated Parkinson’s Disease.

Patients with Parkinson's disease (PD) frequently present autonomic cardiovascular dysfunction. This study investigated the involvement of autonomic centers in the upper thoracic spinal cord in cardiovascular dysfunction in patients with PD using multimodal MRI and markers of orthostatic hypotension. We recruited 26 patients with PD, stratified based on the presence (PDRBD(+), n = 11) or absence (PDRBD(-), n = 15) of rapid-eye movement sleep behavior disorder (RBD), and 22 matched healthy controls (HC). Participants underwent multimodal MRI of the cervical and upper thoracic spinal cord. Quantitative metrics, including T1 relaxation times, diffusion metrics, and magnetization transfer ratio (MTR) values, were extracted from gray and white matter spinal cord regions. MRI metrics were compared across groups and examined for associations with blood pressure drops, both cross-sectionally and longitudinally, as indicators of orthostatic hypotension. No significant differences in MRI metrics were found between patients with PD and HCs, nor between PD subgroups. A multivariate analysis pooling all MRI metrics together allowed for the separation of HCs and PD subgroups. In the PDRBD(+) subgroup, positive correlations were found between systolic blood pressure drop and T1 relaxation times as well as mean diffusivity values at the cervicothoracic junction. Longitudinal changes in blood pressure drops were associated with MRI measurements after adjusting for baseline blood pressure, age, and sex, suggesting that these metrics may serve as potential markers of future blood pressure changes. These preliminary findings suggest that spinal cord quantitative MRI measurements at the cervicothoracic junction may be associated with orthostatic hypotension in PDRBD(+) patients.