Characteristics of amnestic patients with hypometabolism patterns suggestive of Lewy body pathology.

A clinical diagnosis of Alzheimer's disease dementia (ADD) encompasses considerable pathological and clinical heterogeneity. While Alzheimer's disease patients typically show a characteristic temporo-parietal pattern of glucose hypometabolism on 18F-fluorodeoxyglucose (FDG)-PET imaging, previous studies have identified a subset of patients showing a distinct posterior-occipital hypometabolism pattern associated with Lewy body pathology. Here, we aimed to improve the understanding of the clinical relevance of these posterior-occipital FDG-PET patterns in patients with Alzheimer's disease-like amnestic presentations. Our study included 1214 patients with clinical diagnoses of ADD (n = 305) or amnestic mild cognitive impairment (aMCI, n = 909) from the Alzheimer's Disease Neuroimaging Initiative, who had FDG-PET scans available. Individual FDG-PET scans were classified as being suggestive of Alzheimer's (AD-like) or Lewy body (LB-like) pathology by using a logistic regression classifier trained on a separate set of patients with autopsy-confirmed Alzheimer's disease or Lewy body pathology. AD- and LB-like subgroups were compared on amyloid-ß and tau-PET, domain-specific cognitive profiles (memory versus executive function performance), as well as the presence of hallucinations and their evolution over follow-up (≈6 years for aMCI, ≈3 years for ADD). Around 12% of the aMCI and ADD patients were classified as LB-like. For both aMCI and ADD patients, the LB-like group showed significantly lower regional tau-PET burden than the AD-like subgroup, but amyloid-ß load was only significantly lower in the aMCI LB-like subgroup. LB- and AD-like subgroups did not significantly differ in global cognition (aMCI: d = 0.15, P = 0.16; ADD: d = 0.02, P = 0.90), but LB-like patients exhibited a more dysexecutive cognitive profile relative to the memory deficit (aMCI: d = 0.35, P = 0.01; ADD: d = 0.85 P < 0.001), and had a significantly higher risk of developing hallucinations over follow-up [aMCI: hazard ratio = 1.8, 95% confidence interval = (1.29, 3.04), P = 0.02; ADD: hazard ratio = 2.2, 95% confidence interval = (1.53, 4.06) P = 0.01]. In summary, a sizeable group of clinically diagnosed ADD and aMCI patients exhibit posterior-occipital FDG-PET patterns typically associated with Lewy body pathology, and these also show less abnormal Alzheimer's disease biomarkers as well as specific clinical features typically associated with dementia with Lewy bodies.

Distribution of cholinergic nerve terminals in the aged human brain measured with [18F]FEOBV PET and its correlation with histological data.

INTRODUCTION: [18F]fluoroetoxybenzovesamicol ([18F]FEOBV) is a positron emission topography (PET) tracer for the vesicular acetylcholine transporter (VAChT), a protein located predominantly in synaptic vesicles in cholinergic nerve terminals. We aimed to use [18F]FEOBV PET to study the cholinergic topography of the healthy human brain. MATERIALS AND METHODS: [18F]FEOBV PET brain data volumes of healthy elderly humans were normalized to standard space and intensity-normalized to the white matter. Stereotactic atlases of regions of interest were superimposed to describe and quantify tracer distribution. The spatial distribution of [18F]FEOBV PET uptake was compared with histological and gene expression data. RESULTS: Twenty participants of both sexes and a mean age of 73.9 ± 6.0 years, age-range [64; 86], were recruited. Highest tracer binding was present in the striatum, some thalamic nuclei, and the basal forebrain. Intermediate binding was found in most nuclei of the brainstem, thalamus, and hypothalamus; the vermis and flocculonodular lobe; and the hippocampus, amygdala, insula, cingulate, olfactory cortex, and Heschl's gyrus. Lowest binding was present in most areas of the cerebral cortex, and in the cerebellar nuclei and hemispheres. The spatial distribution of tracer correlated with immunohistochemical post-mortem data, as well as with regional expression levels of SLC18A3, the VAChT coding gene. DISCUSSION: Our in vivo findings confirm the regional cholinergic distribution in specific brain structures as described post-mortem. A positive spatial correlation between tracer distribution and regional gene expression levels further corroborates [18F]FEOBV PET as a validated tool for in vivo cholinergic imaging. The study represents an advancement in the continued efforts to delineate the spatial topography of the human cholinergic system in vivo.

Basal Forebrain Atrophy, Cortical Thinning, and Amyloid-ß Status in Parkinson's disease-Related Cognitive Decline.

BACKGROUND: Degeneration of the cortically-projecting cholinergic basal forebrain (cBF) is a well-established pathologic correlate of cognitive decline in Parkinson's disease (PD). In Alzheimer's disease (AD) the effect of cBF degeneration on cognitive decline was found to be mediated by parallel atrophy of denervated cortical areas. OBJECTIVES: To examine whether the association between cBF degeneration and cognitive decline in PD is mediated by parallel atrophy of cortical areas and whether these associations depend on the presence of comorbid AD pathology. METHODS: We studied 162 de novo PD patients who underwent serial 3 T magnetic resonance imaging scanning (follow-up: 2.33 ± 1.46 years) within the Parkinson's Progression Markers Initiative. cBF volume and regional cortical thickness were automatically calculated using established procedures. Individual slopes of structural brain changes and cognitive decline were estimated using linear-mixed models. Associations between longitudinal cBF degeneration, regional cortical thinning, and cognitive decline were assessed using regression analyses and mediation effects were assessed using nonparametric bootstrap. Complementary analyses assessed the effect of amyloid-ß biomarker positivity on these associations. RESULTS: After controlling for global brain atrophy, longitudinal cBF degeneration was highly correlated with faster cortical thinning (PFDR < 0.05), and thinning in cBF-associated cortical areas mediated the association between cBF degeneration and cognitive decline (rcBF-MoCA = 0.30, P < 0.001). Interestingly, both longitudinal cBF degeneration and its association with cortical thinning were largely independent of amyloid-ß status. CONCLUSIONS: cBF degeneration in PD is linked to parallel thinning of cortical target areas, which mediate the effect on cognitive decline. These associations are independent of amyloid-ß status, indicating that they reflect proper features of PD pathophysiology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical and structural brain correlates of hypomimia in early-stage Parkinson's disease.

BACKGROUND AND PURPOSE: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. METHODS: The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross-sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used. RESULTS: After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS-III speech and bradykinesia items and was significantly related to the severity of apathy (ß = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-temporo-parietal regions involved in the decoding, recognition and production of facial expression of emotions. CONCLUSION: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-motor aspects converge.

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight.

BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country. METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.

Differential Effects of Tau Stage, Lewy Body Pathology, and Substantia Nigra Degeneration on 18F-FDG PET Patterns in Clinical Alzheimer Disease.

Comorbid Lewy body (LB) pathology is common in Alzheimer disease (AD). The effect of LB copathology on 18F-FDG PET patterns in AD is yet to be studied. We analyzed associations of neuropathologically assessed tau pathology, LB pathology, and substantia nigra neuronal loss (SNnl) with antemortem 18F-FDG PET hypometabolism in patients with a clinical AD presentation. Methods: Twenty-one patients with autopsy-confirmed AD without LB neuropathologic changes (LBNC) (pure-AD), 24 with AD and LBNC copathology (AD-LB), and 7 with LBNC without fulfilling neuropathologic criteria for AD (pure-LB) were studied. Pathologic groups were compared regarding regional and voxelwise 18F-FDG PET patterns, the cingulate island sign ratio (CISr), and neuropathologic ratings of SNnl. Additional analyses assessed continuous associations of Braak tangle stage and SNnl with 18F-FDG PET patterns. Results: Pure-AD and AD-LB showed highly similar patterns of AD-typical temporoparietal hypometabolism and did not differ in CISr, regional 18F-FDG SUVR, or SNnl. By contrast, pure-LB showed the expected pattern of pronounced posterior-occipital hypometabolism typical for dementia with LB (DLB), and both CISr and SNnl were significantly higher compared with the AD groups. In continuous analyses, Braak tangle stage correlated significantly with more AD-like, and SNnl with more DLB-like, 18F-FDG PET patterns. Conclusion: In autopsy-confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional 18F-FDG PET pattern. A more DLB-like 18F-FDG PET pattern was observed in relation to SNnl, but advanced SNnl was mostly limited to relatively pure LB cases. AD pathology may have a dominant effect over LB pathology in determining the regional neurodegeneration phenotype.

ADCoC: Adaptive Distribution Modeling Based Collaborative Clustering for Disentangling Disease Heterogeneity from Neuroimaging Data.

Conventional clustering techniques for neuroimaging applications usually focus on capturing differences between given subjects, while neglecting arising differences between features and the potential bias caused by degraded data quality. In practice, collected neuroimaging data are often inevitably contaminated by noise, which may lead to errors in clustering and clinical interpretation. Additionally, most methods ignore the importance of feature grouping towards optimal clustering. In this paper, we exploit the underlying heterogeneous clusters of features to serve as weak supervision for improved clustering of subjects, which is achieved by simultaneously clustering subjects and features via nonnegative matrix tri-factorization. In order to suppress noise, we further introduce adaptive regularization based on coefficient distribution modeling. Particularly, unlike conventional sparsity regularization techniques that assume zero mean of the coefficients, we form the distributions using the data of interest so that they could better fit the non-negative coefficients. In this manner, the proposed approach is expected to be more effective and robust against noise. We compared the proposed method with standard techniques and recently published methods demonstrating superior clustering performance on synthetic data with known ground truth labels. Furthermore, when applying our proposed technique to magnetic resonance imaging (MRI) data from a cohort of patients with Parkinson's disease, we identified two stable and highly reproducible patient clusters characterized by frontal and posterior cortical/medial temporal atrophy patterns, respectively, which also showed corresponding differences in cognitive characteristics.

Increased homocysteine levels correlate with cortical structural damage in Parkinson's disease.

BACKGROUND: Blood homocysteine appears to be increased in Parkinson's disease (PD) and may play a role in the development and progression of this disorder. However, the specific contribution of abnormal homocysteine levels to cortical degeneration in PD remains elusive. OBJECTIVE: To characterize the cortical structural correlates of homocysteine levels in PD. METHODS: From the COPPADIS cohort, we identified a subset of PD patients and healthy controls (HC) with available homocysteine and imaging data. Surface-based vertex-wise multiple regression analyses were performed to investigate the cortical macrostructural (cortical thinning) and microstructural (increased intracortical diffusivity) correlates of homocysteine levels in this sample. RESULTS: A total of 137 PD patients and 43 HC were included. Homocysteine levels were increased in the PD group (t = -2.2, p = 0.03), correlating in turn with cognitive performance (r = -0.2, p = 0.03). Homocysteine in PD was also associated with frontal cortical thinning and, in a subset of patients with available DTI data, with microstructural damage in frontal and posterior-cortical regions (p < 0.05 Monte-Carlo corrected). CONCLUSIONS: Homocysteine in PD appears to be associated with cognitive performance and structural damage in the cerebral cortex. These findings not only reinforce the presence and importance of cortical degeneration in PD, but also suggest that homocysteine plays a role among the multiple pathological processes thought to be involved in its development.

Levodopa-Induced Dyskinesia in Parkinson Disease Specifically Associates With Dopaminergic Depletion in Sensorimotor-Related Functional Subregions of the Striatum.

PURPOSE: To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum. METHODS: Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker's Initiative using mixed linear model analysis. RESULTS: Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker's Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = -2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time. CONCLUSION: Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study.

INTRODUCTION: We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia. METHODS: The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models. RESULTS: Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02). CONCLUSIONS: Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.

A geroscience approach for Parkinson's disease: Conceptual framework and design of PROPAG-AGEING project.

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naïve and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development.