Differential effects of tau stage, Lewy body pathology, and substantia nigra degeneration on FDG-PET patterns in clinical AD

PURPOSE: Comorbid Lewy body (LB) pathology is common in AD. The effect of LB co-pathology on FDG-PET patterns in AD is yet to be studied. We analysed associations of neuropathologically-assessed tau pathology, LB pathology, and substantia nigra neuron loss (SNnl) with ante-mortem FDG-PET hypometabolism in patients with a clinical AD presentation. METHODS: Twenty-one patients with autopsy-confirmed AD (‘pure-AD’), 24 with AD and LB co-pathology (‘AD-LB’), and 7 with LB but no or low evidence of AD pathology (‘pure-LB’) were studied. Pathologic groups were compared on regional and voxel-wise FDG-PET patterns, the cingulate island sign ratio (CISr), and neuropathological ratings of SNnl. Additional analyses assessed continuous associations of Braak tangle stage and SNnl with FDG-PET patterns. RESULTS: Pure-AD and AD-LB showed highly similar patterns of AD-typical temporo-parietal hypometabolism and did not differ in CISr, regional FDG SUVR, or SNnl. By contrast, pure-LB showed the expected DLB-like pattern, accompanied by pronounced occipital hypometabolism and elevated CISr and SNnl compared to the AD groups. In continuous analyses, Braak tangle stage was significantly correlated with more AD-like, and SNnl with more DLB-like, FDG-PET patterns. CONCLUSIONS: In autopsy-confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional FDG-PET pattern. A more DLB-like 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

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

A clinical diagnosis of Alzheimer's disease dementia encompasses considerable pathological and clinical heterogeneity. While Alzheimer's disease patients typically show a characteristic temporo-parietal pattern of glucose hypometabolism on FDG-PET imaging, previous studies 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 suggestive of Lewy body pathology in patients with Alzheimer's disease-like amnestic presentations. Our study included 1214 patients with clinical diagnoses of Alzheimer's disease dementia (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 suggestive of Alzheimer's (AD-like) or Lewy body (LB-like) pathology by using a logistic regression classifier previously 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 Aβ- and tau-PET, domain-specific cognitive profiles (memory vs executive function performance), as well as the presence of hallucinations and their evolution over follow-up (≈6y for aMCI, ≈3y for ADD). 13.7% of the aMCI patients and 12.5% of the 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 AD-like, but Aβ 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: HR=1.8, 95% CI = [1.29, 3.04], p=0.02; ADD: HR=2.2, 95% CI = [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

Non‑motor symptom burden in patients with parkinson’s disease with impulse control disorders and compulsive behaviours: results from the coppADiS cohort

The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson’s disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS‑2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for impulsive‑compulsive Disorders in parkinson’s Disease-Rating Scale (QUIP‑RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment‑related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved under- standing of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, inter- rogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain tran- scriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

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

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

Altres ajuts: acord transformatiu CRUE-CSICBackground 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 (β = 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

Metabolite and lipoprotein profiles reveal sex-related oxidative stress imbalance in de novo drug-naive Parkinson's disease patients

Parkinson's disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age- and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients

Abstract: A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings’ risk is not elevated