Longitudinal cognitive decline characterizes the profile of non-PD-manifest GBA1 mutation carriers.

With disease-modifying treatment for Parkinson's disease (PD) associated with variants in the glucocerebrosidase gene (GBA1) under way, the challenge to design clinical trials with non-PD-manifest GBA mutation carriers (GBA1NMC) comes within close reach. To delineate trajectories of motor and non-motor markers as well as serum neurofilament light (sNfL) levels and to evaluate clinical endpoints as outcomes for clinical trials in GBA1NMC, longitudinal data of 56 GBA1NMC carriers and 112 age- and sex-matched GBA1 wildtype participants (GBA1wildtype) with up to 9 years of follow-up was analyzed using linear mixed-effects models (LMEM) and Kaplan-Meier survival analysis of clinical endpoints for motor and cognitive function. GBA1NMC showed worse performance in Pegboard, 20 m fast walking, global cognition as well as in executive and memory function at baseline. Longitudinally, LMEM revealed a higher annual increase of the MDS-UPDRS III bradykinesia subscore in GBA1NMC compared to GBA1wildtype, but comparable trajectories of all other motor and non-motor markers as well as sNfL. Kaplan-Meier survival analysis showed a significantly earlier progression to clinical endpoints of cognitive decline in GBA1NMC. Incidence of PD was significantly higher in GBA1NMC. In conclusion, our study extends data on GBA1NMC indicating early cognitive decline as a potentially characteristic feature. Comprehensive longitudinal assessments of cognitive function are crucial to delineate the evolution of early changes in GBA1NMC enabling a more accurate stratification and allow for a more precise definition of trial design and sample size.

The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis.

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management. OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®. RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue. CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.

CSF α-synuclein seed amplification kinetic profiles are associated with cognitive decline in Parkinson's disease.

Seed amplification assays have been implemented in Parkinson's disease to reveal disease-specific misfolded alpha-synuclein aggregates in biospecimens. While the assays' qualitative dichotomous seeding response is valuable to stratify and enrich cohorts for alpha-synuclein pathology in general, more quantitative parameters that are associated with clinical dynamics of disease progression and that might potentially serve as exploratory outcome measures in clinical trials targeting alpha-synuclein would add important information. To evaluate whether the seeding kinetic parameters time required to reach the seeding threshold (LAG phase), the peak of fluorescence response (Imax), and the area under the curve (AUC) are associated with clinical trajectories, we analyzed LAG, Imax, and AUC in relation to the development of cognitive decline in a longitudinal cohort of 199 people with Parkinson's disease with positive CSF alpha-synuclein seeding status. Patients were stratified into tertiles based on their individual CSF alpha-synuclein seeding kinetic properties. The effect of the kinetic parameters on longitudinal development of cognitive impairment defined by MoCA ≤25 was analyzed by Cox-Regression. Patients with a higher number of positive seeding replicates and tertile groups of shorter LAG, higher Imax, and higher AUC showed a higher prevalence of and a shorter duration until cognitive impairment longitudinally (3, 6, and 3 years earlier with p ≤ 0.001, respectively). Results remained similar in separate subgroup analyses of patients with and without GBA mutation. We conclude that a more prominent alpha-synuclein seeding kinetic profile translates into a more rapid development of cognitive decline.

Inflammatory CSF profiles and longitudinal development of cognitive decline in sporadic and GBA-associated PD.

Inflammation modifies the incidence and progression of Parkinson's disease (PD). By using 30 inflammatory markers in CSF in 498 people with PD and 67 people with dementia with Lewy bodies (DLB) we show that: (1) levels of ICAM-1, Interleukin-8, MCP-1, MIP-1 beta, SCF and VEGF were associated with clinical scores and neurodegenerative CSF biomarkers (Aß1-42, t-Tau, p181-Tau, NFL and α-synuclein). (2) PD patients with GBA mutations show similar levels of inflammatory markers compared to PD patients without GBA mutations, even when stratified by mutation severity. (3) PD patients who longitudinally developed cognitive impairment during the study had higher levels of TNF-alpha at baseline compared to patients without the development of cognitive impairment. (4) Higher levels of VEGF and MIP-1 beta were associated with a longer duration until the development of cognitive impairment. We conclude that the majority of inflammatory markers is limited in robustly predicting longitudinal trajectories of developing cognitive impairment.

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort.

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The prodromal phase of hereditary spastic paraplegia type 4: the preSPG4 cohort study.

This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-ß (Aß). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aß to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.

SWATH Mass Spectrometry-Based CSF Proteome Profile of GBA-Linked Parkinson's Disease Patients.

ß-glucocerebrosidase (GBA)-associated mutations are a significant risk factor for Parkinson's disease (PD) that aggravate the disease pathology by upregulating the deposition of α-Synuclein (α-Syn). The resultant clinical profile varies for PD patients without GBA mutations. The current study aimed to identify the proteomic targets involved in the pathogenic pathways leading to the differential clinical presentation of GBA-associated PD. CSF samples (n = 32) were obtained from PD patients with GBA mutations (n = 22), PD patients without GBA mutations (n = 7), and healthy controls that were carriers of GBA mutations (n = 3). All samples were subjected to in-gel tryptic digestion followed by the construction of the spectral library and quantitative SWATH-based analysis. CSF α-Syn levels were reduced in both PDIdiopathic and PDGBA cases. Our SWATH-based mass spectrometric analysis detected 363 proteins involved in immune response, stress response, and cell signaling in various groups. Intergroup analysis showed that 52 proteins were significantly up- or downregulated in various groups. Of these 52 targets, 20 proteins were significantly altered in PDGBA cases only while 2 showed different levels in PDIdiopathic patients. Our results show that the levels of several pathologically relevant proteins, including Contactin-1, Selenium-binding protein 1, Adhesion G Protein-Coupled Receptor, and Apolipoprotein E are significantly different among the sporadic and genetic variants of PD and hint at aggravated synaptic damage, oxidative stress, neuronal loss, and aggregation of α-Syn in PDGBA cases.

Linking the phenotype of SNCA Triplication with PET-MRI imaging pattern and alpha-synuclein CSF seeding.

Lewy-body pathology with aggregation of abnormal conformations of the protein alpha-synuclein (α-Syn) represent the histopathological hallmarks of Parkinson's disease (PD). Genetic prototypes such as PD due to mutations in the alpha-synuclein gene (SNCA) offer the opportunity to evaluate α-Syn-related profiles in patient-derived biomaterial. We identified a family with a SNCA triplication and assessed the index patient for CSF α-Syn seeding capacity and levels of total α-Syn along with other neurodegenerative CSF markers (Aß1-42, total-Tau, phospho-Tau, NFL). As no published CSF data in patients with SNCA triplication are available, we descriptively compared his CSF profiles to those of sporadic PD patients and PD patients with GBA mutations as these are also specifically associated with prominent α-Syn pathology. Additionally, skin biopsies with staining for phospho-α-Syn were done. To assess cerebral glucose metabolism and brain atrophy combined positron emission tomography and magnetic resonance imaging ([18F]FDG-PET/MRI) was performed. Age at onset was 24 years and motor impairment was accompanied by prominent non-motor symptoms with early development of dementia, depression, REM sleep behavior disorder, hyposmia, and dysautonomia. Correspondingly, PET-MRI showed hypometabolism and atrophy in frontal, temporoparietal and occipital regions. CSF levels of total α-Syn were threefold higher and RT-QuIC showed remarkable α-Syn seeding activity in all kinetic categories in the SNCATriplication patient compared to patients with GBA mutations. Our results are consistent with findings that not only mutant forms but also overexpression of the wild-type α-Syn protein lead to PD and PD dementia and show a striking CSF α-Syn seeding profile, thus substantiating the role of RT-QuIC as a specific in vivo biomarker of α-Syn brain pathology.

CSF and Serum Levels of Inflammatory Markers in PD: Sparse Correlation, Sex Differences and Association With Neurodegenerative Biomarkers.

Background: An involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established. Objectives: We face several open questions in preparation of clinical trials aiming at disease-modification by targeting the immune system: Do peripheral (blood) inflammatory profiles reflect central (CSF) inflammatory processes? Are blood/CSF inflammatory markers associated with CSF levels of neurodegenerative/PD-specific biomarkers? Methods: Using a multiplex assay we assessed 41 inflammatory markers in CSF/serum pairs in 453 sporadic PD patients. We analyzed CSF/serum correlation as well as associations of inflammatory markers with clinical outcome measures (UPDRS-III, H&Y, MoCA) and with CSF levels of α-synuclein, Aß1-42, t-Tau, p181-Tau and NFL. All analyses were stratified by sex as the immune system shows relevant sex-specific differences. Results: Correlations between CSF and serum were sparse and detected in only 25% (9 out of 36) of the analysable inflammatory markers in male PD patients and in only 38% (12 out of 32) of female PD patients. The most important pro-inflammatory mediators associated with motor and cognitive decline as well as with neurodegenerative/PD-specific biomarkers were FABP, ICAM-1, IL-8, MCP-1, MIP-1-beta, and SCF. Results were more robust for CSF than for serum. Interpretation: Levels of central-nervous and peripheral inflammatory markers might be regulated independently of each other with CSF inflammatory markers reflecting CNS pathology more accurately than peripheral markers. These findings along with sex-specific characteristics have to be considered when designing clinical trials aiming at disease-modification by targeting the immune system.

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson's disease and dementia with Lewy bodies.

The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn.

Impaired Executive Function and Depression as Independent Risk Factors for Reported Delirium Symptoms: An Observational Cohort Study Over 8 Years.

BACKGROUND: Acute medical illnesses, surgical interventions, or admissions to hospital in older individuals are frequently associated with a delirium. In this cohort study, we investigated the impact of specific cognitive domains and depression before the occurrence of delirium symptoms in an 8-year observation of older non-hospitalized individuals. METHODS: In total, we included 807 participants (48-83 years). Deficits in specific cognitive domains were measured using the CERAD test battery, and depressive symptoms were measured using Beck Depression Inventory and the Geriatric Depression Scale (GDS) before the onset of a delirium. Delirium symptoms were retrospectively assessed by a questionnaire based on the established Nursing Delirium Screening Scale. RESULTS: Fifty-eight of eight hundred seven participants (7.2%) reported delirium symptoms over the 8-year course of the study. Sixty-nine percent (n = 40) of reported delirium symptoms were related to surgeries. In multivariate regression analysis, impaired executive function was an independent risk factor (p = 0.034) for the occurrence of delirium symptoms. Furthermore, age (p = 0.014), comorbidities [captured by the Charlson Comorbidity Index (CCI)] (p < 0.001), and depression (p = 0.012) were significantly associated with reported delirium symptoms. CONCLUSION: Especially prior to elective surgery or medical interventions, screening for impaired executive function and depression could be helpful to identify patients who are at risk to develop delirium symptoms.

CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB.

BACKGROUND: Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. OBJECTIVE: The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis. METHODS: We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories. RESULTS: (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile. CONCLUSION: CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neurofilament light chain is a cerebrospinal fluid biomarker in hereditary spastic paraplegia.

OBJECTIVE: Despite the need for diagnostics and research, data on fluid biomarkers in hereditary spastic paraplegia (HSP) are scarce. We, therefore, explore Neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of patients with hereditary spastic paraplegia and provide information on the influence of demographic factors. METHODS: The study recruited 59 HSP cases (33 genetically confirmed) and 59 controls matched in age and sex. Neurofilament light chain levels were assessed by enzyme-linked immunosorbent assay. The statistical analysis included the effects of age, sex, and genetic status (confirmed vs. not confirmed). RESULTS: Levels of CSF NfL were significantly increased in patients with hereditary spastic paraplegia compared to controls (median 741 pg/mL vs. 387 pg/mL, p < 0.001). Age (1.4% annual increase) and male sex (81% increase) impacted CSF NfL levels in patients. The age-dependent increase of CSF NfL levels was steeper in controls (2.6% annual increase). Thus, the CSF NfL ratio of patients and matched controls-expressing patients' fold increases in CSF NfL-declined considerably with age. INTERPRETATION: CSF NfL is a reliable cross-sectional biomarker in hereditary spastic paraplegia. Sex is a relevant factor to consider, as male patients have remarkably higher CSF NfL levels. While levels also increase with age, the gap between patients and controls is narrowing in older subjects. This indicates distinct temporal dynamics of CSF NfL in patients with hereditary spastic paraplegia, with a rise around phenotypic conversion and comparatively static levels afterward.

The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PDGBA.

BACKGROUND: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PDGBA ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement. OBJECTIVE: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI). METHODS: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PDGBA patients compared to PDGBA_wildtype patients. RESULTS: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PDGBA compared to PDGBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PDGBA compared to PDGBA_wildtype . (3) CSF levels of total α-synuclein were lower in PDGBA compared to PDGBA_wildtype . All of these findings were most pronounced in PDGBA with severe mutations (PDGBA_severe ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PDGBA_severe . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PDGBA_severe . INTERPRETATION: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society.

The longevity gene Klotho and its cerebrospinal fluid protein profiles as a modifier for Parkinson´s disease.

BACKGROUND: Parkinson´s disease (PD) has a large phenotypic variability, which may, at least partly, be genetically driven including alterations of gene products. Candidates might not only be proteins associated with disease risk but also pathways that play a role in aging. OBJECTIVE: To evaluate phenotype-modifying effects of genetic variants in Klotho, a longevity gene. METHODS: We analyzed two longitudinal cohorts: one local cohort comprising 459 PD patients who underwent genotyping for the KL-VS haplotype in Klotho including a subgroup of 125 PD patients and 50 healthy controls who underwent biochemical cerebrospinal fluid (CSF) analyses of Klotho and fibroblast growth factor 23 as well as vitamin D metabolites. The second cohort comprised 297 patients from the Parkinson's Progression Markers Initiative (PPMI) for validation of genetic-clinical findings. RESULTS: PD patients carrying the KL-VS haplotype demonstrated a shorter interval between PD onset and onset of cognitive impairment (both cohorts) and higher Unified Parkinson´s Disease Rating Scale part III (UPDRS III) scores (PPMI). CSF protein levels of Klotho and fibroblast growth factor 23 were lower in PD patients irrespective of gender compared to controls. Moreover, low CSF levels of Klotho were associated with higher scores in the UPDRS III and Hoehn and Yahr Scale. CONCLUSIONS: Our results indicate that genetic variants in Klotho together with its corresponding CSF protein profiles are associated with aspects of disease severity in PD. These findings suggest that pathways associated with aging might be targets for future biomarker research in PD.

A time-efficient screening tool for activities of daily living functions in Parkinson's disease dementia.

INSTRUCTION: In Parkinson's disease (PD), activities of daily living (ADL) impairments are crucial for diagnosis of dementia (PDD). Performance-based tests are promising tools to discriminate between different levels of cognitive impairment in PD; however, the value of those tests for diagnosis of PDD is only sparsely investigated. Therefore, we evaluated the Erlangen Test of Activities of Daily Living (E-ADL), a time-efficient performance-based ADL test, in PD. METHOD: In this cross-sectional study, 40 PD patients with normal cognition (PD-NC), 45 patients with mild cognitive impairment (PD-MCI) and 21 patients with PDD were assessed with a comprehensive ADL and cognitive test battery. RESULTS: Interrater reliability (rs =.86) indicated high consistency of the standardized E-ADL scoring system between raters. The E-ADL correlated significantly with other tests of ADL functions (p <.01), highest with an alternative performance-based ADL test (rs = -.52), and lowest with self-ratings and a physician-rated scale. The E-ADL was also associated with cognitive impairment (p <.01), but also with motor impairment. A binary logistic regression model verified that the E-ADL (p =.04) was an independent predictor of PDD, in addition to motor impairment explaining 53.3% of variance. Receiver operating characteristic curve analysis of the E-ADL revealed an area under the curve of 0.78, a specificity of 77%, and a sensitivity of 67% for diagnosis PDD. CONCLUSIONS: The standardized, easy, and quick to administer E-ADL showed acceptable levels of reliability, and validity in PD and measures cognitive-driven ADL functions. Therefore, it might be a suitable test to support diagnosis of PDD in the clinical daily routine.

CSF NFL in a Longitudinally Assessed PD Cohort: Age Effects and Cognitive Trajectories.

BACKGROUND: Neurofilament light protein is an unspecific biofluid marker that reflects the extent of neuronal/axonal damage and thereby offers the chance monitor disease severity and progression. The objective of this study was to investigate cerebrospinal fluid (CSF) levels of neurofilament light protein in Parkinson's disease (PD) patients with clinical trajectories of motor and cognitive function longitudinally. METHODS: CSF neurofilament light protein levels were assessed in 371 PDsporadic , 126 genetic PD patients (91 PDGBA , 8 PDLRRK2 , 21 PDPRKN/PINK1/DJ1_heterozygous , 6 PDPRKN/PINK1/DJ1_homozygous ), and 71 healthy controls. Participants were followed up longitudinally for up to 8 years. RESULTS: At baseline, mean CSF neurofilament light protein levels were highest in PD patients with cognitive impairment (Montreal Cognitive Assessment score ≤ 25; 1207 pg/mL) but also higher in PD patients with normal cognitive function (757 pg/mL) compared with healthy controls (593 pg/mL; P ≤ 0.001). In healthy controls and in PD patients older age was associated with higher CSF levels of neurofilament light protein (P ≤ 0.001). In PD patients, male gender, older age at onset, longer disease duration, higher Hoehn and Yahr stages, higher UPDRS-III scores, and lower Montreal Cognitive Assessment scores were associated with higher CSF levels of neurofilament light protein (P < 0.01). In patients who developed cognitive impairment during study, CSF neurofilament light protein levels prior to conversion to cognitive impairment were not significantly different compared with CSF neurofilament light protein levels of patients who remained cognitively normal. CONCLUSIONS: Increased CSF levels of neurofilament light protein are associated with cognitive decline and motor impairment in PD. However, this increase seems not a very early event and does not mark the conversion to cognitive impairment beforehand. Therefore, the predictive value needs to be discussed critically. © 2020 International Parkinson and Movement Disorder Society.

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha-Synuclein Profiles.

BACKGROUND: Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha-synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease-modifying treatment options such as alpha-synuclein lowering compounds are under way, patient stratification according to alpha-synuclein-specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite. OBJECTIVE: Are GBA1 mutations associated with a CSF alpha-synuclein profile in PD? METHODS: Screening of the GBA1 gene and analysis of CSF levels of total alpha-synuclein were performed in 80 PDGBA , 80 PDGBA _wildtype and 39 healthy controls cross-sectionally. Subgroup analyses based on mutation severity was done for PDGBA . RESULTS: Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha-synuclein. CONCLUSION: The effects of GBA1 mutations on CSF alpha-synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society.

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha-synuclein profile.

BACKGROUND: Patients with dementia with Lewy bodies reveal a variable pathology including alpha-synuclein, amyloid-beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. PD patients with GBA1 mutations show reduced CSF levels of total alpha-synuclein. OBJECTIVE: Whether GBA1 mutations are associated with a CSF alpha-synuclein profile in dementia with Lewy bodies. METHODS: Screening of the GBA1 gene and single-nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha-synuclein, amyloid-beta1-42 , total-Tau, phospho-Tau, and neurofilament light chain were assessed in 100 dementia with Lewy bodies and 39 controls cross-sectionally. RESULTS: Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha-synuclein were lowest in DLBGBA_pathogenic compared to DLBGBA_mild and DLBGBA_wildtype . CONCLUSION: Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha-synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha-synuclein-lowering compounds. © 2019 International Parkinson and Movement Disorder Society.