Low-intensity vestibular noise stimulation improves postural symptoms in progressive supranuclear palsy.

BACKGROUND: Postural imbalance and falls are an early disabling symptom in patients with progressive supranuclear palsy (PSP) of multifactorial origin that may involve abnormal vestibulospinal reflexes. Low-intensity noisy galvanic vestibular stimulation (nGVS) is a non-invasive treatment to normalize deficient vestibular function and attenuate imbalance in Parkinson's disease. The presumed therapeutic mode of nGVS is stochastic resonance (SR), a mechanism by which weak sensory noise stimulation can enhance sensory information processing. OBJECTIVE: To examine potential treatment effects of nGVS on postural instability in 16 patients with PSP with a clinically probable and [18F]PI-2620 tau-PET-positive PSP. METHODS: Effects of nGVS of varying intensity (0-0.7 mA) on body sway were examined, while patients were standing with eyes closed on a posturographic force plate. We assumed a bell-shaped response curve with maximal sway reductions at intermediate nGVS intensities to be indicative of SR. An established SR-curve model was fitted on individual patient outcomes and three experienced human raters had to judge whether responses to nGVS were consistent with the exhibition of SR. RESULTS: We found nGVS-induced reductions of body sway compatible with SR in 9 patients (56%) with optimal improvements of 31 ± 10%. In eight patients (50%), nGVS-induced sway reductions exceeded the minimal clinically important difference (improvement: 34 ± 5%), indicative of strong SR. CONCLUSION: nGVS yielded clinically relevant reductions in body sway compatible with the exhibition of SR in vestibular sensorimotor pathways in at least half of the assessed patients. Non-invasive vestibular noise stimulation may be thus a well-tolerated treatment strategy to ameliorate postural symptoms in PSP.

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

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.

Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies.

PURPOSE: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [18F]PI-2620 tau-positron-emission-tomography (PET) imaging with [123I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. METHODS: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [18F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. RESULTS: In patients with 4R-tauopathies, [18F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (ß = - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [18F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (ß = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [18F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (ß = - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. CONCLUSION: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.

A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria.

With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.

Associations between sex, body mass index and the individual microglial response in Alzheimer's disease.

BACKGROUND AND OBJECTIVES: 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between ß-amyloid-accumulation and microglial activation in AD. METHODS: 49 patients with AD (29 females, all Aß-positive) and 15 Aß-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and ß-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aß-PET on TSPO-PET was used to determine the Aß-plaque-dependent microglial response (slope) and the Aß-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI). RESULTS: In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aß-PET z-scores were similar. The Aß-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD - 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aß-plaque-dependent microglial response was not different between sexes. The Aß-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aß-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F(3,52) = 3.077, p = 0.005). CONCLUSION: While microglia response to fibrillar Aß is similar between sexes, women with AD show a stronger Aß-plaque-independent microglia response. This sex difference in Aß-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aß-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.

Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With ß-Amyloid-Negative CBS.

BACKGROUND AND OBJECTIVES: Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in ß-amyloid (Aß)-negative CBS. METHODS: We included patients with clinically diagnosed Aß-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction). RESULTS: Overall, 21 patients with Aß-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model. DISCUSSION: [18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aß-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.

Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

PURPOSE: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). METHODS: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. RESULTS: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). CONCLUSION: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

Reduced Gastric Contraction in Rapid-Eye-Movement Sleep Behavior Disorder and De Novo Parkinson's Disease.

BACKGROUND: Reduced gastric motility in Parkinson's disease (PD) has been reported, but hardly any study exists in subjects with isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD), a specific prodrome of α-synucleinopathies. OBJECTIVES: We compared the gastric motility of 17 iRBD subjects with that of 18 PD subjects (15 drug naive, 3 early treated in defined off) and 15 healthy controls (HC) with real-time magnetic resonance imaging (rtMRI). METHODS: After overnight fasting, participants consumed a standardized breakfast and underwent a 3-T rtMRI of the stomach. Amplitude and velocity of the peristaltic waves were analyzed under blinded conditions. Gastric motility index (GMI) was calculated. The procedure was repeated in 12 of 17 iRBD subjects ~2.5 years later. Nine of these 12 iRBD subjects were hyposmic. RESULTS: In iRBD and PD subjects the amplitude of the peristaltic waves was significantly reduced compared with HCs (iRBD vs. HC: 8.7 ± 3.7 vs. 11.9 ± 4.1 mm, P = 0.0097; PD vs. HC: 6.8 ± 2.2 vs. 11.9 ± 4.1 mm, P = 0.0001). The amplitude in iRBD and PD subjects was decreased to the same extent. The GMI was reduced in only PD subjects (PD vs. HC: P = 0.0027; PD vs. iRBD: P = 0.0203). After ~2.5 years the amplitude in iRBD subjects did not significantly decrease further. CONCLUSION: The amplitude of the peristaltic waves was markedly reduced in iRBD, a prodrome of α-synucleinopathies. This reduction was similar to the extent observed already in manifest early PD. This finding implies that the α-synuclein pathology affects the innervation of the stomach already in the prodromal stage. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Tau seed amplification assay reveals relationship between seeding and pathological forms of tau in Alzheimer's disease brain.

Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent tau in Alzheimer's disease (AD). However, the precise relationship between tau seeding measured by SAA and the levels of pathological forms of tau in the AD brain remains unknown. We developed a new tau SAA based on full-length 0N3R tau with sensitivity in the low fg/ml range and used it to characterize 103 brain samples from three independent cohorts. Tau seeding clearly discriminated between AD and control brain samples. Interestingly, seeding was absent in Progressive Supranuclear Palsy (PSP) putamen, suggesting that our tau SAA did not amplify 4R tau aggregates from PSP brain. The specificity of our tau SAA for AD brain was further supported by analysis of matched hippocampus and cerebellum samples. While seeding was detected in hippocampus from Braak stages I-II, no seeding was present in AD cerebellum that is devoid of tau inclusions. Analysis of 40 middle frontal gyrus samples encompassing all Braak stages showed that tau SAA seeding activity gradually increased with Braak stage. This relationship between seeding activity and the presence of tau inclusions in AD brain was further supported by robust correlations between tau SAA results and the levels of phosphorylated tau212/214, phosphorylated tau181, aggregated tau, and sarkosyl-insoluble tau. Strikingly, we detected tau seeding in the middle frontal gyrus already at Braak stage II-III, suggesting that tau SAA can detect tau pathology earlier than conventional immunohistochemical staining. In conclusion, our data suggest a quantitative relationship between tau seeding activity and pathological forms of tau in the human brain and provides an important basis for further development of tau SAA for accessible human samples.

Assessment of synaptic loss in mouse models of ß-amyloid and tau pathology using [18F]UCB-H PET imaging.

OBJECTIVE: In preclinical research, the use of [18F]Fluorodesoxyglucose (FDG) as a biomarker for neurodegeneration may induce bias due to enhanced glucose uptake by immune cells. In this study, we sought to investigate synaptic vesicle glycoprotein 2A (SV2A) PET with [18F]UCB-H as an alternative preclinical biomarker for neurodegenerative processes in two mouse models representing the pathological hallmarks of Alzheimer's disease (AD). METHODS: A total of 29 PS2APP, 20 P301S and 12 wild-type mice aged 4.4 to 19.8 months received a dynamic [18F]UCB-H SV2A-PET scan (14.7 ± 1.5 MBq) 0-60 min post injection. Quantification of tracer uptake in cortical, cerebellar and brainstem target regions was implemented by calculating relative volumes of distribution (VT) from an image-derived-input-function (IDIF). [18F]UCB-H binding was compared across all target regions between transgenic and wild-type mice. Additional static scans were performed in a subset of mice to compare [18F]FDG and [18F]GE180 (18 kDa translocator protein tracer as a surrogate for microglial activation) standardized uptake values (SUV) with [18F]UCB-H binding at different ages. Following the final scan, a subset of mouse brains was immunohistochemically stained with synaptic markers for gold standard validation of the PET results. RESULTS: [18F]UCB-H binding in all target regions was significantly reduced in 8-months old P301S transgenic mice when compared to wild-type controls (temporal lobe: p = 0.014; cerebellum: p = 0.0018; brainstem: p = 0.0014). Significantly lower SV2A tracer uptake was also observed in 13-months (temporal lobe: p = 0.0080; cerebellum: p = 0.006) and 19-months old (temporal lobe: p = 0.0042; cerebellum: p = 0.011) PS2APP transgenic versus wild-type mice, whereas the brainstem revealed no significantly altered [18F]UCB-H binding. Immunohistochemical analyses of post-mortem mouse brain tissue confirmed the SV2A PET findings. Correlational analyses of [18F]UCB-H and [18F]FDG using Pearson's correlation coefficient revealed a significant negative association in the PS2APP mouse model (R = -0.26, p = 0.018). Exploratory analyses further stressed microglial activation as a potential reason for this inverse relationship, since [18F]FDG and [18F]GE180 quantification were positively correlated in this cohort (R = 0.36, p = 0.0076). CONCLUSION: [18F]UCB-H reliably depicts progressive synaptic loss in PS2APP and P301S transgenic mice, potentially qualifying as a more reliable alternative to [18F]FDG as a biomarker for assessment of neurodegeneration in preclinical research.

Individual regional associations between Aß-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies.

ß-amyloid (Aß) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aß-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aß (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aß (AD: ßT = 0.412 ± 0.196 vs. ßA = 0.142 ± 0.123, p < 0.001; AD-CBS: ßT = 0.385 ± 0.176 vs. ßA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (ßT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aß related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Variants in the GBA1 gene, which encodes lysosomal acid glucocerebrosidase, are among the most common genetic risk factors for Parkinson's disease and are associated with faster disease progression. The mechanisms involved are unresolved but might include accumulation of glucosylceramide. Venglustat is a brain-penetrant glucosylceramide synthase inhibitor that, in previous studies, reduced amounts of the glycosphingolipid. We aimed to assess the safety, efficacy, and target engagement of venglustat in people with early-stage Parkinson's disease carrying pathogenic GBA1 variants. METHODS: MOVES-PD part 2 was a randomised, double-blinded, placebo-controlled phase 2 study done at 52 centres (academic sites, specialty clinics, and general neurology centres) in 16 countries. Eligible adults aged 18-80 years with Parkinson's disease (Hoehn and Yahr stage ≤2) and one or more GBA1 variants were randomly assigned using an interactive voice-response system (1:1) to 52 weeks of treatment with oral venglustat (15 mg/day) or matching placebo. Investigators, site personnel, participants, and their caregivers were masked to treatment allocation. The primary outcome measure was the change from baseline to 52 weeks in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score (a higher score indicates greater impairment), and it was analysed in a modified intention-to-treat population (ie, all randomly assigned participants with a baseline and at least one post-baseline measurement during the treatment period). This study was registered with ClinicalTrials.gov (NCT02906020) and is closed to recruitment. FINDINGS: Between Dec 15, 2016, and May 27, 2021, 221 participants were randomly assigned to venglustat (n=110) or placebo (n=111). The least squares mean change in MDS-UPDRS parts II and III combined score was 7·29 (SE 1·36) for venglustat (n=96) and 4·71 (SE 1·27) for placebo (n=105); the absolute difference between groups was 2·58 (95% CI -1·10 to 6·27; p=0·17). The most common treatment-emergent adverse events (TEAEs) were constipation and nausea (both were reported by 23 [21%] of 110 participants in the venglustat group and eight [7%] of 111 participants in the placebo group). Serious TEAEs were reported for 12 (11%) participants in each group. There was one death in the venglustat group owing to an unrelated cardiopulmonary arrest and there were no deaths in the placebo group. INTERPRETATION: In people with GBA1-associated Parkinson's disease in our study, venglustat had a satisfactory safety profile but showed no beneficial treatment effect compared with placebo. These findings indicate that glucosylceramide synthase inhibition with venglustat might not be a viable therapeutic approach for GBA1-associated Parkinson's disease. FUNDING: Sanofi.

Whole-Brain Magnetic Resonance Spectroscopy Reveals Distinct Alterations in Neurometabolic Profile in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized by supranuclear gaze palsy, early postural instability, and a frontal dysexecutive syndrome. Contrary to normal brain magnetic resonance imaging in Parkinson's disease (PD), PSP shows specific cerebral atrophy patterns and alterations, but these findings are not present in every patient, and it is still unclear if these signs are also detectable in early disease stages. OBJECTIVE: The aim of the present study was to analyze the metabolic profile of patients with clinically diagnosed PSP in comparison with matched healthy volunteers and PD patients using whole-brain magnetic resonance spectroscopic imaging (wbMRSI). METHODS: Thirty-nine healthy controls (HCs), 29 PD, and 22 PSP patients underwent wbMRSI. PSP and PD patients were matched for age and handedness with HCs. Clinical characterization was performed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, PSP rating scale, and DemTect (test for cognitive assessment). RESULTS: In PSP patients a significant reduction in N-acetyl-aspartate (NAA) was detected in all brain lobes. Fractional volume of the cerebrospinal fluid significantly increased in PSP patients compared to PD and healthy volunteers. CONCLUSIONS: In PSP much more neuronal degeneration and cerebral atrophy have been detected compared with PD. The most relevant alteration is the decrease in NAA in all lobes of the brain, which also showed a partial correlation with clinical symptoms. However, more studies are needed to confirm the additional value of wbMRSI in clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adoptive Allogeneic T-Cell Therapy Improves the Clinical Outcome of JC Virus Granule Cell Neuronopathy: A Case Report.

OBJECTIVES: JC virus granule cell neuronopathy is a potentially fatal otherwise highly disabling disease without an approved therapeutic option. This case report presents the positive record to T-cell therapy in JC virus granule cell neuronopathy. METHODS: The patient represented with subacute cerebellar symptoms. Diagnosis of JC virus granule cell neuronopathy was made because of infratentorially accentuated brain volume atrophy shown by brain MRI and the detection of JC virus DNA in the CSF. RESULTS: Six doses of virus-specific T cells were administered. Within 12 months after therapy initiation, the patient showed clear clinical benefit with improvement of symptoms, and JC viral DNA load significantly declined. DISCUSSION: We present the case report of a positive response to T-cell therapy in JC virus granule cell neuronopathy, leading to an improvement of symptoms.

Detection of a Parkinson's Disease-Specific MicroRNA Signature in Nasal and Oral Swabs.

BACKGROUND: Biomaterials from oral and nasal swabs provide, in theory, a potential resource for biomarker development. However, their diagnostic value has not yet been investigated in the context of Parkinson's disease (PD) and associated conditions. OBJECTIVE: We have previously identified a PD-specific microRNA (miRNA) signature in gut biopsies. In this work, we aimed to investigate the expression of miRNAs in routine buccal (oral) and nasal swabs obtained from cases with idiopathic PD and isolated rapid eye movement sleep behavior disorder (iRBD), a prodromal symptom that often precedes α-synucleinopathies. We aimed to address their value as a diagnostic biomarker for PD and their mechanistic contribution to PD onset and progression. METHODS: Healthy control cases (n = 28), cases with PD (n = 29), and cases with iRBD (n = 8) were prospectively recruited to undergo routine buccal and nasal swabs. Total RNA was extracted from the swab material, and the expression of a predefined set of miRNAs was quantified by quantitative real-time polymerase chain reaction. RESULTS: Statistical analysis revealed a significantly increased expression of hsa-miR-1260a in cases who had PD. Interestingly, hsa-miR-1260a expression levels correlated with diseases severity, as well as olfactory function, in the PD and iRBD cohorts. Mechanistically, hsa-miR-1260a segregated to Golgi-associated cellular processes with a potential role in mucosal plasma cells. Predicted hsa-miR-1260a target gene expression was reduced in iRBD and PD groups. CONCLUSIONS: Our work demonstrates oral and nasal swabs as a valuable biomarker pool in PD and associated neurodegenerative conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuropathology of incidental Lewy body & prodromal Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing. METHODS: Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD. RESULTS: Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons. CONCLUSIONS: Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.

Development of a cell-free screening assay for the identification of direct PERK activators.

The activation of the unfolded protein response, particularly via the PERK pathway, has been suggested as a promising therapeutic approach in tauopathies, a group of neurodegenerative disorders characterized by the abnormal phosphorylation and aggregation of tau protein. So far, a shortage of available direct PERK activators has been limiting the progresses in this field. Our study aimed at the development of a cell-free screening assay enabling the detection of novel direct PERK activators. By applying the catalytic domain of recombinant human PERK, we initially determined ideal conditions of the kinase assay reaction, including parameters such as optimal kinase concentration, temperature, and reaction time. Instead of using PERK's natural substrate proteins, eIF2α and NRF2, we applied SMAD3 as phosphorylation-accepting protein and successfully detected cell-free PERK activation and inhibition by selected modulators (e.g., calcineurin-B, GSK2606414). The developed assay revealed to be sufficiently stable and robust to assess an activating EC50-value. Additionally, our results suggested that PERK activation may take place independent of the active site which can be blocked by a kinase inhibitor. Finally, we confirmed the applicability of the assay by measuring PERK activation by MK-28, a recently described PERK activator. Overall, our data show that a cell-free luciferase-based assay with the recombinant human PERK kinase domain and SMAD3 as substrate protein is capable of detecting PERK activation, which enables to screen large compound libraries for direct PERK activators, in a high-throughput-based approach. These activators will be useful for deepening our understanding of the PERK signaling pathway, and may also lead to the identification of new therapeutic drug candidates for neurodegenerative tauopathies.

Symptomatology in 4-repeat tauopathies is associated with data-driven topology of [18F]-PI-2620 tau-PET signal.

In recent years in vivo visualization of tau deposits has become possible with various PET radiotracers. The tau tracer [18F]PI-2620 proved high affinity both to 3-repeat/4-repeat tau in Alzheimer's disease as well as to 4-repeat tau in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). However, to be clinically relevant, biomarkers should not only correlate with pathological changes but also with disease stage and progression. Therefore, we aimed to investigate the correlation between topology of [18F]PI-2620 uptake and symptomatology in 4-repeat tauopathies. 72 patients with possible or probable 4-repeat tauopathy, i.e. 31 patients with PSP-Richardson's syndrome (PSP-RS), 30 with amyloid-negative CBS and 11 with PSP-non-RS/CBS, underwent [18F]PI-2620-PET. Principal component analysis was performed to identify groups of similar brain regions based on 20-40 min p.i. regional standardized uptake value ratio z-scores. Correlations between component scores and the items of the PSP Rating Scale were explored. Motor signs like gait, arising from chair and postural instability showed a positive correlation with tracer uptake in mesial frontoparietal lobes and the medial superior frontal gyrus and adjacent anterior cingulate cortex. While the signs disorientation and bradyphrenia showed a positive correlation with tracer uptake in the parietooccipital junction, the signs disorientation and arising from chair were negatively correlated with tau-PET signal in the caudate nucleus and thalamus. Total PSP Rating Scale Score showed a trend towards a positive correlation with mesial frontoparietal lobes and a negative correlation with caudate nucleus and thalamus. While in CBS patients, the main finding was a negative correlation of tracer binding in the caudate nucleus and thalamus and a positive correlation of tracer binding in medial frontal cortex with gait and motor signs, in PSP-RS patients various correlations of clinical signs with tracer binding in specific cerebral regions could be detected. Our data reveal [18F]PI-2620 tau-PET topology to correlate with symptomatology in 4-repeat tauopathies. Longitudinal studies will be needed to address whether a deterioration of signs and symptoms over time can be monitored by [18F]PI-2620 in 4-repeat tauopathies and whether [18F]PI-2620 may serve as a marker of disease progression in future therapeutic trials. The detected negative correlation of tracer binding in the caudate nucleus and thalamus with the signs disorientation and arising from chair may be due to an increasing atrophy in these regions leading to partial volume effects and a relative decrease of tracer uptake in the disease course. As cerebral regions correlating with symptomatology differ depending on the clinical phenotype, a precise knowledge of clinical signs and symptoms is necessary when interpreting [18F]PI-2620 PET results.

Different MAPT haplotypes influence expression of total MAPT in postmortem brain tissue.

The MAPT gene, encoding the microtubule-associated protein tau on chromosome 17q21.31, is result of an inversion polymorphism, leading to two allelic variants (H1 and H2). Homozygosity for the more common haplotype H1 is associated with an increased risk for several tauopathies, but also for the synucleinopathy Parkinson's disease (PD). In the present study, we aimed to clarify whether the MAPT haplotype influences expression of MAPT and SNCA, encoding the protein α-synuclein (α-syn), on mRNA and protein levels in postmortem brains of PD patients and controls. We also investigated mRNA expression of several other MAPT haplotype-encoded genes. Postmortem tissues from cortex of fusiform gyrus (ctx-fg) and of the cerebellar hemisphere (ctx-cbl) of neuropathologically confirmed PD patients (n = 95) and age- and sex-matched controls (n = 81) were MAPT haplotype genotyped to identify cases homozygous for either H1 or H2. Relative expression of genes was quantified using real-time qPCR; soluble and insoluble protein levels of tau and α-syn were determined by Western blotting. Homozygosity for H1 versus H2 was associated with increased total MAPT mRNA expression in ctx-fg regardless of disease state. Inversely, H2 homozygosity was associated with markedly increased expression of the corresponding antisense MAPT-AS1 in ctx-cbl. PD patients had higher levels of insoluble 0N3R and 1N4R tau isoforms regardless of the MAPT genotype. The increased presence of insoluble α-syn in PD patients in ctx-fg validated the selected postmortem brain tissue. Our findings in this small, but well controlled cohort of PD and controls support a putative biological relevance of tau in PD. However, we did not identify any link between the disease-predisposing H1/H1 associated overexpression of MAPT with PD status. Further studies are required to gain a deeper understanding of the potential regulatory role of MAPT-AS1 and its association to the disease-protective H2/H2 condition in the context of PD.