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.

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

PURPOSE: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. METHODS: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). RESULTS: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). CONCLUSION: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Feasibility of short imaging protocols for [18F]PI-2620 tau-PET in progressive supranuclear palsy.

PURPOSE: Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [18F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [18F]PI-2620 tau-PET imaging of PSP. METHODS: Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [18F]PI-2620 PET was performed by a dynamic 60-min scan. Distribution volume ratios (DVRs) were calculated using full and truncated scan durations (0-60, 0-50, 0-40, 0-30, and 0-20 min p.i.). Standardized uptake value ratios (SUVrs) were obtained 20-40, 30-50, and 40-60 min p.i.. All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP-RS from HCs in predefined subcortical and cortical target regions (effect size, area under the curve (AUC), multi-region classifier). RESULTS: 0-50 and 0-40 DVR showed equivalent effect sizes as 0-60 DVR (averaged Cohen's d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0-30 or 0-20 DVR. The 20-40 SUVr indicated the best performance of all static acquisition windows (averaged Cohen's d: 0.99). The globus pallidus internus discriminated patients with PSP-RS and HCs at a similarly high level for 0-60 DVR (AUC: 0.96), 0-40 DVR (AUC: 0.96), and 20-40 SUVr (AUC: 0.94). The multi-region classifier sensitivity of these time windows was consistently 86%. CONCLUSION: Truncated and static imaging windows can be used for [18F]PI-2620 PET imaging of PSP. 0-40 min dynamic scanning offers the best balance between accuracy and economic scanning.

Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury.

PURPOSE: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several ß-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG). METHODS: Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson's disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0-60 min p.i.) and static [18F]FDG-PET (30-50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers. RESULTS: Highest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5-2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers. CONCLUSION: Early-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes.

Several studies have demonstrated that intrastriatal injections of fibrillar α-synuclein in rodent brain induced a Parkinson's disease-like propagation of Lewy body pathology with significant nigrostriatal neurodegeneration. This study evaluated the pathological features when exogenous α-synuclein preformed fibrils were injected into the putamen of non-human primates. Eight cynomolgus monkeys received unilateral intraputamen injections of α-synuclein preformed fibrils and four monkeys received sham surgery. Monkeys were assessed with 123I-PE2I single-photon emission computerized tomography scans targeting the dopamine transprter at baseline, 3, 6, 9, 12, and 15 months. Imaging revealed a robust increase in dopamine transporter binding, an effect confirmed by port-mortem immunohistochemical analyses, suggesting that upregulation of dopamine transporter occurs as part of an early pathological process. Histochemistry and immunohistochemistry revealed that α-synuclein preformed fibrils injections into the putamen induced intraneuronal inclusions positive for phosphorylated α-synuclein in ipsilateral substantia nigra and adjacent to the injection site. α-Synuclein inclusions were thioflavin-S-positive suggesting that the inclusions induced by α-synuclein preformed fibrils exhibited pathological properties similar to amyloid-like Lewy body pathology in Parkinson's disease brains. The α-synuclein preformed fibrils resulted in Lewy pathology in the ipsilateral substantia nigra with significant reduction (-29.30%) of dopaminergic neurons as compared with controls. Nigral neurons with α-synuclein inclusions exhibited a phenotypic downregulation of the dopamine markers tyrosine hydroxylase and Nurr1. Taken together, our findings demonstrate that α-synuclein preformed fibrils induce a synucleinopathy in non-human primates with authentic Lewy pathology and nigrostriatal changes indicative of early Parkinson's disease.

Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease.

BACKGROUND: Excessive daytime sleepiness (EDS) is common and disabling in Parkinson's disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD. METHODS: The Parkinson's Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS. RESULTS: ESS increased in PD from baseline to year 3 (mean±SD 5.8±3.5 to 7.55±4.6, p<0.0001), with no change in HC. Longitudinally, EDS in PD was associated with non-tremor dominant phenotype, autonomic dysfunction, depression, anxiety and probable behaviour disorder, but not cognitive dysfunction or motor severity. Dopaminergic therapy was associated with EDS at years 2 and 3, as dose increased. EDS was also associated with presynaptic dopaminergic dysfunction, whereas biofluid markers at year 1 showed no significant associations with EDS. A predictive index for EDS was generated, which included seven baseline characteristics, including non-motor symptoms and cerebrospinal fluid phosphorylated-tau/total-tau ratio. CONCLUSIONS: In early PD, EDS increases significantly over time and is associated with several clinical variables. The influence of dopaminergic therapy on EDS is dose dependent. Further longitudinal analyses will better characterise associations with imaging and biomarkers.

Vitamin D in the Parkinson Associated Risk Syndrome (PARS) study.

BACKGROUND: Lower vitamin D levels have been associated with manifest Parkinson's disease, prompting the hypothesis that vitamin D insufficiency or deficiency may increase risk for PD. OBJECTIVES: To evaluate vitamin D levels in a population at risk for developing PD. METHODS: Plasma vitamin D levels were measured in the Parkinson Associated Risk Syndrome Study, a cohort of asymptomatic individuals, some of whom are at high risk for PD. Vitamin D levels were compared between subjects at high risk for PD (hyposmia and dopamine transporter scan deficit) versus all others and examined for correlations with dopaminergic system integrity. RESULTS: Mean vitamin D levels did not differ between groups, with a level of 27.8 ng/mL (standard deviation = 12.0) in the high-risk group versus 24.7 ng/mL (standard deviation = 9.0) in all others (P = 0.09). Vitamin D levels did not associate with putaminal dopamine transporter uptake. CONCLUSIONS: Our data from the asymptomatic Parkinson Associated Risk Syndrome cohort do not support the hypothesis that chronic vitamin D insufficiency threatens dopaminergic system integrity, contributing to PD pathogenesis. © 2017 International Parkinson and Movement Disorder Society.

Cerebrospinal fluid biomarkers and clinical features in leucine-rich repeat kinase 2 (LRRK2) mutation carriers.

BACKGROUND: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of inherited Parkinson's disease (PD). Nonmanifesting carriers of LRRK2 mutations are at high risk for developing PD. Information available on cerebrospinal fluid (CSF) biomarkers in LRRK2 carriers remains preliminary. OBJECTIVES: To measure CSF levels of α-synuclein, ß amyloid1-42 , total-tau, and phospho-tau181 , in LRRK2-associated PD, idiopathic PD, nonmanifesting carriers, and first-degree relatives of LRRK2-associated PD patients without the mutation (nonmanifesting noncarriers). To correlate the clinical features and the integrity of the nigrostriatal pathway assessed by neuroimaging with the CSF biomarkers. METHODS: 138 CSF samples provided by the Michael J. Fox Foundation LRRK2 Cohort Consortium were analyzed: 28 LRRK2-associated PD, 35 idiopathic PD, 41 nonmanifesting carriers, and 34 nonmanifesting noncarriers. All of the participants in the study were clinically assessed. Most of the participants underwent a dopamine transporter scan to assess the integrity of the nigrostriatal pathway. RESULTS: CSF levels of α-synuclein were similar in LRRK2-associated PD, nonmanifesting carriers, and nonmanifesting noncarriers but significantly higher than in idiopathic PD (P = .041). No differences were found in the concentrations of ß amyloid1-42 , total-tau, or phospho-tau181 among study groups. CSF alpha-synuclein levels strongly correlated with total-tau and phospo-tau181 levels in all groups. No significant correlation was found between the CSF biomarkers and the striatal binding ratios for (123)I-FP-CIT in nonmanifesting carriers. CONCLUSION: The CSF protein profile differs in LRRK2-associated PD and idiopathic PD, suggesting that pathophysiological mechanisms different from IPD underlie LRRK2-associated PD. Cerebrospinal fluid biomarkers did not prove helpful in differentiating asymptomatic LRRK2 mutation carriers from noncarriers. © 2016 International Parkinson and Movement Disorder Society.

Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.

Correlates of excessive daytime sleepiness in de novo Parkinson's disease: A case control study.

OBJECTIVE: This study was undertaken to determine the frequency and correlates of excessive daytime sleepiness in de novo, untreated Parkinson's disease (PD) patients compared with the matched healthy controls. METHODS: Data were obtained from the Parkinson's Progression Markers Initiative, an international study of de novo, untreated PD patients and healthy controls. At baseline, participants were assessed with a wide range of motor and nonmotor scales, including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Excessive daytime sleepiness was assessed based on the Epworth Sleepiness scale (ESS), with a cutoff of 10. RESULTS: Four hundred twenty-three PD subjects and 196 healthy controls were recruited into the study. Mean ESS (min, max) score was 5.8 (0, 20) for the PD subjects and 5.6 (0, 19) for healthy controls (P = 0.54). Sixty-six (15.6%) PD subjects and 24 (12%) healthy controls had ESS of at least 10 (P = 0.28). No difference was seen in demographic characteristics, age of onset, disease duration, PD subtype, cognitive status, or utilization of sedatives between the PD sleepiness-positive versus the negative group. The sleepiness-positive group had higher MDS-UPDRS Part I and II but not III scores, and higher depression and autonomic dysfunction scores. Sleepiness was associated with a marginal reduction of A-beta (P = 0.05) but not alpha-synuclein spinal fluid levels in PD. CONCLUSIONS: This largest case control study demonstrates no difference in prevalence of excessive sleepiness in subjects with de novo untreated PD compared with healthy controls. The only clinical correlates of sleepiness were mood and autonomic dysfunction. Ongoing longitudinal analyses will be essential to further examine clinical and biological correlates of sleepiness in PD and specifically the role of dopaminergic therapy.

Plasma apolipoprotein A1 as a biomarker for Parkinson disease.

OBJECTIVE: To identify plasma-based biomarkers for Parkinson disease (PD) risk. METHODS: In a discovery cohort of 152 PD patients, plasma levels of 96 proteins were measured by multiplex immunoassay; proteins associated with age at PD onset were identified by linear regression. Findings from discovery screening were then assessed in a second cohort of 187 PD patients, using a different technique. Finally, in a third cohort of at-risk, asymptomatic individuals enrolled in the Parkinson's Associated Risk Study (PARS, n = 134), plasma levels of the top candidate biomarker were measured, and dopamine transporter (DAT) imaging was performed, to evaluate the association of plasma protein levels with dopaminergic system integrity. RESULTS: One of the best candidate protein biomarkers to emerge from discovery screening was apolipoprotein A1 (ApoA1; p = 0.001). Low levels of ApoA1 correlated with earlier PD onset, with a 26% decrease in risk of developing PD associated with each tertile increase in ApoA1 (Cox proportional hazards, p < 0.001, hazard ratio = 0.742). The association between plasma ApoA1 levels and age at PD onset was replicated in an independent cohort of PD patients (p < 0.001). Finally, in the PARS cohort of high-risk, asymptomatic subjects, lower plasma levels of ApoA1 were associated with greater putaminal DAT deficit (p = 0.037). INTERPRETATION: Lower ApoA1 levels correlate with dopaminergic system vulnerability in symptomatic PD patients and in asymptomatic individuals with physiological reductions in dopamine transporter density consistent with prodromal PD. Plasma ApoA1 may be a new biomarker for PD risk.

Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [18F]PI-2620.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [18F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.

LRRK2-Associated Parkinsonism With and Without In Vivo Evidence of Alpha-Synuclein Aggregates.

Background: Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Methods: Data were from the Parkinson's Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient- reported outcome assessments were administered. Biomarkers included dopamine transporter SPECT scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups. Results: 148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70]; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found. Conclusion: Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.

Movement disorder society unified Parkinson disease rating scale experiences in daily living: longitudinal changes and correlation with other assessments.

The Movement Disorder Society (MDS) commissioned a revision of the UPDRS with the goals of improving instructions and definitions, more accurately evaluating milder features, and assessing patient-reported outcomes and nonmotor features. To date, no study has evaluated longitudinal changes in components of the MDS-UPDRS over time or correlated these with changes in other scales of various symptoms. We assessed Parts I and II of the MDS-UPDRS (non-Motor and Motor Experiences of Daily Living [nM-EDL, M-EDL]) as well as a number of other scales of motor, cognitive and behavioral function in a large population of patients (n = 383) with early- to mid-stage Parkinson's disease (PD) who had previously participated in a trial of a putative disease-modifying agent. Both parts of a MDS-UPDRS showed significant change over the 3-year follow-up period, with M-EDL scores declining to a greater extent than nM-EDL. Both the scores and their changes over time correlated relatively well with other rating scales of similar disease aspects. Modest correlations with the original version of the UPDRS supported the increased attention to nonmotor symptoms as well as milder levels of severity in the MDS-UPDRS. The M-EDL was much more sensitive to change over time in these early- to mid-stage patients than the original UPDRS Activities of Daily Living (ADL) scale. Finally, we showed no change over time in a small group of individuals with dopamine transporter single-photon emission computed tomography scans without evidence for dopamine deficiency. The nM-EDL and M-EDL components of the MDS-UPDRS provide an effective, relevant measure of change in the broad spectrum of symptoms of PD over the first decade of the disease.

LRRK2 and GBA1 variant carriers have higher urinary bis(monacylglycerol) phosphate concentrations in PPMI cohorts.

We quantified concentrations of three isoforms of the endolysosomal lipid, bis(monoacylglycerol) phosphate (BMP) in the urine of deeply phenotyped cohorts in the Parkinson's Progression Markers Initiative: LRRK2 G2019S PD (N = 134) and non-manifesting carriers (NMC) (G2019S+ NMC; N = 182), LRRK2 R1441G PD (N = 15) and R1441G+ NMC (N = 15), GBA1 N409S PD (N = 76) and N409S+ NMC (N = 178), sporadic PD (sPD, N = 379) and healthy controls (HC) (N = 190). The effects of each mutation and disease status were analyzed using nonparametric methods. Longitudinal changes in BMP levels were analyzed using linear mixed models. At baseline, all LRRK2 carriers had 3-7× higher BMP levels compared to HC, irrespective of the disease status. GBA1 N409S carriers also showed significant, albeit smaller, elevation (~30-40%) in BMP levels compared to HC. In LRRK2 G2019S PD, urinary BMP levels remained stable over two years. Furthermore, baseline BMP levels did not predict disease progression as measured by striatal DaT imaging, MDS-UPDRS III Off, or MoCA in any of the cohorts. These data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.

A proteogenomic view of Parkinson's disease causality and heterogeneity.

The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.

Defining at-risk populations for Parkinson's disease: lessons from ongoing studies.

It is currently widely acknowledged that the natural history of PD includes a preclinical phase, and there are increasing efforts to identify markers that would allow the identification of individuals at risk for PD. Here, we discuss the issues related to defining at-risk populations for PD and review findings of current population-based cohorts that have reported potential biomarkers for PD, such as the Honolulu-Asia Aging Study (HAAS) and the PRIPS (Prospective Validation of Risk factors for the development of Parkinson Syndromes) study. We also discuss enriched risk cohorts designed to evaluate specificity and predictive value of markers exemplified by the PARS (Parkinson Associated Risk Study) and the TREND (Tübinger evaluation of Risk factors for the Early detection of NeuroDegeneration) study. Although there is still a long way to go, studies designed according to these concepts might eventually provide sufficient data to form the basis for future screening programs for PD risk to be applied at a population level.

Identification and prediction of Parkinson's disease subtypes and progression using machine learning in two cohorts.

The clinical manifestations of Parkinson's disease (PD) are characterized by heterogeneity in age at onset, disease duration, rate of progression, and the constellation of motor versus non-motor features. There is an unmet need for the characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. We used unsupervised and supervised machine learning methods on comprehensive, longitudinal clinical data from the Parkinson's Disease Progression Marker Initiative (n = 294 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson's Disease Biomarker Program (n = 263 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate, and fast disease progression. We achieved highly accurate projections of disease progression 5 years after initial diagnosis with an average area under the curve (AUC) of 0.92 (95% CI: 0.95 ± 0.01) for the slower progressing group (PDvec1), 0.87 ± 0.03 for moderate progressors, and 0.95 ± 0.02 for the fast-progressing group (PDvec3). We identified serum neurofilament light as a significant indicator of fast disease progression among other key biomarkers of interest. We replicated these findings in an independent cohort, released the analytical code, and developed models in an open science manner. Our data-driven study provides insights to deconstruct PD heterogeneity. This approach could have immediate implications for clinical trials by improving the detection of significant clinical outcomes. We anticipate that machine learning models will improve patient counseling, clinical trial design, and ultimately individualized patient care.

Predictors of time to requiring dopaminergic treatment in 2 Parkinson's disease cohorts.

The rate of progression of Parkinson's disease (PD) is highly variable. Knowledge of factors associated with disease milestones and commonly used research outcome measures helps with patient counseling and guides the design and interpretation of clinical studies. The objective of the study was to identify prognostic factors for time to acquiring disability requiring dopaminergic therapy that are reproducible within 2 large prospectively followed cohorts. Potential prognostic factors were identified using data from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial, and their reproducibility was examined using data from the Parkinson Research Examination of CEP-1347 trial (PRECEPT). In multivariable analyses of the DATATOP cohort, higher baseline Unified Parkinson's Disease Rating Scale (UPDRS) scores, full-time employment, a lesser smoking history, and onset on the left side were associated with a shorter time to disability requiring dopaminergic therapy. PRECEPT data confirmed the associations of higher baseline UPDRS scores and full-time employment with shorter time to requiring treatment. Any clinical trial using the end point of time to disability requiring dopaminergic therapy should ensure that groups are well balanced with respect to baseline UPDRS scores and the proportion of subjects employed full time and should consider including these variables as covariates in the statistical model for primary analysis of treatment effects. We suspect that individuals employed full time may have a lower threshold for requiring dopaminergic therapy because of occupational demands.

PET/MRI Delivers Multimodal Brain Signature in Alzheimer's Disease with De Novo PSEN1 Mutation.

BACKGROUND: Little is known so far about the brain phenotype and the spatial interplay of different Alzheimer's disease (AD) biomarkers with structural and functional brain connectivity in the early phase of autosomal-dominant AD (ADAD). Multimodal PET/MRI might be suitable to fill this gap. MATERIAL AND METHODS: We presented a 31-year-old male patient without a family history of dementia with progressive worsening of memory and motor function. Two separate sessions of 3T PET/MRI acquisitions were arranged with the ß-amyloid tracer [18F]Florbetaben and the secondgeneration tau tracer [18F]PI-2620. Simultaneously acquired MRI consisted of high-resolution 3D T1, diffusion-tensor imaging (DTI), and resting-state fMRI. PET/MRI data were compared with ten age-matched healthy controls. RESULTS: Widespread ß-amyloid depositions were found in cortical regions, and striatum (Thal stage III) along with tau pathology restricted to the mesial-temporal structures (Braak stage III/IV). Volumetric/shape analysis of subcortical structures revealed atrophy of the hippocampal-amygdala complex. In addition, cortical thinning was detected in the right middle temporal pole. Alterations of multiple DTI indices were noted in the major white matter fiber bundles, together with disruption of default mode and sensory-motor network functional connectivity. Molecular genetic analysis by next-generation sequencing revealed a heterozygote missense pathogenic variant of the PSEN1 (Met233Val). CONCLUSION: Multimodal PET/MR imaging is able to deliver, in a one-stop-shop approach, an array of molecular, structural and functional brain information in AD due to de novo pathogenic variant, which can be studied for spatial interplay and might provide a rationale for initiating anti- amyloid/tau therapeutic approaches.