Epidemiology of early-onset Parkinson disease (EOPD) worldwide: East versus west.

Parkinson disease (PD) is characterized by the presence of bradykinesia with either rest tremor, muscle rigidity, or postural instability. If the features for PD are present but the age at onset (AAO) is before the usual but later than 21 years of age, it is considered as early-onset PD (EOPD). With Eastern countries projected to account for over 60 % of the world's population, it is paramount to understand the differences in EOPD between Western and Eastern countries. Epidemiology can differ substantially between the East and West, such as China showing a much steeper rise in EOPD prevalence and incidence with age, or Japan and Korea showing a female predominance in EOPD for certain age groups. Symptomatology appears to be similar across Western and Eastern populations, though some Eastern populations may have a higher prevalence of the akinetic-rigid or postural instability/gait difficulty motor phenotypes. Genetic epidemiology, conversely, varies significantly between the East and West, though some genes are frequently implicated in both (such as LRRK2, PINK1, PRKN, and GBA). Next, treatment patterns also exhibit substantial geographical variation, which could be driven by local availability of medications, adequacy of staff training and infrastructure, and local regulatory bodies. Lastly, regardless of region, EOPD exerts a profound psychosocial impact on patients, such as strained relationships, unemployment, and psychological distress. In summary, understanding these differences (and similarities) between the East and West could help generate innovative solutions, while the development of healthy habits and robust social networks should also be actively encouraged in all patients.

Targeting heterozygous dominant negative variant of KCNA2 using Gapmer ASO for the treatment of drug-resistant epilepsy.

A missense mutation c.1220C>G of KCN2A gene was recently identified in an infant with epilepsy. KCNA2 encodes KV1.2 subunits that form voltage-gated potassium channels (VGKC) via tetrameric assembly. The mutation results in amino acid change P407R at the highly conserved PVP motif. Functional characterization revealed that mutant KV1.2_P407R subunits formed loss-of-function channels and suppressed both KV1.2 and KV1.1 channel activities. Hetero-tetrameric assembly of the KV1.2_P407R subunits with other neuronal voltage-gated potassium channels of Shaker subfamily could lead to general deficit of repolarizing potassium current and potentially underlie the enhanced seizure susceptibility. Indeed, expression of human KV1.2_P407R in early postnatal rat cortical neurons or genetically engineered hESC-derived neurons disclosed broadening of action potential duration and early afterdepolarization (EAD), associating with reduced potassium current. We hypothesize that Gapmer antisense oligonucleotides (ASOs) targeted to c.1220C>G mutation will selectively degrade the mutant mRNA while allowing the remaining wild-type (WT) subunits to form functional channels. As a proof of principle, delivery of Gapmer packaged in lipid nanoparticle into cortical neurons selectively suppressed KV1.2_P407R over the WT protein expression, reversing the broadening of action potential duration, abrogating the EAD and leading to overall increase in potassium current.

Classification of Parkinson's disease by deep learning on midbrain MRI.

Purpose: Susceptibility map weighted imaging (SMWI), based on quantitative susceptibility mapping (QSM), allows accurate nigrosome-1 (N1) evaluation and has been used to develop Parkinson's disease (PD) deep learning (DL) classification algorithms. Neuromelanin-sensitive (NMS) MRI could improve automated quantitative N1 analysis by revealing neuromelanin content. This study aimed to compare classification performance of four approaches to PD diagnosis: (1) N1 quantitative "QSM-NMS" composite marker, (2) DL model for N1 morphological abnormality using SMWI ("Heuron IPD"), (3) DL model for N1 volume using SMWI ("Heuron NI"), and (4) N1 SMWI neuroradiological evaluation. Method: PD patients (n = 82; aged 65 ± 9 years; 68% male) and healthy-controls (n = 107; 66 ± 7 years; 48% male) underwent 3 T midbrain MRI with T2*-SWI multi-echo-GRE (for QSM and SMWI), and NMS-MRI. AUC was used to compare diagnostic performance. We tested for correlation of each imaging measure with clinical parameters (severity, duration and levodopa dosing) by Spearman-Rho or Kendall-Tao-Beta correlation. Results: Classification performance was excellent for the QSM-NMS composite marker (AUC = 0.94), N1 SMWI abnormality (AUC = 0.92), N1 SMWI volume (AUC = 0.90), and neuroradiologist (AUC = 0.98). Reasons for misclassification were right-left asymmetry, through-plane re-slicing, pulsation artefacts, and thin N1. In the two DL models, all 18/189 (9.5%) cases misclassified by Heuron IPD were controls with normal N1 volumes. We found significant correlation of the SN QSM-NMS composite measure with levodopa dosing (rho = -0.303, p = 0.006). Conclusion: Our data demonstrate excellent performance of a quantitative QSM-NMS marker and automated DL PD classification algorithms based on midbrain MRI, while suggesting potential further improvements. Clinical utility is supported but requires validation in earlier stage PD cohorts.

Innovative technology-based interventions in Parkinson's disease: A systematic review and meta-analysis.

OBJECTIVE: Novel technology-based interventions have the potential to improve motor symptoms and gait in Parkinson's disease (PD). Promising treatments include virtual-reality (VR) training, robotic assistance, and biofeedback. Their effectiveness remains unclear, and thus, we conducted a Bayesian network meta-analysis. METHODS: We searched the Medline, Embase, Cochrane CENTRAL, and Clinicaltrials.gov databases until 2 April 2024 and only included randomized controlled trials. Outcomes included changes in UPDRS-III/MDS-UPDRS-III score, stride length, 10-meter walk test (10MWT), timed up-and-go (TUG) test, balance scale scores and quality-of-life (QoL) scores. Results were reported as mean differences (MD) or standardized mean differences (SMD), with 95% credible intervals (95% CrI). RESULTS: Fifty-one randomized controlled trials with 2095 patients were included. For UPDRS (motor outcome), all interventions had similar efficacies. VR intervention was the most effective in improving TUG compared with control (MD: -4.36, 95% CrI: -8.57, -0.35), outperforming robotic, exercise, and proprioceptive interventions. Proprioceptive intervention significantly improved stride length compared to control intervention (MD: 0.11 m, 95% CrI: 0.03, 0.19), outperforming VR, robotic and exercise interventions. Virtual reality improved balance scale scores significantly compared to exercise intervention (SMD: 0.75, 95% CrI: 0.12, 1.39) and control intervention (SMD: 1.42, 95% CrI: 0.06, 2.77). Virtual reality intervention significantly improved QoL scores compared to control intervention (SMD: -0.95, 95% CrI: -1.43, -0.52), outperforming Internet-based interventions. INTERPRETATION: VR-based and proprioceptive interventions were the most promising interventions, consistently ranking as the top treatment choices for most outcomes. Their use in clinical practice could be helpful in managing motor symptoms and QoL in PD.

Risk of aspiration pneumonia and hospital mortality in Parkinson disease: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This study was undertaken to conduct a meta-analysis on the prevalence of aspiration pneumonia (AP) and hospital mortality in Parkinson disease (PD) as well as the risk of AP in PD patients compared to controls. METHODS: We searched MEDLINE and Embase from inception to 19 March 2024 to identify cross-sectional, cohort, and case-control studies comparing the frequency of AP and hospital mortality in PD patients. We computed risk ratios (RRs) with accompanying 95% confidence intervals (CIs) for each study and pooled the results using a random-effects meta-analysis. RESULTS: A total of 781 studies were initially screened, and 13 studies involving 541,785,587 patients were included. Patients with PD had >3 times higher risk of AP compared to controls (RR = 3.30, 95% CI = 1.82-6.00, p < 0.0001). This increased risk was similar in both cohort studies (RR = 3.01, 95% CI = 1.10-8.24, p = 0.03) and case-control studies (RR = 3.86, 95% CI = 3.84-3.87, p < 0.00001). The prevalence of AP in 12 studies was 2.74% (95% CI = 1.69-4.41), and hospital mortality was 10% in six studies (10.0%, 95% CI = 5.32-18.0). Prevalence of AP was higher in studies with smaller sample size (5.26%, 95% CI = 3.08-8.83 vs. 2.06%, 95% CI = 1.19-3.55, p = 0.02). CONCLUSIONS: Our meta-analysis showed that patients with PD had >3 times higher risk of AP, with an average 2.74% prevalence and 10.0% hospital mortality. Early recognition and treatment of AP in PD patients will help reduce morbidity and mortality. A multidisciplinary holistic approach is needed to address the multifactorial causes of AP.

Disease progression in Parkinson's disease patients with mild cognitive impairment: 5-year longitudinal study from the early Parkinson's disease longitudinal Singapore (PALS) cohort.

AIM: To investigate motor, non-motor and cognitive progression in early Parkinson's disease (PD) patients with Mild Cognitive Impairment (MCI). METHODS: PD patients were recruited within 1 year of diagnosis and were classified into PD-MCI group and PD with normal cognition (PD-NC) group. H&Y staging scale, MDS-UPDRS part III were used to assess disease severity and motor progression. Non-motor symptom scale (NMSS) was used to evaluate the NMS progression. Cognitive progression was assessed from 5 cognitive domains. Annual progression changes in the longitudinal outcomes were examined via linear mixed model with random intercept effect. False discovery rate (FDR) method was performed to control for multiple testing comparison and q-value was calculated. We set the threshold of q-values as 0.1. RESULT: A total of 205 PD patients, including 107 PD-MCI and 98 PD-NC patients were assessed prospectively over a 5-year period. PD-MCI patients, compared to PD-NC group, had a significantly higher progression rate in H&Y score (0.11 vs. 0.06, p=0.03, q=0.08), MDS-UPDRS motor score (3.11 vs. 1.90 p<0.001, q=0.06) and postural instability gait difficulty (PIGD) score (0.40 vs. 0.20, p=0.02, q=0.07). PD-MCI group also exhibited significantly faster deterioration in NMSS perceptual domain (PD-MCI vs. PD-NC: 0.38 vs. -0.04, p=0.01, q=0.06) and cognitive visuospatial domain (PD-MCI vs. PD-NC: 0.13 vs. -0.06, p=0.048, q=0.09) after adjustment for confounders and multiple comparisons. CONCLUSIONS: PD-MCI patients had faster decline in motor functions, visuo-perceptual and visuospatial performance. These findings provide a more comprehensive prognosis of PD-MCI, which could be helpful for clinician to manage PD-MCI patients.

Hosts manipulate lifestyle switch and pathogenicity heterogeneity of opportunistic pathogens in the single-cell resolution.

Host-microbe interactions are virtually bidirectional, but how the host affects their microbiome is poorly understood. Here, we report that the host is a critical modulator to regulate the lifestyle switch and pathogenicity heterogeneity of the opportunistic pathogens Serratia marcescens utilizing the Drosophila and bacterium model system. First, we find that Drosophila larvae efficiently outcompete S. marcescens and typically drive a bacterial switch from pathogenicity to commensalism toward the fly. Furthermore, Drosophila larvae reshape the transcriptomic and metabolic profiles of S. marcescens characterized by a lifestyle switch. More importantly, the host alters pathogenicity and heterogeneity of S. marcescens in the single-cell resolution. Finally, we find that larvae-derived AMPs are required to recapitulate the response of S. marcescens to larvae. Altogether, our findings provide an insight into the pivotal roles of the host in harnessing the life history and heterogeneity of symbiotic bacterial cells, advancing knowledge of the reciprocal relationships between the host and pathogen.

Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia.

BACKGROUND: Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome-wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations. OBJECTIVES: Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients. METHODS: Next-generation sequencing (whole-exome, whole-genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients. RESULTS: We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7-genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN. CONCLUSIONS: The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society.

Interaction between caffeine consumption & genetic susceptibility in Parkinson's disease: A systematic review.

BACKGROUND: Caffeine is one of the most consumed psychoactive substances globally. Caffeine-gene interactions in Parkinson's disease (PD) has not been systematically examined. OBJECTIVES: To conduct a systematic review on the interaction between caffeine consumption and genetic susceptibility to PD. METHODOLOGY: We conducted PubMed and Embase search using terms "Genetic association studies", "Caffeine", "polymorphism" and "Parkinson's disease", from inception till 2023. Of the initial 2391 studies, 21 case-control studies were included. The demographic, genetic and clinical data were extracted and analyzed. RESULTS: We identified 21 studies which involved a total of 607,074 study subjects and 17 gene loci (SNCA, MAPT, HLA-DRA, NOS1, NOS3, GBA, ApoE, BST1, ESR2, NAT2, SLC2A13, LRRK2, NOS2A, GRIN2A, CYP1A2, ESR1, ADORA2A) have been investigated for the effect of gene-caffeine interaction and PD risk. The genes were identified through PD GWAS or involved in caffeine or related metabolism pathways. Based on the genetic association and interaction studies, only MAPT, SLC2A13, LRRK2, ApoE, NOS2A, GRIN2A, CYP1A2, and ADORA2A have been shown by at least one study to have a positive caffeine-gene interaction influencing the risk of PD. CONCLUSION: Studies have shown an interaction between caffeine with genetic variants of MAPT, SLC2A13, LRRK2, ApoE, NOS2A, GRIN2A, CYP1A2, and ADORA2A in modulating the risk of PD. Due to the potential limitations of these discovery/pilot studies, further independent replication studies are needed. Better designed genetic association studies in multi-ancestry and admixed cohorts to identify potential shared or unique multivariate gene-environmental interactions, as well as functional studies of gene-caffeine interactions will be useful.

Disease Progression of Data-Driven Subtypes of Parkinson's Disease: 5-Year Longitudinal Study from the Early Parkinson's Disease Longitudinal Singapore (PALS) Cohort.

Background: The detailed trajectory of data-driven subtypes in Parkinson's disease (PD) within Asian cohorts remains undisclosed. Objective: To evaluate the motor, non-motor symptom (NMS) progression among the data-driven PD clusters. Methods: In this 5-year longitudinal study, NMS scale (NMSS), Hospital Anxiety Depression Scale (HADS), and Epworth sleepiness scale (ESS) were carried out annually to monitor NMS progression. H& Y staging scale, MDS-UPDRS part III motor score, and postural instability gait difficulty (PIGD) score were assessed annually to evaluate disease severity and motor progression. Five cognitive standardized scores were used to assess detailed cognitive progression. Linear mixed model was performed to assess the annual progression rates of the longitudinal outcomes. Results: Two hundred and six early PD patients, consisting of 43 patients in cluster A, 98 patients in cluster B and 65 subjects in cluster C. Cluster A (severe subtype) had significantly faster progression slope in NMSS Domain 3 (mood/apathy) score (p = 0.01), NMSS Domain 4 (perceptual problems) score (p = 0.02), NMSS Domain 7 (urinary) score (p = 0.03), and ESS Total Score (p = 0.04) than the other two clusters. Cluster A also progressed significantly in PIGD score (p = 0.04). For cognitive outcomes, cluster A deteriorated significantly in visuospatial domain (p = 0.002), while cluster C (mild subtype) deteriorated significantly in executive domain (p = 0.04). Conclusions: The severe cluster had significantly faster progression, particularly in mood and perceptual NMS domains, visuospatial cognitive performances, and postural instability gait scores. Our findings will be helpful for clinicians to stratify and pre-emptively manage PD patients by developing intervention strategies to counter the progression of these domains.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

Transcriptomic imputation of genetic risk variants uncovers novel whole-blood biomarkers of Parkinson's disease.

Blood-based gene expression signatures could potentially be used as biomarkers for PD. However, it is unclear whether genetically-regulated transcriptomic signatures can provide novel gene candidates for use as PD biomarkers. We leveraged on the Genotype-Tissue Expression (GTEx) database to impute whole-blood transcriptomic expression using summary statistics of three large-scale PD GWAS. A random forest classifier was used with the consensus whole-blood imputed gene signature (IGS) to discriminate between cases and controls. Outcome measures included Area under the Curve (AUC) of Receiver Operating Characteristic (ROC) Curve. We demonstrated that the IGS (n = 37 genes) is conserved across PD GWAS studies and brain tissues. IGS discriminated between cases and controls in an independent whole-blood RNA-sequencing study (1176 PD, 254 prodromal, and 860 healthy controls) with mean AUC and accuracy of 64.8% and 69.4% for PD cohort, and 78.8% and 74% for prodromal cohort. PATL2 was the top-performing imputed gene in both PD and prodromal PD cohorts, whose classifier performance varied with biological sex (higher performance for males and females in the PD and prodromal PD, respectively). Single-cell RNA-sequencing studies (scRNA-seq) of healthy humans and PD patients found PATL2 to be enriched in terminal effector CD8+ and cytotoxic CD4+ cells, whose proportions are both increased in PD patients. We demonstrated the utility of GWAS transcriptomic imputation in identifying novel whole-blood transcriptomic signatures which could be leveraged upon for PD biomarker derivation. We identified PATL2 as a potential biomarker in both clinical and prodromic PD.

Association of Gene Expression and Tremor Network Structure.

BACKGROUND: Transcriptomic changes in the essential tremor (ET)-associated cerebello-thalamo-cortical "tremor network" and their association to brain structure have not been investigated. OBJECTIVE: The aim was to characterize molecular changes associated with network-level imaging-derived phenotypes (IDP) found in ET. METHODS: We performed an imaging-transcriptomic study in British adults using imaging-genome-wide association study summary statistics (UK Biobank "BIG40" cohort; n = 33,224, aged 40-69 years). We imputed imaging-transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network-level phenotypes. Validation was performed in cerebellar-tissue RNA-sequencing data from ET patients and controls (n = 55). RESULTS: Among 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome-wide significant associations (Bonferroni P < 2.102e-7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole-tremor-network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e-70), whereas white-gray T1-weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = -0.90, P = 2e-68). Imputed association effect sizes and RNA-sequencing log-fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ2 = 6.40, P = 0.006). CONCLUSIONS: The identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Passive immunotherapy for Alzheimer's disease: challenges & future directions.

Passive immunotherapy with specific antibodies targeting Amyloid ß (Aß) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer's disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aß peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aß antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aß antibodies, such as lecanemab (a humanized mAb binds to soluble Aß protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aß peptides) and aducanumab (a human mAb binds to the aggregated form of Aß), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aß antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aß antibodies and other pharmaceutical agents should also be explored.

Reelin links Apolipoprotein E4, Tau, and Amyloid-ß in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the cerebral cortex and hippocampus, and is characterised by progressive cognitive decline and memory loss. A recent report of a patient carrying a novel gain-of-function variant of RELN (H3447R, termed RELN-COLBOS) who developed resilience against presenilin-linked autosomal-dominant AD (ADAD) has generated enormous interest. The RELN-COLBOS variant enhances interactions with the apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), which are associated with delayed AD onset and progression. These findings were validated in a transgenic mouse model. Reelin is involved in neurodevelopment, neurogenesis, and neuronal plasticity. The evidence accumulated thus far has demonstrated that the Reelin pathway links apolipoprotein E4 (ApoE4), amyloid-ß (Aß), and tubulin-associated unit (Tau), which are key proteins that have been implicated in AD pathogenesis. Reelin and key components of the Reelin pathway have been highlighted as potential therapeutic targets and biomarkers for AD.