npj Parkinson's Disease

Importance: Dementia is common in Parkinson's disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. Objective: To investigate whether visual deficits and genetic factors predict PD dementia. Design: Large prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. Setting: Cases were recruited between...

Olfactory decline is a well-established aspect of Parkinsons disease (PD) and is considered one of its earliest signs, often preceding motor symptoms by years to decades. However, because olfactory impairment is also common in healthy aging and other medical conditions, current olfactory tests that score performance (odor detection, discrimination, and identification) lack disease specificity. In contrast to performance scores, olfactory perceptual fingerprints are derived from odor ratings and ...

We describe the design of the first non-pharmacological prevention trials of Parkinsons Disease worldwide: the randomised controlled Slow-SPEED trials. The three trials examine the feasibility and preliminary efficacy of a gamified, remotely administered exercise intervention vs. active control program over 18-36 months in the Netherlands (n=110), United Kingdom (n=110) and United States (n=600). Each trial focuses on a complementary prodromal subgroup: isolated/idiopathic REM sleep behavioural...

Gait impairment (GI) and freezing of gait (FOG) affect 80% of patients with advanced Parkinsons disease. Continuous deep brain stimulation (cDBS) provides limited adaptability to address the episodic nature of FOG due to fixed parameters. Neural biomarkers for adaptive DBS are limited by signal artifacts and poor FOG classification. Wearable inertial measurement units (IMUs) offer a promising alternative by directly measuring signatures of GI&FOG. We developed Kinematic adaptive DBS (KaDBS), the...

BackgroundPrognosis and therapeutic management in Parkinsons disease remain challenging due to the diseases heterogeneous progression and symptom presentation and lack of reliable biomarkers to predict individual disease trajectories. ObjectiveTo determine whether baseline blood transcriptomes, analyzed through biologically defined pathway gene sets, contain signatures that distinguish distinct motor and non-motor progression trajectories in Parkinsons disease. MethodsUsing data from the Parki...

BackgroundThe Montreal Cognitive Assessment (MoCA) is a recommended brief screening tool to detect cognitive impairment in people with Parkinsons disease (PD). ObjectiveTo compare English and Bengali MoCA performance in Bangladeshi individuals with PD in East London. MethodsThis cross-sectional study involved participants completing both English and Bengali MoCA. Analyses included ANCOVA, paired and unpaired t-tests, and Bland-Altman methods in full and age-matched samples. ResultsFifty PD pa...

BackgroundOscillations underpin a large spectrum of brain function. Brain oscillations are altered by neuromodulation approaches including deep brain stimulation (DBS), but a mechanistic understanding of the brain oscillation - DBS interaction is missing. DBS is predominantly used in the treatment of Parkinsons disease. DBS can induce or alter pre-existing narrow frequency band gamma oscillations at half the stimulation frequency. Such half-harmonic responses have been interpreted as entrainmen...

Lysosomal dysfunction is central to Parkinsons disease pathogenesis, with GBA1 as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinsons disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency < 0.01) across 36 lysosomal genes (excluding GBA1) in 8,267 individuals with Parkins...

BackgroundHuntingtons disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they c...

ATP1A3-related syndromes represent a continuously expanding clinical spectrum and present with an extraordinarily wide range of symptoms. New phenotypes continue to emerge, posing ongoing challenges for both diagnosis and development of treatments. In this context, telemedicine offers a unique opportunity to greatly expand outreach to patients. Remote, high-resolution assessments help refine phenotypic characterization and the identification of novel and intermediate phenotypes. In this study w...

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to affecting motor neuron survival, SMN deficiency impacts multisystem physiology and neurotransmission. Dopaminergic dysfunction has been reported in mouse models of SMA, leading to postural and locomotor impairments that improve upon treatment with L-DOPA and benserazide. However, whether altered dopamine metabolism contributes to clinical sympto...

Amyotrophic Lateral Sclerosis (Lou Gehrigs disease) is a progressive neurodegenerative disease affecting hundreds of thousands of people worldwide. It is characterized by the degeneration of the neurons in the brain and spinal cord of the patients, leading to a loss of control of muscles. Over time, without nerves to stimulate them muscles tend to atrophy. ALS may occur sporadically or run in families; many mutations have been identified for the latter. Treatment of ALS is mostly limited to thre...

Parkinsons disease (PD) is a disabling neurodegenerative disorder with a substantial heritable component. Despite major advances in genome-wide association studies (GWAS), polygenic risk scores (PRS) show reduced predictive performance outside European populations, limiting equitable translation. Latin American populations represent a particularly difficult case because of their characteristic three-way admixture. We evaluated the cross-ancestry transferability of PD PRS in 1,872 PD cases and 1,...

Background/ObjectivesElectromyography (EMG), video-polysomnography (vPSG), and wrist actigraphy are each used to develop diagnostic algorithms for Rapid eye movement sleep behavior disorder (RBD). However, the extent to which they capture overlapping versus distinct motor phenomena remains unknown. We evaluated the respective contributions of actigraphy, EMG and vPSG to the measurement of REM-sleep motor activity. MethodsSeventeen adults with RBD (Mount Sinai n = 9; Stanford n = 8) and eight co...

Type 1 narcolepsy (NT1), a disorder caused by the loss of hypocretin/orexin transmission, is characterized by daytime sleepiness and symptoms where Rapid Eye Movement (REM) sleep, a state normally occurring from middle to late in the night, can intermingle with wakefulness. This results in cataplexy and sleep paralysis, episodes of muscle paralysis when awake, or in the generation of dream-like hallucinations and vivid dreaming, periods of visual imagery or sensory experiences that occur while a...

Parkinsons disease (PD) is a progressive movement disorder that affects over ten million individuals worldwide. While the involvement of genetically-driven cellular mechanisms in PD pathogenesis is well-established, there is increasing evidence that epigenetic dysregulation also plays a key role. We profiled genome-wide DNA methylation in isolated neuronal, oligodendrocyte and other glial nuclei populations from the prefrontal cortex of 71 PD and 56 control individuals. We identified seven sign...

IntroductionGenome-wide association studies (GWAS) have identified over 130 risk loci for Parkinsons disease (PD), yet the majority derive from studies performed in European ancestry populations. African (AFR) and African admixed (AAC) ancestry individuals remain underrepresented in PD genetics research, limiting our understanding of ancestry-specific genetic architecture and the generalizability of known risk factors. MethodsWe conducted GWAS in AFR and AAC populations by integrating individua...

While 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is an established biomarker in amyotrophic lateral sclerosis (ALS), the metabolic correlates of motor neuron disease motor variants remain poorly defined. This is why we investigated patterns of cerebral glucose metabolism across the spectrum of motor neuron disorders (MND), including progressive muscular atrophy (PMA), primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS). We retrospectively included 18 PMA, ...

Study ObjectivesNarcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy. Previous studies have implicated the amygdala, thalamus, brainstem and hippocampus in the pathophysiology of NT1. We here aimed to examine more detailed subregional case-control differences in MRI-based segmentations of these brain regions to gain deeper insights. MethodsWe obtained 3T MRI brain scans from 54 NT1 patients (39 females, mean age 21.8 {+/-} 11.0 years, 51 with confirmed hypocret...

1Amyotrophic lateral sclerosis (ALS) is highly heritable, yet the vast majority of cases lack an identifiable genetic cause and clinical progression remains largely unpredictable. To connect noncoding and rare genetic variation to disease phenotypes in a relevant cell type, we generated a multi-omic quantitative trait locus (QTL) atlas from 594 induced-pluripotent-stem-cell-derived human motor neuron lines (522 ALS patients, 72 controls). By mapping cis-QTLs for chromatin accessibility, splicing...