Action tremor of the legs in essential tremor : prevalence, clinical correlates, and comparison with age-matched controls

The hallmark feature of essential tremor (ET) is action tremor of the arms. Leg tremor may also occur yet it has not been the central focus of previous studies. Its prevalence has only rarely been reported, its clinical correlates have yet to be explored. Our aims were to report the prevalence and analyze the clinical correlates of leg action tremor in patients with ET and, given the propensity for normal elderly individuals to manifest mild limb tremors, compare the prevalence with that in age-matched controls. Kinetic leg tremor rated ≥1 occurred in 28/63 (44.4%) ET cases and in only 9/63 (14.3%) controls (p < 0.001); moderate leg tremor occurred in 14.3% of cases. Leg tremor severity modestly correlated with disease duration (r = 0.31, p = 0.02). However, the severity and laterality of leg tremor did not correlate with those of arm tremor. The pathophysiological implications of this finding deserve further exploration

An Explainable Geometric-Weighted Graph Attention Network for Identifying Functional Networks Associated with Gait Impairment

One of the hallmark symptoms of Parkinson's Disease (PD) is the progressive loss of postural reflexes, which eventually leads to gait difficulties and balance problems. Identifying disruptions in brain function associated with gait impairment could be crucial in better understanding PD motor progression, thus advancing the development of more effective and personalized therapeutics. In this work, we present an explainable, geometric, weighted-graph attention neural network (xGW-GAT) to identify functional networks predictive of the progression of gait difficulties in individuals with PD. xGW-GAT predicts the multi-class gait impairment on the MDS Unified PD Rating Scale (MDS-UPDRS). Our computational- and data-efficient model represents functional connectomes as symmetric positive definite (SPD) matrices on a Riemannian manifold to explicitly encode pairwise interactions of entire connectomes, based on which we learn an attention mask yielding individual- and group-level explainability. Applied to our resting-state functional MRI (rs-fMRI) dataset of individuals with PD, xGW-GAT identifies functional connectivity patterns associated with gait impairment in PD and offers interpretable explanations of functional subnetworks associated with motor impairment. Our model successfully outperforms several existing methods while simultaneously revealing clinically-relevant connectivity patterns. The source code is available at https://github.com/favour-nerrise/xGW-GAT .Comment: Accepted by the 26th International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI 2023). MICCAI Student-Author Registration (STAR) Award. 11 pages, 2 figures, 1 table, appendix. Source Code: https://github.com/favour-nerrise/xGW-GA

Substantia Nigra Volume Dissociates Bradykinesia and Rigidity from Tremor in Parkinson’s Disease: A 7 Tesla Imaging Study

Background: In postmortem analysis of late stage Parkinson’s disease (PD) neuronal loss in the substantial nigra (SN) correlates with the antemortem severity of bradykinesia and rigidity, but not tremor. Objective: To investigate the relationship between midbrain nuclei volume as an in vivo biomarker for surviving neurons in mild-to-moderate patients using 7.0 Tesla MRI. Methods: We performed ultra-high resolution quantitative susceptibility mapping (QSM) on the midbrain in 32 PD participants with less than 10 years duration and 8 healthy controls. Following blinded manual segmentation, the individual volumes of the SN, subthalamic nucleus, and red nucleus were measured. We then determined the associations between the midbrain nuclei and clinical metrics (age, disease duration, MDS-UPDRS motor score, and subscores for bradykinesia/rigidity, tremor, and postural instability/gait difficulty). Results: We found that smaller SN correlated with longer disease duration (r = –0.49, p = 0.004), more severe MDS-UPDRS motor score (r = –0.42, p = 0.016), and more severe bradykinesia-rigidity subscore (r = –0.47, p = 0.007), but not tremor or postural instability/gait difficulty subscores. In a hemi-body analysis, bradykinesia-rigidity severity only correlated with SN contralateral to the less-affected hemi-body, and not contralateral to the more-affected hemi-body, possibly reflecting the greatest change in dopamine neuron loss early in disease. Multivariate generalized estimating equation model confirmed that bradykinesia-rigidity severity, age, and disease duration, but not tremor severity, predicted SN volume

Substantia Nigra Volume Dissociates Bradykinesia and Rigidity from Tremor in Parkinson’s Disease: A 7 Tesla Imaging Study

Background: In postmortem analysis of late stage Parkinson’s disease (PD) neuronal loss in the substantial nigra (SN) correlates with the antemortem severity of bradykinesia and rigidity, but not tremor. Objective: To investigate the relationship between midbrain nuclei volume as an in vivo biomarker for surviving neurons in mild-to-moderate patients using 7.0 Tesla MRI. Methods: We performed ultra-high resolution quantitative susceptibility mapping (QSM) on the midbrain in 32 PD participants with less than 10 years duration and 8 healthy controls. Following blinded manual segmentation, the individual volumes of the SN, subthalamic nucleus, and red nucleus were measured. We then determined the associations between the midbrain nuclei and clinical metrics (age, disease duration, MDS-UPDRS motor score, and subscores for bradykinesia/rigidity, tremor, and postural instability/gait difficulty). Results: We found that smaller SN correlated with longer disease duration (r = –0.49, p = 0.004), more severe MDS-UPDRS motor score (r = –0.42, p = 0.016), and more severe bradykinesia-rigidity subscore (r = –0.47, p = 0.007), but not tremor or postural instability/gait difficulty subscores. In a hemi-body analysis, bradykinesia-rigidity severity only correlated with SN contralateral to the less-affected hemi-body, and not contralateral to the more-affected hemi-body, possibly reflecting the greatest change in dopamine neuron loss early in disease. Multivariate generalized estimating equation model confirmed that bradykinesia-rigidity severity, age, and disease duration, but not tremor severity, predicted SN volume

Assessment of heterogeneity amongaAssessment of Heterogeneity Among Participants in the Parkinson’s Progression Markers Initiative Cohort Using α-Synuclein Seed Amplification: A Cross-Sectional Study participants in the Parkinson\u27s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study

BACKGROUND: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson\u27s disease from healthy controls. We used the well characterised, multicentre Parkinson\u27s Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. METHODS: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson\u27s disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson\u27s disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson\u27s disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. FINDINGS: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson\u27s disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson\u27s disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson\u27s disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson\u27s disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson\u27s disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. INTERPRETATION: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson\u27s disease. Our results show that the assay classifies people with Parkinson\u27s disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson\u27s disease and to establish biomarker-defined at-risk cohorts. FUNDING: PPMI is funded by the Michael J Fox Foundation for Parkinson\u27s Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson\u27s, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity

Lunar Volatiles and Solar System Science

Understanding the origin and evolution of the lunar volatile system is not only compelling lunar science, but also fundamental Solar System science. This white paper (submitted to the US National Academies' Decadal Survey in Planetary Science and Astrobiology 2023-2032) summarizes recent advances in our understanding of lunar volatiles, identifies outstanding questions for the next decade, and discusses key steps required to address these questions

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

peer reviewed[en] BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax  = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax  = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax  = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions