Objective
We recently demonstrated that 998 features derived from a simple 7‐minute smartphone test could distinguish between controls, people with Parkinson's and people with idiopathic Rapid Eye ...Movement sleep behavior disorder, with mean sensitivity/specificity values of 84.6‐91.9%. Here, we investigate whether the same smartphone features can be used to predict future clinically relevant outcomes in early Parkinson's.
Methods
A total of 237 participants with Parkinson's (mean (SD) disease duration 3.5 (2.2) years) in the Oxford Discovery cohort performed smartphone tests in clinic and at home. Each test assessed voice, balance, gait, reaction time, dexterity, rest, and postural tremor. In addition, standard motor, cognitive and functional assessments and questionnaires were administered in clinic. Machine learning algorithms were trained to predict the onset of clinical outcomes provided at the next 18‐month follow‐up visit using baseline smartphone recordings alone. The accuracy of model predictions was assessed using 10‐fold and subject‐wise cross validation schemes.
Results
Baseline smartphone tests predicted the new onset of falls, freezing, postural instability, cognitive impairment, and functional impairment at 18 months. For all outcome predictions AUC values were greater than 0.90 for 10‐fold cross validation using all smartphone features. Using only the 30 most salient features, AUC values greater than 0.75 were obtained.
Interpretation
We demonstrate the ability to predict key future clinical outcomes using a simple smartphone test. This work has the potential to introduce individualized predictions to routine care, helping to target interventions to those most likely to benefit, with the aim of improving their outcome.
Abstract Introduction Changes in personality have been described in Parkinson's disease (PD), with suggestion that those with established disease tend to be risk averse with a disinclination for ...addictive behaviour. However, little is known about the earliest and prodromal stages. Personality and its relationship with addictive behaviours can help answer important questions about the mechanisms underlying PD and addiction. Methods 941 population-ascertained PD subjects within 3.5 years of diagnosis, 128 patients with rapid eye movement sleep behaviour disorder (RBD) and 292 control subjects were fully characterised for motor symptoms, non-motor symptoms and across the following 5 personality domains: 1) neuroticism 2) extraversion 3) conscientiousness 4) agreeableness 5) openness using the Big Five Inventory. Results Patients with early PD were more neurotic (p < 0.001), less extraverted (p < 0.001) and less open than controls (p < 0.001). RBD subjects showed the same pattern of being more neurotic (p < 0.001), less extraverted (p = 0.03) and less open (p < 0.001). PD patients had smoked less (p = 0.02) and drunk less alcohol (p = 0.03) than controls, but caffeine beverage consumption was similar. Being more extraverted (p < 0.001), more open (p < 0.001), and less neurotic (p < 0.001) predicted higher alcohol use, while being more extravert (p = 0.007) and less agreeable (p < 0.001) was associated with smoking more. Conclusions A similar pattern of personality changes is seen in PD and RBD compared to a control population. Personality characteristics were associated with addictive behaviours, suggestive of a common link, but the lower rates of addictive behaviours before and after the onset of motor symptoms in PD persisted after accounting for personality.
L-dopa responsiveness in Parkinson's disease (PD) varies, but the clinical correlates and significance of this are ill-defined.
Patients were assessed before and after their usual morning L-dopa ...dose, using the MDS Unified PD Rating Scale Part 3 (MDS UPDRS 3), and rated as definite responders (≥24.5% improvement) or limited responders (<24.5%).
1007 cases, mean age 66.1 years (SD 9.1) at diagnosis, were assessed 3.4 (SD 0.9) years after diagnosis. The L-dopa response was definite in 614 cases (61.0%), median reduction in MDS UPDRS 3 scores was 42.0%, (IQR 33.3, 53.1), and was limited in 393 cases (39.0%), median reduction in MDS UPDRS 3 scores 11.5% (IQR 4.3, 18.2). Definite responders were younger (66.3 years at study entry, SD 9.3) than limited responders (69.2 years, SD 8.4, p < 0.001). The MDS UPDRS 3 score at study entry in definite responders (21.0, SD 10.5) was significantly lower than in limited responders (24.7, SD 13.4, p < 0.001). The MDS UPDRS 3 increase over 18 months was less in definite responders at 3.0 (SD 10.4), compared to limited responders (6.4, SD 11.0, p < 0.001). The levodopa equivalent daily dose (LEDD) was not significantly different at study entry (definite responders 317 mg, SD 199, vs limited responders 305 mg, SD 191, p = 0.53). However, LEDD was significantly higher at the time of the L-dopa challenge test in definite responders (541 mg, SD 293) compared to limited responders (485 mg, SD 215, p = 0.01). Responsiveness to L-dopa was unaffected by the challenge test dose (p = 0.54).
The main determinants of variation in the L-dopa response in early PD are age and motor severity. A limited L-dopa response is associated with faster motor progression.
•L-Dopa responsiveness in Parkinson's disease varies with age.•L-Dopa responsiveness in early Parkinson's disease is associated with the rate of motor progression.•L-Dopa responsiveness in early disease is unaffected by gender.•Response to L-Dopa in early disease is unaffected by acute challenge test dose.
ABSTRACT
Background
Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50–80%. Functional ...neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly.
Objective
To quantify dopamine transporter (DaT) activity by neuroimaging in early PD.
Methods
Systematic review and novel analysis of DaT imaging studies in early PD.
Results
In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6).
Conclusions
Loss of striatal DaT activity in early PD is less at 35–45%, rather than the 50–80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.
Cerebellar arteriovenous malformations (CAVMs) are challenging to treat given their close proximity to the brain stem, greater propensity for rupture, and greater rates of morbidity and mortality ...than other brain arteriovenous malformations. The present investigation sought to describe and characterize the features of these rare and unique lesions.
A retrospective review of CAVM cases treated at 2 tertiary medical centers was performed. Patients surgically treated at institution 1 from September 1999 to February 2013 and institution 2 from October 2008 to October 2015 were included.
A total of 120 patients had been treated. Of the 120 patients, 85 (70.8%) had initially presented with hemorrhage, 45 (37.5%) of whom experienced hemorrhage requiring emergent surgery. A favorable neurological outcome was observed in 76 patients (63.3%; modified Rankin Scale score <3). The perioperative mortality was 2.5% (n = 3). The long-term mortality rate was 7.5% (n = 9). The mean follow-up time was 1.82 years. On average, the patients with large CAVMs (≥3 cm; P ≤ 0.001), who had received embolization before surgery (P = 0.04), did not have an associated aneurysm (P ≤ 0.001), or had a residual CAVM after surgery (P = 0.008) were significantly younger. Female patients had fewer CAVMs with deep venous drainage (54.3% vs. 72.3%; P = 0.049), experienced decreased mortality (1.4% vs. 16.7%; P = 0.003), and were less likely to have worse neurological status after treatment (P = 0.003).
CAVMs are rare lesions that exhibit unique disease characteristics. Although most patients will experience a favorable outcome, CAVMs frequently present with hemorrhage, result in high rates of morbidity and mortality, and characteristically differ depending on patient age and gender.
•Favorable outcomes were seen in 63.3% after surgery; 45.8% had improved neurological status (long-term mortality, 7.5%).•Most (89.9%) had complete resection; 12 had residual CAVMs on postoperative imaging.•Relative risk was 1.7 (OR, 2.3; univariate regression analysis) for preoperative hemorrhage and poor outcomes (P = 0.03).•Patient age differed significantly for preoperative hemorrhage, AVM size, embolization, associated aneurysm, and residual AVM.•Females had reduced mortality and greater improvement in neurologic status compared to males.
Dopa Responsiveness in Parkinson's Disease Gandhi, Sacha E.; Nodehi, Anahita; Lawton, Michael A. ...
Movement disorders clinical practice (Hoboken, N.J.),
06/2024
Journal Article
Recenzirano
Odprti dostop
Abstract Background Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. Objectives To examine serial ...dopaminergic responses, if there are distinct patterns, and which factors predict these. Methods We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth‐mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters. Results 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1–74.3%). We identified 3 response groups: “Striking” ( n = 29, 8.7%); “Excellent” ( n = 110; 32.7%) and “Modest” ( n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier ( P = 0.02), were less likely to be on dopamine agonist monotherapy ( P = 0.01), and had better cognition ( P < 0.01) and activities of daily living ( P = 0.01). Excellent responders had higher challenge doses ( P = 0.03) and were more likely to be on combination therapy ( P < 0.01). Conclusion Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid.
Depression in individuals with Alzheimer's disease (AD) is common, distressing, difficult to treat, and inadequately understood. It occurs more frequently in AD than in older adults without dementia. ...The reasons why some patients develop depression during AD and others do not remain obscure.
We aimed to characterize depression in AD and to identify risk factors.
We used data from three large dementia focused cohorts: ADNI (
= 665 with AD, 669 normal cognition), NACC (
= 698 with AD, 711 normal cognition), and BDR (
= 757 with AD). Depression ratings were available using the GDS and NPI and in addition for BDR the Cornell. A cut-off of≥8 was used for the GDS and the Cornell Scale for Depression in Dementia,≥6 for the NPI depression sub-scale, and≥2 for the NPI-Q depression sub-scale. We used logistic regression to examine potential risk factors and random effects meta-analysis and an interaction term to look for interactions between each risk factor and the presence of cognitive impairment.
In individual studies there was no evidence of a difference in risk factors for depressive symptoms in AD. In the meta-analysis the only risk factor which increased the risk of depressive symptoms in AD was previous depression, but information on this was only available from one study (OR 7.78 95% CI 4.03-15.03).
Risk factors for depression in AD appear to differ to those for depression per se supporting suggestions of a different pathological process, although a past history of depression was the strongest individual risk factor.
Abstract There are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression ...is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1 , ASNS , PDE5A , and XPO1 . Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.
Cadmium chloride (CdCl2) is a toxic compound found as a pollutant in the environment due to agricultural and industrial sources. Exposure to Cd2+ is known to promote malignant tumors such as lung ...cancer and leukemia. While the current medications for cadmium toxicity focus on treatments to promote the excretion from the body, treatments to improve health after cadmium exposure are less well studied. Modified citrus pectin (MCP) is a polysaccharide derived from citrus peels that has been shown to induce natural killer cell activity in myeloid leukemia cells and also act as a natural chelation agent to help excrete toxic metals from healthy human subjects. We hypothesized that MCP might have a counteracting effect against CdCl2 toxicity through cancer-related pathways. This study investigates the effects of MCP on CdCl2 toxicity in C. elegans, which shares a number of cancer-related pathways with mammals. The results indicated that MCP was able to significantly counter the toxic effects of CdCl2 on C. elegans lifespan and development. Our studies suggest that the beneficial effects of MCP may result from its ability to mitigate the effects of CdCl2 on gene expression, particularly in conserved pathways associated with apoptosis, tumor induction and suppression and inflammation-related pathways.
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