Functional Impairment in Individuals With Prodromal or Unrecognized Parkinson Disease.

Importance: Daily functioning in individuals with prodromal Parkinson disease requires more detailed description. Objective: To evaluate whether functional limitations exist in individuals with Parkinson disease prior to diagnosis compared with the general population. Design, Setting, and Participants: This case-control study used Medicare-linked data from the National Health and Aging Trends Study (NHATS), a longitudinal survey in the US, for a random subsample of Medicare beneficiaries aged 65 years or older, with Black and older individuals oversampled by design. Patients with incident Parkinson disease were defined as having 2 or more Medicare diagnoses from January 2011 to December 2017, with Medicare eligibility 2 or more consecutive years prior to the first diagnosis. Controls were defined as individuals with Medicare eligibility at a baseline year and 2 or more years prior, with no Parkinson disease diagnosis. Analyses were conducted from November 2021 to June 2022. Exposures: Responses to survey questions addressing dexterity, eating, mobility, mood, pain, sleep, speech, strength, and vision. Main Outcome and Measures: Associations between survey responses and Parkinson disease diagnosis in the first year of diagnosis (baseline) and up to 3 years prior to diagnosis (ie, during the prodromal phase) were examined using logistic regression. Results: A total of 6674 participants were included. The participant numbers and case prevalence each year varied from 3492 to 5049 and from 700 to 1180 per 100 000 population, respectively. The median age groups were 75 to 79 years and 80 to 84 years, and the percentage of females varied from 48.21% (27 of 56 cases) to 59.98% (2079 of 3466 controls) across all years, with similar proportions among cases and controls. Individuals with prodromal Parkinson disease were less likely to report being able to walk 6 blocks (odds ratio [OR], 0.34; 95% CI, 0.15-0.82), stand independently from a kneeling position (OR, 0.30; 95% CI, 0.11-0.85), or lift a heavy object above one's head (OR, 0.36; 95% CI, 0.15-0.87) and were more likely to report imbalance (OR, 2.77; 95% CI, 1.24-6.20) 3 years prior to diagnosis. Conclusions and Relevance: The findings suggest that individuals with prodromal or unrecognized Parkinson disease may have greater impairment in activities involving mobility and strength up to 3 years prior to diagnosis compared with the general population. Identification of prodromal disease may facilitate earlier intervention to improve function.

Selected autonomic signs and symptoms as risk markers for phenoconversion and functional dependence in prodromal Parkinson's disease.

PURPOSE: To determine whether dysautonomia can stratify individuals with other prodromal markers of Parkinson's disease (PD) for risk of phenoconversion and functional decline, which may help identify subpopulations appropriate for experimental studies. METHODS: Data were obtained from Parkinson's Progression Markers Initiative. Cohorts without PD but with at-risk features were included (hyposmia and/or rapid-eye-movement-sleep behavior disorder, LRRK2 gene mutation, GBA gene mutation). Dysautonomia measures included Scales-for-Outcomes-in-Parkinson's-Disease Autonomic (SCOPA-AUT), seven SCOPA-AUT subscales, and cardiovascular dysfunction (supine hypertension, low pulse pressure, neurogenic orthostatic hypotension). Outcome measures were phenoconversion and Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤ 70, which indicates functional dependence. Cox proportional-hazards regression was used to evaluate survival to phenoconversion/SE-ADL ≤ 70 for each dysautonomia measure. If a significant association was identified, a likelihood-ratio test was employed to evaluate whether a significant interaction existed between the measure and cohort. If so, regression analysis was repeated stratified by cohort. RESULTS: Median follow-up was 30 months. On multivariable analysis, gastrointestinal and female sexual dysfunction subscales were associated with increased risk of phenoconversion, while the cardiovascular subscale and neurogenic orthostatic hypotension were associated with increased risk of SE-ADL ≤ 70; respective hazard ratios (95% confidence intervals) were 1.13 (1.01-1.27), 3.26 (1.39-7.61), 1.87 (1.16-2.99), 5.45 (1.40-21.25). Only the association between the cardiovascular subscale and SE-ADL ≤ 70 was modified by cohort. CONCLUSIONS: Symptoms of gastrointestinal and female sexual dysfunction predict phenoconversion in individuals with other risk markers for PD, while signs and symptoms of cardiovascular dysfunction may be associated with functional decline.

Early Autonomic Symptoms Predict Functional Decline in Parkinson's Disease Independent of Dopaminergic Therapy.

INTRODUCTION: Parkinson's disease (PD) has variable progression; identifying determinants of functional decline in PD is needed for accurate prognostication. Autonomic symptoms can result from dopaminergic therapy but may also independently predict functional decline. METHODS: The sample included individuals with newly diagnosed PD in Parkinson's Progression Markers Initiative. Autonomic symptoms were measured with the Scales-for-Outcomes-in-Parkinson's-Disease-Autonomic (SCOPA-AUT). Presence/absence of autonomic symptoms for SCOPA-AUT total scale and seven subscales was defined, and baseline demographic/clinical data were compared between groups with and without autonomic symptoms. Time-to-functional-dependence, or Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤70, was compared between groups using hazard models, adjusting for covariates including time-varying levodopa-equivalent daily dosage. If a subscale was associated with a significant subhazard ratio (SHR), hazard models for items in that subscale were generated and gender was evaluated as an effect modifier. RESULTS: 399 participants were included. Over a median of 72 months (range 6-84), 91 (22.81%) reached SE-ADL ≤70. SCOPA-AUT total/gastrointestinal/urinary/pupillomotor scales were associated with SE-ADL ≤70; respective multivariable SHRs (95% CI, p value) were 1.98 (1.06-3.70, 0.03), 1.71 (1.04-2.81, 0.03), 1.94 (1.25-3.01, <0.01), 2.56 (1.24-5.31, 0.01). Individual items in the gastrointestinal and urinary scales drove associations. Urinary scale associations were seen in males only. CONCLUSIONS: Symptoms of gastrointestinal, urinary, pupillomotor dysfunction are associated with functional decline risk in PD, independent of dopaminergic therapy. Detailed assessments of autonomic symptomatology should be utilized in studies attempting to refine predictive models of PD progression.

Clinical and neuroimaging correlates of progression of mild parkinsonian signs in community-dwelling older adults.

INTRODUCTION: Mild parkinsonian signs (MPS) are associated with morbidity. Identification of MPS progression markers may be vital for preventive management, yet has not been pursued. This study aimed to ascertain clinical/neuroimaging features predictive of MPS progression. METHODS: 205 participants in the Health ABC Study were included. MPS was defined using published guidelines. MPS progression was evaluated by determining UPDRS-III change between baseline and follow-up ≥2 years later. Standard brain MRI and DTI were obtained at baseline. Correlation coefficients between demographics, vascular risk factors, imaging markers, and UPDRS-III change were adjusted for follow-up time. Linear regression was used to adjust for possible confounders in the relationship between imaging markers and MPS progression. RESULTS: 30% of participants had baseline MPS. Demographics and risk factors did not differ significantly between participants with MPS (MPS+) and without MPS (MPS-). Mean follow-up time was 3.8±0.8 years. Older age, male gender, diabetes were associated with faster rate of UPDRS-III change in MPS- but not MPS+ participants. Among MPS- participants, the only imaging marker associated with faster UPDRS-III progression was higher gray matter mean diffusivity (MD), widespread in various cortico-subcortical bihemispheric regions, independent of age, gender, diabetes. No imaging features were associated with UPDRS-III change among MPS+ participants. CONCLUSIONS: Lower gray matter integrity predicted MPS progression in those who did not have baseline MPS. Microstructural imaging may capture early changes related to MPS development, prior to macrostructural change. Any future management promoting gray matter preservation may inhibit MPS development.

PD and DLB: Brain imaging in Parkinson's disease and dementia with Lewy bodies.

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are both neurodegenerative diseases characterized by the abnormal intraneuronal accumulation of misfolded α-Synuclein into Lewy bodies and Lewy neurites. They are distinguished in part by the temporal relationship between the onset of parkinsonism versus cognitive signs, with the former occurring earlier in PD and the latter generally occurring earlier in DLB, along with additional clinical features more prominent in DLB. While clinical criteria help to elucidate diagnosis based on history and exam, definitive diagnosis can only be made at autopsy. More recently, various brain imaging modalities have been utilized to augment diagnostic accuracy made at the bedside and are being studied as possible means to monitor progression or to provide early diagnostic biomarkers. Structural imaging techniques such as structural MRI have some utility in differentiating PD from other causes of parkinsonism, and in differentiating DLB from Alzheimer's disease (AD). In addition, molecular and metabolic brain imaging modalities have shown great promise in elucidating possible diagnostic biomarkers and in providing insight into disease severity and pathogenesis for both PD and DLB. In this review, we summarize the utility of clinically available and research-based brain imaging in diagnosis and monitoring in PD and DLB, which are helping to improve early diagnosis, are providing insight into pathologic mechanisms of disease, and may help to provide biomarker monitoring for disease progression and clinical trials.

Motor asymmetry over time in Parkinson's disease.

BACKGROUND: Motor symptoms in Parkinson's disease (PD) patients are usually asymmetric at onset. The literature on change in asymmetry over time has mixed results, with some studies suggesting a retained asymmetry and others suggesting a progression towards symmetry. The aim of this study was to assess change in asymmetry over time. METHODS: Charts of 109 consecutive patients who had been followed in a movement disorders clinic for routine PD care were retrospectively reviewed. All patients had been treated for PD symptoms and had been seen during at least 2 annual time points over 5 years. Interval absolute differences in Unified PD rating scale (UPDRS) scores for bradykinesia, rigidity, and tremor between the right and left sides were calculated for annual time points. RESULTS: Neither bradykinesia, rigidity, nor tremor became more symmetric over a 5-year period; there was not a statistically significant change in asymmetry at any annual time point for these motor symptoms. CONCLUSIONS: The lack of observed change in UPDRS score difference suggests that motor symptoms in PD patients remain asymmetric. This is important to consider clinically when predicting the natural course of PD and considering alternative diagnoses to PD. These results may also be important in developing hypotheses for disease progression.

Pazopanib-associated posterior reversible encephalopathy syndrome with intracerebral haemorrhage.

Pazopanib is a tyrosine kinase receptor antagonist used for renal cell carcinoma and soft tissue sarcoma that inhibits tumour growth and angiogenesis. A common side effect of pazopanib is hypertension. We report a case of a 69-year-old woman with clear cell renal cell carcinoma who developed a large right occipital intracerebral haemorrhage 3 weeks after initiating pazopanib. Although this was initially suspected to be a haemorrhagic metastasis, MRI revealed bi-occipital oedema, supporting a diagnosis of posterior reversible encephalopathy syndrome (PRES). A craniectomy was required. Immunohistochemical stains for renal cell carcinoma antigen, CA IX and PAX8 were negative. This case suggests that PRES and intracerebral haemorrhage may result from pazopanib use and are important complications to consider prior to initiating this agent.

Magnesium for Treatment of Reversible Cerebral Vasoconstriction Syndrome: Case Series.

We describe 2 cases of reversible cerebral vasoconstriction syndrome (RCVS) with refractory headache aborted by intravenous magnesium. Case 1 is a 53-year-old woman with subarachnoid hemorrhage due to RCVS presented with refractory headache and persistent vasospasm, despite aggressive treatment with calcium channel blockers (CCBs) and systemic corticosteroids. Subsequently, she experienced dramatic relief of symptoms with intravenous magnesium therapy. She continued oral maintenance therapy and remained symptom free. Case 2 is a 71-year-old female with bilateral temporo-occipital infarcts due to RCVS, presented with refractory headache and persistent vasospasm on transcranial Doppler (TCD), despite aggressive treatment with CCBs. She experienced dramatic relief of symptoms with intravenous magnesium and resolution of vasospasm on TCD. Magnesium may be beneficial for the treatment of refractory headaches in patients with RCVS. Future studies are needed to determine whether it should be considered as a first-line agent.