Health Care Utilization in the Last Year of Life in Parkinson Disease and Other Neurodegenerative Movement Disorders.

Background and Objectives: Neurodegenerative movement disorders are rising in prevalence and are associated with high health care utilization. Generally, health care resources are disproportionately expended in the last year of life. Health care utilization by those with neurodegenerative movement disorders in the last year of life is not well-understood. The goal of this study was to assess the utilization of acute care in the last year of life among individuals with neurodegenerative movement disorders and determine whether outpatient neurology or palliative care affected acute care utilization and place of death. Methods: We conducted a retrospective cross-sectional study including health system administrative data in Alberta, Canada, from 2011 to 2017. Administrative data were used to determine place of death and quantify emergency department (ED) visits, hospitalizations, intensive care unit admissions, and outpatient generalist and specialist visits. Diagnoses were classified by 10th revision of the International Classification of Diseases codes. Stata 16v was used for statistical analyses. Results: Among 1439 individuals (60% male), Parkinson disease (n = 1226), progressive supranuclear palsy (n = 78), multiple system atrophy (n = 47), and Huntington disease (n = 58) were the most common diagnoses. The most frequent place of death was in hospital (45.9%), followed by long-term care (36.3%), home (7.9%), and residential hospice (4.0%). Most (64.2%) had >1 ED visit, and 14.4% had >3 emergency department visits. Fifty-five percent had >1 hospitalization, and 23.3% spent >30 days in hospital. Few (2.6%) were admitted to ICU. Only 37.2% and 8.8% accessed outpatient neurologist and specialist palliative care services, respectively. Multivariate logistic regression found the odds of dying at home was higher for those who received outpatient palliative consultation (OR, 2.49, 95% confidence interval [CI], 1.48-4.21, p < 0.001) and were with a longer duration of home care support (OR, 1.0007, 95% CI, 1.0004-1.0009, p < 0.001). Discussion: There are high rates of in-hospital death and acute care utilization in the year before death among those with neurodegenerative movement disorders. Most did not access specialist palliative or neurologic care in the last year of life. Outpatient palliative care and home care services were associated with increased odds of dying at home. Our results indicate the need for further research into the causes, costs, and potential modifiers to inform public health planning.

Cerebrovascular Reactivity Across the Entire Brain in Cerebral Amyloid Angiopathy.

BACKGROUND AND OBJECTIVES: Reduced cerebrovascular reactivity is proposed to be a feature of cerebral amyloid angiopathy (CAA) but has not been measured directly. Employing a global vasodilatory stimulus (hypercapnia), this study assessed the relationships between cerebrovascular reactivity and MRI markers of CAA and cognitive function. METHODS: In a cross-sectional study, individuals with probable CAA, mild cognitive impairment, or dementia due to Alzheimer disease and healthy controls underwent neuropsychological testing and an MRI that included a 5% carbon dioxide challenge. Cerebrovascular reactivity was compared across groups controlling for age, sex, and the presence of hypertension, and its associations with MRI markers of CAA in participants with CAA and with cognition across all participants were determined using multivariable linear regression adjusting for group, age, sex, education, and the presence of hypertension. RESULTS: Cerebrovascular reactivity data (mean ± SD) were available for 26 participants with CAA (9 female; 74.4 ± 7.7 years), 19 participants with mild cognitive impairment (5 female; 72.1 ± 8.5 years), 12 participants with dementia due to Alzheimer disease (4 female; 69.4 ± 6.6 years), and 39 healthy controls (30 female; 68.8 ± 5.4 years). Gray and whiter matter reactivity averaged across the entire brain was lower in participants with CAA and Alzheimer disease dementia compared to healthy controls, with a predominantly posterior distribution of lower reactivity in both groups. Higher white matter hyperintensity volume was associated with lower white matter reactivity (standardized coefficient [ß], 95% CI -0.48, -0.90 to -0.01). Higher gray matter reactivity was associated with better global cognitive function (ß 0.19, 0.03-0.36), memory (ß 0.21, 0.07-0.36), executive function (ß 0.20, 0.02-0.39), and processing speed (ß 0.27, 0.10-0.45) and higher white matter reactivity was associated with higher memory (ß 0.22, 0.08-0.36) and processing speed (ß 0.23, 0.06-0.40). CONCLUSIONS: Reduced cerebrovascular reactivity is a core feature of CAA and its assessment may provide an additional biomarker for disease severity and cognitive impairment.

Association of Dual-Task Gait With Incident Dementia in Mild Cognitive Impairment: Results From the Gait and Brain Study.

Importance: Gait performance is affected by neurodegeneration in aging and has the potential to be used as a clinical marker for progression from mild cognitive impairment (MCI) to dementia. A dual-task gait test evaluating the cognitive-motor interface may predict dementia progression in older adults with MCI. Objective: To determine whether a dual-task gait test is associated with incident dementia in MCI. Design, Setting, and Participants: The Gait and Brain Study is an ongoing prospective cohort study of community-dwelling older adults that enrolled 112 older adults with MCI. Participants were followed up for 6 years, with biannual visits including neurologic, cognitive, and gait assessments. Data were collected from July 2007 to March 2016. Main Outcomes and Measures: Incident all-cause dementia was the main outcome measure, and single- and dual-task gait velocity and dual-task gait costs were the independent variables. A neuropsychological test battery was used to assess cognition. Gait velocity was recorded under single-task and 3 separate dual-task conditions using an electronic walkway. Dual-task gait cost was defined as the percentage change between single- and dual-task gait velocities: ([single-task gait velocity - dual-task gait velocity]/ single-task gait velocity) × 100. Cox proportional hazard models were used to estimate the association between risk of progression to dementia and the independent variables, adjusted for age, sex, education, comorbidities, and cognition. Results: Among 112 study participants with MCI, mean (SD) age was 76.6 (6.9) years, 55 were women (49.1%), and 27 progressed to dementia (24.1%), with an incidence rate of 121 per 1000 person-years. Slow single-task gait velocity (<0.8 m/second) was not associated with progression to dementia (hazard ratio [HR], 3.41; 95% CI, 0.99-11.71; P = .05)while high dual-task gait cost while counting backward (HR, 3.79; 95% CI, 1.57-9.15; P = .003) and naming animals (HR, 2.41; 95% CI, 1.04-5.59; P = .04) were associated with dementia progression (incidence rate, 155 per 1000 person-years). The models remained robust after adjusting by baseline cognition except for dual-task gait cost when dichotomized. Conclusions and Relevance: Dual-task gait is associated with progression to dementia in patients with MCI. Dual-task gait testing is easy to administer and may be used by clinicians to decide further biomarker testing, preventive strategies, and follow-up planning in patients with MCI. Trial Registration: clinicaltrials.gov: NCT03020381.

Homocysteine is not associated with global motor or cognitive measures in nondemented older Parkinson's disease patients.

Levodopa (L-dopa) treatment of Parkinson's disease (PD) is associated with elevated homocysteine (Hcy). To examine the relationship between Hcy, methylenetetrahydrofolate reductase polymorphisms (MTHFR: 677C/T; 1298A/C), and B-vitamins in older PD patients and whether Hcy or MTHFR polymorphisms were associated with clinical measures. MTHFR polymorphisms, B-vitamin intake, and blood concentrations of Hcy, vitamin B12 and folate, and creatinine were determined and compared between groups (PD and controls). The relationship of Hcy to clinical measures was examined in PD. Among 51 patients [30M/21F, mean age (SD): 71.5 (4.7)] and 50 controls [29M/21F, 71.5 (4.8)], Hcy was higher in PD [13.6 (3.8); controls: 10.5 (2.5), P < 0.0005]. Hcy was associated with B-vitamin intake [F = 21.7, P < 0.0005], folate level (R = 0.31, P = 0.035), and the interaction of intake with MTHFR 677T (F = 5.2, P = 0.007), but not MTHFR 1298C genotype. Hcy did not correlate with global measures of cognition, mood, or parkinsonism in PD or with dyskinesias, fluctuations, or freezing. Higher vitamin B12 levels were associated with lower dyskinesia risk. Hcy was influenced by PD, MTHFR 677 genotype, and vitamin use, but not by the MTHFR 1298 genotype. There was no clear association with motor or cognitive measures, but dyskinesias were less likely with higher B12.

Intact presupplementary motor area function in early, untreated Parkinson's disease.

Although motor symptoms of Parkinson's disease (PD) are initially responsive to dopamine replacement therapy, nonresponsive features develop over time, suggesting that impaired dopaminergic function alone may not be wholly responsible for all the motor features of the disease. Previous studies suggest impaired function in the presupplementary motor area (pre-SMA) in PD. Our objective was to determine whether pre-SMA abnormalities are present in untreated patients with early disease. We measured N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in pre-SMA in 26 untreated patients with early PD (disease duration 3.0 +/- 2.0 yr) and 15 control subjects with single voxel magnetic resonance spectroscopy. Neither NAA/Cr nor Cho/Cr ratios differed significantly between groups. These observations suggest that, although pre-SMA function is impaired in moderately advanced PD, it is relatively spared in early disease. We suggest that pre-SMA dysfunction is in part responsible for the dopamine nonresponsive features associated with disease progression.

Early, untreated Parkinson's disease patients show reaction time variability.

While Parkinson's disease (PD) is associated with motor slowing, less attention has been paid to variability in performance on motor and cognitive tasks. To examine reaction time latencies and intraindividual variability in untreated patients with PD compared to healthy controls. Twenty-nine (19 men/10 women) patients with untreated PD and 16 controls (8 men/8 women) were examined using measures of simple reaction time (SRT) and choice reaction time (CRT) in addition to cognitive measures of executive function (Trail Making Test; adaptive digit ordering). Latencies and intraindividual variability were compared between groups. Partial correlation coefficients, adjusting for age, sex and education were used to examine the relationship between RT measures and motor or cognitive measures. Patients and controls did not differ with respect to age or sex distribution. Education and cognitive status differed between groups, but no subject was demented or clinically depressed. After adjusting for age, sex and education, significant group differences were found in latencies (2-choice RT and 8-choice RT) and intraindividual variability scores (all CRT conditions). Latencies did not differ significantly after adjusting for finger tapping rate. In the PD group neither the motor nor the executive measures correlated significantly with any of the reaction time measures. We conclude that CRT intraindividual variability and latencies are increased in untreated PD.

Age and dementia-associated atrophy predominates in the hippocampal head and amygdala in Parkinson's disease.

The hippocampus (HC) and amygdala (AG) decrease in volume with age and in Parkinson's disease (PD) with (PDD) and without dementia. We compared 44 PD to 44 age, sex and education-matched subjects without PD (non-PD) and 13 PDD subjects. T1-weighted MR images were used to manually segment the head, body and tail of the HC and the AG. HC volumes, corrected to intracranial volume, were smaller in PDD than non-PD (p=0.04), reflected predominantly by head atrophy. Right AG volumes were smaller in PD compared to non-PD (p=0.03). HC volumes in older (>70), but not younger, non-demented PD differed from non-PD (HC, p=0.02; head, p=0.03). Age correlated negatively with overall HC (r=-0.43, p=0.004) and head (r=-0.48, p=0.001) in PD, but not in non-PD. In PD, left HC head volumes correlated with recall, but not recognition scores on the CVLT-II (r=0.35, p=0.02) and BVMT-R (r=0.35, p=0.02); AG volumes correlated with CVLT-II recall (r=0.35, p=0.02). No correlations were found in non-PD (p>0.4). In conclusion, functionally meaningful age-associated hippocampal and amygdala atrophy occurs in PD.

Axial signs and magnetic resonance imaging correlates in Parkinson's disease.

BACKGROUND: Age-related brain changes may contribute to axial features in Parkinson's disease (PD). OBJECTIVES: To determine if ventricular volume and white matter high signal changes (WMC) are related to motor signs in PD and controls independent of age. METHODS: Patients were rated with the Unified Parkinson's Disease Rating Scale (subscore A: tremor, rigidity, bradykinesia, and facial expression; subscore B: speech and axial impairment). Steps and time taken to walk 9.144 meters were measured. Total ventricular volume (TVV) and intracranial volume (ICV) were measured on T1-weighted MRI using manual tracing software. WMC were rated on axial T2-weighted, dual-echo or FLAIR MR images using a visual scale. RESULTS: TVV (cm3) (PD: 36.48 +/- 15.93; controls: 32.16 +/- 14.20, p = 0.21) and WMC did not differ between groups (PD: 3.7 +/- 4.2; controls: 3.2 +/- 3.1, p = 0.55). Age correlated positively with ICV-corrected TVV and WMC in PD (cTVV: r = 0.48, p = 0.003; WMC: r = 0.42, p = 0.01) and controls (cTVV: r = 0.31, p = 0.04; WMC: r = 0.44, p = 0.003). Subscore B (r = 0.42, p = 0.01) but not subscore A (r = 0.25, p = 0.14) correlated with cTVV in PD. Steps and walking time correlated with cTVV and WMC in PD; cadence correlated with cTVV and steps with WMC in controls. Age-adjustment eliminated correlations. CONCLUSION: Subscore B, but not subscore A correlated positively with ventricular volume in PD, though this association was accounted for by age. Age-related brain change super-imposed on PD may contribute to axial features.

Magnetic resonance spectroscopic evidence for presupplementary motor area neuronal dysfunction in Parkinson's disease.

The anterior cingulate (AC) gyrus and the presupplementary motor area (pre-SMA) show pathological changes in Parkinson's disease (PD). We examined if PD patients show magnetic resonance spectroscopy (MRS) changes in NAA/Cr in the AC, pre-SMA, or posterior cingulate (PC). Forty-four (27 male, 17 female) healthy nondemented PD patients and 38 controls (18 male, 20 female) 65 years of age and older were examined using the Unified Parkinson's Disease Rating Scale (UPDRS), Mini-Mental State Examination, Frontal Assessment Battery, and Geriatric Depression Scale. MRS was performed at 1.5 T. Voxels (8 cc; PRESS; TE = 80; TR = 1,600 ms) were placed mid-sagittally. Gray matter and white matter volumes were measured within voxels using SPM2. Spectra were analyzed using LC model to yield NAA/Cr and Cho/Cr. Demographic and cognitive measures did not differ between groups. Motor UPDRS was 17.7 +/- 8.8 for PD. Pre-SMA NAA/Cr was lower in PD (PD: 1.39 +/- 0.17; control: 1.47 +/- 0.16; P = 0.045) and correlated negatively with age (r = 0.39; P = 0.01), but not with UPDRS, disease duration, or dopamine equivalents. AC and PC NAA/Cr and Cho/Cr in any region did not differ (P > 0.05). In conclusion, pre-SMA NAA/Cr was selectively decreased in PD, consistent with neuronal dysfunction. This should be further examined as a biomarker of disease in PD.

Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease.

BACKGROUND AND PURPOSE: Vascular causes of dementia are increasing in importance because of the aging of the population. Biological markers to distinguish patients with vascular dementia (VaD) from Alzheimer disease (AD) would be very useful. Because cerebrovascular disease increases expression of brain matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs), we hypothesized that MMPs would be elevated in the cerebrospinal fluid (CSF) of patients with VaD, but not in patients with AD. METHODS: Fifteen patients with VaD were identified, including dementia caused by multiple infarcts and progressive dementia caused by disease of the small cerebral blood vessels. Patients were followed-up for 4 to 10 years to confirm the diagnosis. Thirty patients with AD were also studied. Patients had CSF collected at their initial evaluation. Gelatinase A (MMP-2) and gelatinase B (MMP-9) were quantified by gelatin-substrate zymography, and TIMPs were measured by reverse zymography. Control CSF was obtained from neurologically normal subjects. RESULTS: MMP-9 levels were significantly elevated in the CSF of VaD patients compared either to those with AD (P<0.0001) or to controls. MMP-2, TIMP-1, and TIMP-2 were similar in patient groups and controls. CONCLUSIONS: Patients with multiinfarct and small vessel VaD have elevated levels of MMP-9 in the CSF compared with AD and controls. Although CSF MMP-9 increases in other neurological conditions and is not specific for VaD, it could provide an additional biological marker for the separation of patients with VaD and AD.