Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

Mobility, mood and site of care impact health related quality of life in Parkinson's disease.

OBJECTIVE: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson's disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). BACKGROUND: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. METHODS: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. RESULTS: The variability in the PDQ-39 summary index score correlated with H&Y stage (R(2) = 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. CONCLUSIONS: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices.

Direct costs and survival of medicare beneficiaries with early and advanced Parkinson's disease.

BACKGROUND: No recent analysis details Parkinson's Disease (PD) costs or survival for Medicare beneficiaries. This study assesses excess direct costs and survival in Medicare beneficiaries with early and advanced PD. METHODS: Patients with ≥ 2 PD diagnoses (ICD-9-CM: 332.0), ≥ age 65, continuously enrolled in Parts A&B during one-year baseline and study periods were selected from the Medicare 5% sample (N = 3.2 million, 1999-2008). Newly diagnosed patients were defined as having no baseline claims for movement disorder, dementia, Alzheimer's, bipolar disorder, psychosis, falls or related injuries, ambulatory assistance device (walker or wheelchair), or skilled nursing facility. Controls without PD were demographically matched 1:1. Costs to Medicare were compared via Wilcoxon rank-sum tests and inverse probability weighted multivariate regression. Survival was assessed via Cox proportional hazards analysis. RESULTS: Costs in the year post-diagnosis were higher for newly diagnosed patients (N = 9,201, $7423) than controls ($5024), resulting in excess PD-associated costs of $2399 (p < 0.001). Cumulative excess costs were $28,422 from the year prior to index quarter to five years following (p < 0.01). PD patients receiving their first claim for an ambulatory assistance device (N = 11,294) had excess cumulative costs of $50,923 (p < 0.001) over the same period; those receiving their first claim for a skilled nursing facility (N = 10,152) had excess costs of $102,750 (p < 0.001). Hazard rates of mortality were higher among newly diagnosed PD (1.43, p < 0.001), ambulatory assistance device (2.37, p < 0.001) and skilled nursing facility (3.34, p < 0.001) cohorts than in corresponding non-PD groups. CONCLUSIONS: Medicare beneficiaries with PD have substantially and progressively higher costs and mortality compared with controls.

Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease.

OBJECTIVES: Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD. METHODS: A total of 55 subjects with PD and an Inventory of Depressive Symptomatology-Clinician (IDS-C) score > or = 22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (> 50% decrease in IDS-C score or Clinical Global Impression-Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function. RESULTS: There were no between-groups differences in a priori-defined response rates. Using a more liberal response criterion of > 40% decrease in IDS score from baseline, there was a trend (p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition (p = 0.003) and daytime sleepiness (p = 0.001), and atomoxetine was well-tolerated. CONCLUSIONS: Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate. CLASSIFICATION OF EVIDENCE: This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD.

Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease.

BACKGROUND: Due to the high prevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD), routine cognitive screening is important for the optimal management of patients with PD. The Montreal Cognitive Assessment (MoCA) is more sensitive than the commonly used Mini-Mental State Examination (MMSE) in detecting MCI and dementia in patients without PD, but its validity in PD has not been established. METHODS: A representative sample of 132 patients with PD at 2 movement disorders centers was administered the MoCA, MMSE, and a neuropsychological battery with operationalized criteria for deficits. MCI and PD dementia (PDD) criteria were applied by an investigator blinded to the MoCA and MMSE results. The discriminant validity of the MoCA and MMSE as screening and diagnostic instruments was ascertained. RESULTS: Approximately one third of the sample met diagnostic criteria for a cognitive disorder (12.9% PDD and 17.4% MCI). Mean (SD) MoCA and MMSE scores were 25.0 (3.8) and 28.1 (2.0). The overall discriminant validity for detection of any cognitive disorder was similar for the MoCA and the MMSE (receiver operating characteristic area under the curve [95% confidence interval]): MoCA (0.79 [0.72, 0.87]) and MMSE (0.76 [0.67, 0.85]), but as a screening instrument the MoCA (optimal cutoff point = 26/27, 64% correctly diagnosed, lack of ceiling effect) was superior to the MMSE (optimal cutoff point = 29/30, 54% correctly diagnosed, presence of ceiling effect). CONCLUSIONS: The Montreal Cognitive Assessment, but not the Mini-Mental State Examination, has adequate psychometric properties as a screening instrument for the detection of mild cognitive impairment or dementia in Parkinson disease. However, a positive screen using either instrument requires additional assessment due to suboptimal specificity at the recommended screening cutoff point.

Disparities of care in veterans with Parkinson's disease.

BACKGROUND: Disparities of Parkinson's disease (PD) care have not been assessed. METHODS: We examined the medical records of 309 (83%) non-Hispanic White and 65 (17%) non-White Los Angeles veterans with PD from 1998 to 2004 to determine if care quality as measured by 10 PD indicators different by race/ethnicity. RESULTS: In multivariate modeling, adherence to indicators was higher among non-Hispanic Whites (71% vs. 65%, risk ratio 1.15, 95% CI [1.07-1.32]) compared to non-Whites. Differences in adherence by race/ethnicity were greatest for depression treatment (p<0.05). CONCLUSIONS: We detected disparities in quality of PD care, particularly in depression treatment. Future research should determine causes for these so that interventions can be designed to reduce such disparities.

Posey and Spiller and progressive supranuclear palsy: an incorrect attribution.

In 1904 and 1905, respectively, William Campbell Posey and William Spiller both described the case of a patient with progressive ophthalmoparesis and imbalance that has come to be regarded as the earliest report of progressive supranuclear palsy. No autopsy was thought to have been performed on this patient. In this report, we review the clinical history provided by Posey and Spiller. We also report on the subsequent autopsy of their patient, which was performed by Spiller in 1906. The chief finding was a tumor involving the right cerebral peduncle and periaqueductal area. The autopsy findings prove conclusively that the patient described by Spiller and Posey had a midbrain neoplasm and not progressive supranuclear palsy.

Central neurogenic hyperventilation in an awake patient with a pontine glioma.

A 57-year-old awake man developed central neurogenic hyperventilation associated with a pontine mass. Serum pH reached as high as 7.72 with serum carbon dioxide of 6 torr. Examination of CSF during overbreathing showed that CSF pH was markedly alkaline. Pathologic study showed a well-differentiated pontine astrocytoma. The combination of alkaline CSF and an infiltrating pontine lesion supports a structural, rather than chemical, mechanism for central hyperventilation.

Fetal and adult urine flow and ANF responses to vascular volume expansion.

Isotonic saline (2% of body wt) warmed to body temperature was infused intravascularly over 10 min into chronically catheterized, near-term fetal sheep and into nonpregnant adult sheep. Although both groups of animals underwent the same initial increase in urine flow rate relative to body weight, the diuresis was significantly more prolonged in the adult compared with the fetus. The adult demonstrated a sustained increase in plasma atrial natriuretic factor (ANF) concentration with a suppression of plasma renin activity (PRA) and plasma arginine vasopressin (AVP). In the fetus, only a transient rise in plasma ANF with no change in PRA or AVP occurred. The increases in blood volume and arterial pressure were significantly greater in the adult compared with the fetus, but the venous pressure changes were the same. Thus it appears that fetal and adult kidneys have the same initial urine flow response to rapid vascular volume loading presumably due to a pressure diuresis and elevations in ANF. The more prolonged diuresis in the adult appears attributable to more extensive and prolonged changes in plasma hormone concentrations. The latter, in turn, may be due to the greater intravascular retention of the infused fluid in the adult than in the fetus.