Daniel L. Murman

CD4+ Regulatory and Effector/Memory T Cell Subsets Profile Motor Dysfunction in Parkinson’s Disease

Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson’s disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson’s Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.

Predictive Validity of Neuropsychiatric Subgroups on Nursing Home Placement and Survival in Patients With Alzheimer Disease

OBJECTIVE The aim of the study was to conceptualize neuropsychiatric symptoms in patients with Alzheimer disease as distinct symptom profiles with differential disease outcomes. Two outcomes of interest in the study were nursing home placement and survival. METHOD Cluster analysis was used to categorize 122 patients with Alzheimer disease based on their neuropsychiatric symptoms as assessed by the Neuropsychiatric Inventory. Both the presence as well as the severity and frequency of symptoms were considered. After identification of the subgroups, the predictive validity of the categorization was tested on time to nursing home placement and time to death over a three-year period. Cox proportional hazard models were used to perform survival analysis. Important covariates such as severity of cognitive and functional impairments, comorbid medical conditions, presence of parkinsonism, and marital status were adjusted at baseline. RESULTS Based on the presence of neuropsychiatric symptoms, three subgroups were identified: minimally symptomatic, highly symptomatic, and affective/apathetic. Over a three-year period, the highly symptomatic group had an increased risk of nursing home placement. In addition, the rates of survival were significantly lower for the highly symptomatic and the affective/apathetic subgroups. Based on the severity and frequency of symptoms, two-cluster and four-cluster solutions were produced. The groupings based on severity and frequency of symptoms predicted significant differential outcomes in survival and nursing home placement. CONCLUSIONS Neuropsychiatric subgroups were able to predict differential outcomes and identify those with an increased risk for a worse prognosis. The findings were discussed through their research and clinical implications.

The Economic Impact of Neuropsychiatric Symptoms in Alzheimer's Disease Can Drugs Ease the Burden?

The majority of patients with Alzheimer’s disease (AD) will have clinically significant neuropsychiatric symptoms during the course of their disease. There is growing evidence that neuropsychiatric symptoms increase direct costs of care in patients with AD, especially the costs associated with formal long-term care and unpaid caregiving. For example, we have estimated that a 1-point worsening of the neuropsychiatric inventory score is associated with an incremental increase of between

Evaluated need, costs of care, and payer perspective in degenerative dementia patients cared for in the United States

US247 and

The Impact of Age on Cognition

US409 per year in total direct costs of care based upon year 2001 US dollars, depending on the value of unpaid caregiving.Although data are still limited, there have been a series of well designed, controlled clinical trials that have established the efficacy of several drugs used in the treatment of neuropsychiatric symptoms in patients with AD. The economic impact of using efficacious drugs to treat neuropsychiatric symptoms in patients with AD has not been evaluated formally. To successfully complete formal economic evaluations of these drugs there is a need for more research to refine methods for determining the economic value of unpaid caregiving and to collect more data concerning the incremental effects of neuropsychiatric symptoms on QOL, costs of care and survival. The current ongoing treatment trials that are collecting economic and QOL data as a part of the trial will be able to perform cost-effectiveness and cost-utility analyses of these new efficacious drugs. These economic evaluations will provide important information for decision makers who are formulating healthcare policy for the treatment of patients with AD.

Imbalanced estrogen metabolism in the brain: possible relevance to the etiology of Parkinson’s disease

The purpose of this study was to examine the strength of the associations between 5 measures of need that are potentially modifiable in degenerative dementia patients and direct costs of care from 5 payer perspectives in the US healthcare system. Data were derived from a cohort study of 150 patients with a degenerative dementia. We measured need variables at baseline and utilization of healthcare in the year before and after baseline. Utilization data were converted into estimated direct costs and totaled based on the costs paid for by 5 payers in the US healthcare system. Path models were used to quantify and compare the relationships between need variables and direct costs. From Medicares perspective, comorbid medical conditions were the most important predictor of Medicare costs. From Medicaids perspective, neuropsychiatric symptoms and signs of parkinsonism were additional significant predictors. From the perspective of patients, their families and society, all 5 need variables were significant predictors of direct costs (ie, those above, plus cognitive impairment, and dependency). The relationship between evaluated need variables and direct costs depends on the perspective of the payer and provide insights into which need variables could be targeted with interventions to control costs and improve patient outcomes.

The risk of incident mild cognitive impairment and progression to dementia considering mild cognitive impairment subtypes

This article reviews the cognitive changes that occur with normal aging, the structural and functional correlates of these cognitive changes, and the prevalence and cognitive effects of age-associated diseases. Understanding these age-related changes in cognition is important given our growing elderly population and the importance of cognition in maintaining functional independence and effective communication with others. The most important changes in cognition with normal aging are declines in performance on cognitive tasks that require one to quickly process or transform information to make a decision, including measures of speed of processing, working memory, and executive cognitive function. Cumulative knowledge and experiential skills are well maintained into advanced age. Structural and function changes in the brain correlate with these age-related cognitive changes, including alterations in neuronal structure without neuronal death, loss of synapses, and dysfunction of neuronal networks. Age-related diseases accelerate the rate of neuronal dysfunction, neuronal loss, and cognitive decline, with many persons developing cognitive impairments severe enough to impair their everyday functional abilities. There is emerging evidence that healthy lifestyles may decrease the rate of cognitive decline seen with aging and help delay the onset of cognitive symptoms in the setting of age-associated diseases.

Neural correlates of cognitive decline in ALS: An fNIRS study of the prefrontal cortex

Damage to DNA by dopamine quinone and/or catechol estrogen quinones may play a significant role in the initiation of Parkinson’s disease (PD). Depurinating estrogen–DNA adducts are shed from cells and excreted in urine. The aim of this study was to discover whether higher levels of estrogen–DNA adducts are associated with PD. Forty estrogen metabolites, conjugates, and DNA adducts were analyzed in urine samples from 20 PD cases and 40 matched controls by using ultra performance liquid chromatography/tandem mass spectrometry. The levels of adducts in cases versus controls (P < 0.005) suggest that unbalanced estrogen metabolism could play a causal role in the initiation of PD.

Estimating health-related quality of life for unique dependence levels in patients with Alzheimer's disease

Background: It remains unclear how demographic and clinical characteristics are related to the risk of incident mild cognitive impairment (MCI) by its subtypes. Moreover, the contribution of the subtypes of incident MCI to the progression to dementia remains puzzling. Methods: We used data collected by the National Alzheimer Coordinating Center. Our analysis sample included cognitively normal subjects at baseline. The associations were examined using competing-risks survival regression models and Cox proportional hazards models. Results: About 16.3% of subjects developed incident MCI of whom 15.8% progressed to Alzheimer disease (overall mean follow-up of 4.3 years). The risk of incident amnestic MCI (aMCI) was greater in subjects with 1 copy (subhazard ratio [SHR]: 1.23; 95% CI: 1.00–1.50) or 2 copies (SHR: 2.14; 95% CI: 1.49–3.05) of the APOE ε4 allele than in those who had no ε4 allele. Multiple-domain aMCI patients were more likely to progress to dementia than single-domain aMCI patients (hazard ratio: 2.14; 95% CI: 1.28–3.58). Conclusions: Cognitively normal subjects with an APOE ε4 allele had a higher likelihood of developing aMCI and the MCI subtype was associated with the dementia subtype. Our findings provide important information about practical indicators for the prediction of cognitive decline.


Hyperbaric oxygen for late sequelae of carbon monoxide poisoning enhances neurological recovery: case report

Functional near infrared spectroscopy (fNIRS) is a clinically feasible functional neuroimaging modality for detecting early cortical changes due to neurodegenerative diseases that affect cognition. The objective of this preliminary investigation was to test for reduced prefrontal activity in persons with cognitive impairments due to amyotrophic lateral sclerosis (ALS). Participants were required to complete two N-back working memory tasks of increasing complexity during fNIRS recordings. Five participants with ALS and age- and gender-matched healthy participants comprised the experimental and control groups, respectively. Significant reductions in prefrontal oxygenation levels were observed for the left and right hemispheres in the ALS group compared to the control group. Reduced prefrontal activation despite intact behavioral performance for a working memory task may suggest early neuroanatomical, neurophysiological and/or compensatory mechanisms in affected individuals. The fNIRS-derived oxygenation measure shows promise as a sensitive neural marker to identify early neuropsychological impairments due to ALS.