Spongiform change in dementia with Lewy bodies and Alzheimer disease.

BACKGROUND: Dementia with Lewy bodies (DLB) is characterized neuropathologically by brainstem and cortical Lewy bodies and Lewy neurites, neuronal loss in brainstem nuclei, and Alzheimer disease (AD) pathology. Previous studies have suggested that spongiform change in the entorhinal cortex may also be a pathologic feature; however, this change has not been well characterized. DESIGN/METHOD: An autopsy series of 40 subjects with DLB and 40 subjects with AD were matched on age, sex, and last Mini Mental State Examination before death. Using semistereological methods on representative sections through the transentorhinal and perirhinal cortices, quantitative counts and semiquantitative grading of vacuolization were performed by 1 rater (A.S.) blinded to subjects' diagnoses. In addition, electron microscopy of representative sections was performed. RESULTS: Vacuolization was 4- to 5-fold more prominent in the perirhinal, as compared with transentorhinal, cortex. Moderate to severe vacuolization was found in 57.5% of DLB, but only 7.5% of AD subjects. There were statistically significant differences between mean numbers of vacuoles in the perirhinal (DLB mean=27.91; AD mean=2.35; P<0.001) and transentorhinal (DLB mean=5.92; AD mean=0.5; P<0.001) cortices in DLB as well as AD cases. Electron microscopy revealed both axonal and dendritic pathology, with dilatation, vacuole formation, and abnormal membranous profiles. CONCLUSIONS: Although the exact mechanism remains to be elucidated, vacuolization seems to be more specific for DLB than AD, with disproportionate involvement of the perirhinal cortex.

Influence of apolipoprotein E varepsilon4 on rates of cognitive and functional decline in mild cognitive impairment.

BACKGROUND: Apolipoprotein E varepsilon4 (APOE varepsilon4) allele carrier status has been well established as a risk factor for developing Alzheimer's disease. However, the specific influence of APOE varepsilon4 allele status on cognitive and functional rates of decline in mild cognitive impairment (MCI) is poorly understood. We examine the prospective association of APOE varepsilon4 allele status on measures of cognitive and functional decline in subjects with amnestic MCI (aMCI). METHODS: A total of 516 aMCI participants aged 55-90 years who received placebo or vitamin E from the Alzheimer's Disease Cooperative Study's MCI treatment trial were evaluated. During the 36-month study period, neurocognitive and functional measures were collected. These measures were assessed over time for change and association with APOE varepsilon4 status. Generalized Estimating Equations were performed to model each outcome measure over the study period. RESULTS: APOE varepsilon4 status had a significant impact on cognitive and functional decline on multiple measures; those who were APOE varepsilon4 positive had significantly more rapid decline in performance on all cognitive and functional measures except Number Cancellation and Maze tracing (P < .05). The greatest decline was seen in global measures of cognition and function including the Clinical Diagnostic Rating scale, followed by the Mini-Mental State Examination, Global Deterioration scale, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale. CONCLUSIONS: These findings demonstrate that APOE varepsilon4 genotype is predictive of increased general rates of decline with global measures of cognition and function most affected. With accelerated declines in common clinical trial primary efficacy measures, APOE varepsilon4 status needs to be accounted for in treatment trials of MCI.

A review of functional brain imaging correlates of successful cognitive aging.

Preserved cognitive performance is a key feature of successful aging. Several theoretical models have been proposed to explain the putative underlying relationship between brain function and performance. We aimed to review imaging studies of the association between brain functional response and cognitive performance among healthy younger and older adults to understand the neural correlates of successful cognitive aging. MEDLINE-indexed articles published between January 1989 and December 2009 and bibliographies of these articles and related reviews were searched. Studies that measured brain function with functional magnetic resonance imaging or positron emission tomography, evaluated cognitive performance, analyzed how cognitive performance related to brain response, and studied healthy older individuals were included. Eighty of 550 articles met these criteria. Seventy percent of the studies reported some brain regions in which greater activation related to better cognitive performance among older participants. This association was not universal, however, and was seen mainly in frontal cortex brain response and seemed to be more common among older compared with younger individuals. This review supports the notion of compensatory increases in brain activity in old age resulting in better cognitive performance, as suggested by hemispheric asymmetry reduction and posterior-anterior shift models of functional brain aging. However, a simple model of bigger structure → greater brain response → better cognitive performance might not be accurate. Suggestions for future research are discussed.

Inpatient charges and mental illness: Findings from the Nationwide Inpatient Sample 1999-2007.

Inpatient costs related to mental illness are substantial, though declining as a percentage of overall mental health treatment costs. The public sector has become increasingly involved in funding and providing mental health services. Nationwide Inpatient Sample data for the years 1999-2007 were used to: 1) examine Medicare, Medicaid, and private insurance charges related to mental illness hospitalizations, including trends over time; and 2) examine trends in mental comorbidity with physical illness and its effect on charges. There were an estimated 12.4 million mental illness discharges during the 9-year period, with Medicare being the primary payer for 4.3 million discharges, Medicaid for 3.3 million, private insurance for 3.2 million, and 1.6 million for all other payers. Mean inflation-adjusted charges per hospitalization were US$17,528, US$15,651, US$10,539, and US$11,663, respectively. Charges to public sources increased for schizophrenia and dementia-related discharges, with little private/public change noted for mood disorders. Comorbid mood disorders increased dramatically from 1.5 million discharges in 1999 to 3.4 million discharges in 2007. Comorbid illness was noted in 14.0% of the 342 million inpatient discharges during the study period and was associated with increased charges for some medical conditions and decreased charges for other medical conditions.

Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.

OBJECTIVE: To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN: Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING: Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES: Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS: Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS: LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

Glutamate release inhibition ineffective in levodopa-induced motor complications.

Reported benefits of various glutamatergic receptor antagonists in Parkinson's disease (PD) prompted an evaluation of the antidyskinetic effect of a putative glutamate release inhibitor in 15 moderately advanced patients. In a 3-week, double-blind, proof-of-concept study, riluzole (200 mg/day) failed to alter parkinsonian or levodopa-induced motor complication severity. Opposing effects of a generalized inhibition of glutamate-mediated synaptic transmission may limit the usefulness of this approach to treat PD.

Effects of serotonin 5-HT1A agonist in advanced Parkinson's disease.

Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinson's disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5-HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3-week, double-blind, placebo-controlled, proof-of-concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa-induced dyskinesias and prolonged its antiparkinsonian response (P < or = 0.05). Under the conditions of this study, our findings suggest that 5-HT1A receptor stimulation in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as levodopa adjuvants in the treatment of PD.