Faculty Bibliography

The Timed Gait test is a standardized procedure assessing motor dysfunction of lower extremities and gait abnormalities associated with AIDS dementia complex. Heretofore, interpretations of Timed Gait results have been hampered by the lack of normative data. We provide results on this test derived from 1,549 subjects (HIV-seronegatives (HIV-) and seropositives (HIV+) classified according to ADC stage). Timed Gait was found to be a useful screening and assessment tool for evaluating ADC and correlated with clinical ADC staging as well as more extensive structured neurological and neuropsychological evaluations. Analysis of covariance results (with age and education as covariates) revealed symptomatic HIV+(SX) and AIDS groups having significantly slower Timed Gait scores than those in the HIV- and asymptomatic HIV+(ASX) groups. The SX group obtained significantly slower timed gait scores than those in the AIDS group. There was a significant increase in Timed Gait scores with each increase in dementia staging with the HIV- subjects having the fastest mean Timed Gait scores and the HIV+ dementia stage 2+ having the slowest. These normative data should prove useful in both recognition of ADC and treatment response. Given its minimal training requirements, the Timed Gait would have utility in resource limited settings

Dysarthria is a significant feature of the dominantly inherited spinocerebellar ataxias (SCA), but little is known about the patterns of brain activity associated with this disorder of motor speech control. Positron emission tomography (PET) was used to study regional cerebral blood flow during speech and rest in a group of 24 subjects with hereditary ataxia with mild-to-moderate dysarthria. These data were compared to the results obtained from a group of 13 age-matched, normal speakers. In the ataxic subjects, speech rates during scanning were significantly slowed compared to normal speakers. Significant reductions in mean regional blood flow were found in the cerebellum but not in supratentorial regions in the ataxic subjects. Multiple linear regression was used to model speech rate from regional blood flow. Four regions were identified as having significant relationships with speech rate in the model: the left inferior frontal and transverse temporal regions, and the right inferior cerebellar region and caudate nucleus. The relationship between flow and rate was positive in the inferior frontal and cerebellar regions and negative in the caudate and the transverse temporal region. The ataxic model represents an elaboration of the relationship previously reported for normal speakers, likely reflecting both the effects of, and compensation for, cerebellar degeneration in motor speech control. Although the mean regional blood flow values presented a pattern of functional organization for motor speech control at odds with lesion data, the performance-based model was in agreement with clinical experience. Incorporating performance data in functional image analysis may be more revealing of system characteristics than simply examining mean blood flow values

Progress in understanding brain/behavior relationships in adult-acquired dysprosody has led to models of cortical hemispheric representation of prosodic processing based on functional (linguistic vs affective) or physical (timing vs pitch) parameters. These explanatory perspectives have not been reconciled, and also a number of neurobehavior syndromes that include dysprosody among their neurological signs have not yet been integrated. In addition to expanding the functional perspective on prosody, some of these syndromes have implicated a significant role of subcortical nuclei in prosodic competence. In this article, two patients with acquired dysprosodic speech following damage to basal ganglia nuclei were evaluated using behavioral, acoustic, cognitive, and radiographic approaches. Selective quantitative measures were performed on each individual's performance to provide detailed verification and clarification of clinical observations, and to test hypotheses regarding prosodic function. These studies, combined with a review of related clinical research findings, exemplify the value of a broader perspective on the neurobehavioral dysfunction underlying acquired adult dysprosodic speech, and lead to a new, proposed conceptual framework for the cerebral representation of prosody

The glucocorticoid receptor (GR) antagonist mifepristone (RU-486) has been reported to increase early morning plasma ACTH/cortisol in diverse non-demented populations. This pilot study examined the cortisol response to RU 486 in patients with Alzheimer's disease (AD), a condition associated with abnormalities in various aspects of the hypothalamic-pituitary-adrenal (HPA) axis. Nine AD subjects were randomized in a placebo-controlled parallel study: 4 in the placebo group and 5 in the RU 486 group. Subjects received oral doses of RU 486 (200 mg) or placebo daily for 6-weeks. Morning plasma cortisol was determined at baseline, at 12 h following the first study drug dose, and weekly thereafter. RU 486 resulted in a significant increase in cortisol levels [F(1,6)=65.32; P<0.001]. The magnitude of this increase grew over the course of the study [F(1,6)=63.17; P<0.001], was not related to cortisol suppression after dexamethasone and appeared greater than that reported in the literature in younger populations in response to the same drug regimen. However, further studies with age-matched controls should be done to determine possible AD related changes in this response

RATIONALE: Retrograde facilitation (RF) refers to a paradoxical phenomenon in which recall of information presented before acute administration of agents generally associated with anterograde amnestic and sedative effects, such as benzodiazepines, is enhanced relative to a placebo condition. However, it is unclear whether this effect occurs in elderly individuals and if it is influenced by plasma drug levels, baseline cognitive function, or genetic factors such as the APOE e-4 allele, that may modulate drug-induced cognitive toxicity. OBJECTIVES: To determine if acute oral doses of lorazepam (0.5 mg, 1 mg) produced RF in elderly individuals exposed to interference tasks, and the variables associated with RF. MATERIALS AND METHODS: Sixty-four cognitively intact and highly educated (>12 years) older adults (mean age, 66.09 years) participated in a placebo-controlled double-blind crossover study. The Buschke Selective Reminding Test was used to assess RF and amnestic effects for verbal memory. Self-ratings of mood states were also obtained. RESULTS: Lorazepam administration resulted in significant dose-dependent RF, i.e., better recall of pre-drug word lists compared to placebo [F(1,63)= 15.358; p<0.001 and F(1,63)= 46.163; p<0.001 for 0.5 and 1 mg lorazepam, respectively]. Also, more of the pre-drug words were recalled in the 1.0-mg-lorazepam condition relative to the 0.5-mg-lorazepam condition [F(1,63)=29.498; p<0.001]. In both the 0.5 and 1 mg lorazepam conditions, participants who exhibited high RF experienced significantly greater lorazepam-induced memory impairments over time [F(3,61)=2.901; p<0.05; F(3,61)=2.698; p<0.05; 0.5 and 1 mg lorazepam, respectively]. Also, in the 1-mg-lorazepam condition, participants who exhibited high RF reported significantly greater drowsiness relative to participants who showed less RF [t(62)=-2.521; p<0.05]. RF was not significantly associated with age, the APOE epsilon4 allele, years of education, global cognitive status, vocabulary scores, or a memory index score. CONCLUSION: In healthy elderly, acute oral lorazepam administration resulted in dose-dependent RF, which was associated with greater anterograde amnestic and sedative effects

Elevated plasma amyloid beta 1-42 (Abeta42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Abeta levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer's disease, have not been studied. We compared plasma Abeta in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Abeta42 levels and the Abeta42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Abeta42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Abeta levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Abeta42 and Abeta42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD

OBJECTIVE: There is evidence of more widespread use and abuse of benzodiazepines (BZPs) among elderly women. However, factors underlying this observation are poorly understood but could be related to more intense withdrawal reactions, which are a major risk factor for continued BZP use. We previously reported elevations in interdose morning plasma cortisol levels in healthy elderly individuals after chronic treatment with alprazolam, possibly consistent with increased hypothalamic-pituitary-adrenal (HPA) axis activity and drug withdrawal. In this study, we examined sex-related differences in this population. METHOD: Twenty-five cognitively intact healthy elderly (13 women and 12 men) participated in a parallel, double-blind, placebo-controlled study that included a group that received acute and chronic (3 weeks) treatment with alprazolam (0.5 mg b.i.d.). RESULTS: Elderly women, but not men, experienced significant elevations in interdose morning plasma cortisol levels over 3 weeks of chronic treatment with alprazolam (0.5 mg b.i.d.) compared to placebo. In addition, higher morning plasma cortisol levels were significantly associated with better cognitive performance but not with higher plasma drug levels or greater degree of tolerance development to an acute alprazolam challenge. CONCLUSION: Elderly females experienced a greater interdose activation of the HPA axis during treatment with therapeutic doses of alprazolam than men, which could be related to drug withdrawal

OBJECTIVE: Longitudinal changes in plasma beta amyloid protein 1-42 and 1-40 (Abeta42 and Abeta40) levels and possible relationships with cognitive decline and apolipoprotein (APOE) genotype were studied in healthy elderly individuals. Methods: Authors determined cognitive level and plasma Abeta40 and Abeta42 levels twice, approximately 4 years apart, in 34 elderly subjects. Results: Analyses revealed a selective reduction in Abeta42 levels at follow-up, which were not modulated by the epsilon4 allele. Greater reductions and higher baseline plasma Abeta42 levels were associated with reductions in cognitive scores. Conclusions: Alterations in plasma Abeta42 levels may be associated with subtle cognitive decline in elderly subjects without dementia