Faculty Bibliography

The degree to which elderly adults experience cognitive impairments from centrally acting anticholinergic drugs is variable, but the cause of this variability is unknown. The present study examined the epsilon4 allele as a possible modulator of the effects of trihexyphenidyl hydrochloride (Artane( trade mark )), an anticholinergic drug, on memory functioning. Of the 24 cognitively intact, elderly participants (age range 62-76), 12 who possessed the epsilon4 allele, participated in a double-blind, randomized, placebo-controlled, crossover, three-way study. All participants were tested after receiving a single oral dose of trihexyphenidyl (1 or 2 mg) or placebo, with a 7-day washout period between sessions. Memory and psychomotor tests were administered at baseline, and at 1, 2.5, and 5 h post-treatment. Results showed that participants with the epsilon4 allele demonstrated significant impairments in delayed recall after both 1 and 2 mg doses of trihexyphenidyl while the non-epsilon4 group did not. Additionally, while acute administration of the 2 mg dose significantly impaired total recall in both epsilon4 and non-epsilon4 carriers, the epsilon4 carriers showed a more persistent impairment. These findings held when participants with the epsilon2 allele were excluded from the analyses. The epsilon4 groups did not differ with respect to psychomotor performance or plasma drug levels. These results provide evidence suggesting that the epsilon4 allele plays a significant role in increasing cognitive sensitivity to trihexyphenidyl and that a temporal component of memory consolidation may be especially vulnerable. A larger study is warranted to confirm these preliminary findings

Increased platelet activation with release of procoagulant factors from their alpha granules has been demonstrated in individuals with major depression. Platelet activation has also been shown to be associated with release of beta-amyloid peptides, which have been implicated in Alzheimer's disease. Thus, we are hypothesizing that sustained elevations of Abeta peptides might occur in individuals with recurrent depression. We further hypothesize that such elevations contribute to brain abnormalities in depressed individuals through the formation of neurotoxic oligomeric forms of Abeta peptides and amyloid deposition. We also propose that increased amyloid Abeta peptides from platelet activation may be a mechanism underlying the increased risk for cognitive impairment in nondepressed patients who have other reasons for such activation. If true, our hypothesis would imply that platelet inhibitors may have a role in preventing or delaying the neuronal consequences of disorders characterized by activated platelets

The adaptive and maladaptive roles of the hypothalamic-pituitary-adrenal (HPA) axis in stressful conditions and in disorders such as major depression, posttraumatic stress disorder, and Cushing's syndrome, have been the subject of substantial, ongoing study. In particular, HPA disturbances have been associated with memory impairments, and hypercortisolemic conditions with atrophy of the hippocampus, a limbic structure closely associated with declarative memory. Recent discoveries support a more complicated picture of HPA axis function and pathology in acquiring, retrieving, and consolidating new memories. These findings include: the existence of an 'inverted U-shaped relationship' between stimulation of brain glucocorticoid receptors and memory performance; that distinct areas of the hippocampus have been found to respond differently to cortisol stimulation; and that hippocampal atrophy has been found to be potentially reversible in some conditions, although whether such atrophy is a cause or effect of these pathological conditions is currently unclear. More longitudinal studies of HPA axis function in aging normal individuals, those with mild cognitive impairment,and individuals with Alzheimer' disease, examining pertinent variables such as APOEe-4 status, are needed to help clarify these new findings. Antiglucocorticoid agents appear to have therapeutic value in particular conditions. These results are relevant for understanding and treating memory dysfunction in individuals with Alzheimer's disease, a disorder prominently and invariably characterized by early hippocampal lesions and memory impairment. Given the burden of this disease, we feel it timely to encourage controlled trials of antiglucocorticoid agents in the treatment of mild cognitive impairment and Alzheimers disease

BACKGROUND: In vivo magnetic resonance studies have found that cocaine dependence is associated with T2 signal hyperintensities and metabolite abnormalities in cerebral white matter (WM). Functional neuroimaging studies have suggested that chronic cocaine use is primarily associated with frontal lobe deficits in regional cerebral blood flow and brain glucose metabolism levels; however, the effects of cocaine dependence, if any, on frontal WM microstructure are unknown. Thus, we sought to examine the effects of cocaine dependence on frontal WM integrity. METHODS: Diffusion tensor imaging was employed to examine the WM integrity of frontal regions at four levels: 10 mm above, 5 mm above, 0 mm above, and 5 mm below the anterior commissure-posterior commissure (AC-PC) plane. The fractional anisotropy (FA) of 12 cocaine-dependent patients and 13 age-similar control subjects was compared. RESULTS: The cocaine-dependent patients had significantly reduced FA in the frontal WM at the AC-PC plane and a trend toward reduced FA at 5 mm below the AC-PC plane, suggestive of reduced WM integrity in these regions. CONCLUSIONS: These findings were consistent with the hypothesis that cocaine dependence involves alterations in orbitofrontal connectivity, which may be involved in the decision-making deficits seen in this disorder