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The human movement analysis panel (HMAP) measures separable components of arm motion and simple and complex finger coordination. HMAP testing takes 30min to administer. In separate experiments we have validated the HMAP against the standard grooved pegboard and measures of gait speed, and demonstrated important learning effects over both short durations of days, and longer intervals of months to years in normal subjects of different ages. Stepwise regression demonstrated the strongest correlation between the HMAP complex motor times and pegboard both-hand removal (R(2)=0.52, p=0.002 for dominant and R(2)=0.33, p=0.02 for non-dominant hands). The most consistent and sensitive measure of HMAP motor performance overall was the complex motor time. The HMAP is a short-duration, easily administered, objective quantitative test of motor function, with potential applications in aging, and in Parkinson's Disease and related motor disorders. The HMAP has a smaller version used in primates, so that measurements made in primate models of disease and its treatment are directly comparable to analogous clinical measurements made in the corresponding human disease.

Purpose: Inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia is an adult-onset autosomal dominant illness (IBMPFD) caused by mutations in the valosin-containing protein (VCP) on chromosome 9p21.1-p12. The penetrance of the gene is 82% for myopathy, 49% for Paget's disease, but may be as low as 30% for frontotemporal dementia. Modifier genes could account for decreased frontotemporal dementia penetrance. In this study apolipoprotein-E (APOE) was evaluated for this role in IBMPFD families based on its known modifier effect in Alzheimer's disease., Methods: From a database of 231 members of 15 families, 174 had APOE genotype available for analysis. Logistic regressions on APOE genotype and frontotemporal dementia were performed, using appropriate covariates., Results and Conclusion: FTD was associated with APOE 4 genotype (P=0.0002), myopathy (P=0.0006), and age (P=0.01), but not microtubule associated protein tau (MAPT) H2 haplotype (P=0.5) or gender (0.09) after adjustment for membership in pedigrees with at least one APOE 4 genotype. These data suggest a potential link between APOE 4 genotype and the specific form of frontotemporal dementia found in IBMPFD. The molecular basis of this link bears further investigation. We did not observe an association of frontotemporal dementia and H2 MAPT haplotype.

Using an automated test panel, age-associated declines in learning, remembering and performing a novel visuomotor task were assessed in 497 normal adults ranging from 18 to 95 years old. As predicted, task performance times slowed with increasing age in the cross-sectional portion of the study. However in the subsequent longitudinal study, while motor learning was significantly slower in adults over 62 years old, motor memory was pristinely preserved in normal adults from 18 to 95 years old. When tested 2 years after the first training session and without intervening rehearsal, mean performance times were retained and continued to improve by 10% in young adults and 13% in aged adults, reflecting long lasting preservation of motor memories. While the maximum lifetime of an unpracticed, novel motor memory in humans is not known, the present study suggests that new motor memories can be retained for at least 2 years without rehearsal in normal aged adults. This age-resistant component of motor memory stands in contrast to the well-known decrements in other motor and cognitive processes with human aging.

Food restriction (FR) in rodents is known to extend life span, reduce the incidence of age-related tumors, and suppress oxidative damage to proteins, lipids, and DNA in several organ systems. Excitotoxicity and mitochondrial impairment are believed to play major roles in the neuronal degeneration and death that occurs in the brains of patients suffering from both acute brain insults such as stroke and seizures, and chronic neurodegenerative conditions such as Alzheimer's, Parkinson's, and Huntington's diseases. We now report that FR (alternate-day feeding regimen for 2-4 months) in adult rats results in resistance of hippocampal neurons to excitotoxin-induced degeneration, and of striatal neurons to degeneration induced by the mitochondrial toxins 3-nitropropionic acid and malonate. FR greatly increased the resistance of rats to kainate-induced deficits in performance in water-maze learning and memory tasks, and to 3-nitropropionic acid-induced impairment of motor function. These findings suggest that FR not only extends life span, but increases resistance of the brain to insults that involve metabolic compromise and excitotoxicity.

Impaired energy metabolism may contribute to the pathogenesis of late-onset neurodegenerative disorders such as Alzheimer's disease by increasing neuronal vulnerability to excitotoxic damage through the NMDA receptor. The effects of metabolic impairment on the striatum have been extensively examined, but relatively little is known regarding the vulnerability of the hippocampus. To examine the effect of metabolic impairment on the hippocampal formation, malonate (0.25-2.5 mumol), a reversible inhibitor of succinate dehydrogenase, was administered by stereotaxic injection into the hippocampus of male Sprague-Dawley rats. Neuronal loss was assessed by Nissl stain, and immunocytochemistry was used to examine cytoskeletal disruption. Malonate produced a dose-dependent lesion in which CA1 pyramidal neurons were most vulnerable, followed by CA3 and dentate gyrus. Cytoskeletal alterations included the loss of microtubule-associated protein 2 (MAP2) and dendritic MAP1B immunoreactivity, whereas axonal MAP1B and tau proteins were relatively spared. Spatially and temporally correlated with the loss of MAP2 was an increase in the immunoreactivity of calpain-cleaved spectrin. A similar pattern of neuronal damage and cytoskeletal disruption was produced by intrahippocampal injection of quinolinate (0.1 mumol), an NMDA agonist. Although these results are consistent with the hypothesis that metabolic impairment results in excitotoxic death, MK-801 (dizocilipine maleate), a noncompetitive NMDA receptor antagonist, did not attenuate the lesions produced by malonate but was effective against quinolinate. The results suggest that NMDA receptor activation is not required for malonate-induced damage in the hippocampal formation.