In order to determine the relationship between cognitive dysfunction and motor behavior in older adults, 41 cognitively normal elderly (NL), 25 cases exhibiting mild cognitive impairment (MI), and 25 patients with mild Alzheimer's disease (AD) were examined using a broad array to motor/psychomotor and cognitive tests. Relative to the NL group, MI individuals (at risk for future decline to AD) performed worse on tasks involving fine and complex motor function (e.g., tracking and manual dexterity). AD patients also exhibited motor dysfunction on tasks assessing relatively more rudimentary motor control. Motor tasks were able to distinguish NL vs MI and NL vs mild AD individuals as effectively as cognitive tests of memory and language. These results indicate that motor impairment is an important aspect of cognitive decline in older adults. Motor/psychomotor assessments may be comparably sensitive to traditional tests of cognitive function in identifying persons affected by the earliest stages of AD pathology.

Purpose: The purpose of this study was to describe the phenotype (and corresponding genotype) of adult patients with late-onset Tay-Sachs disease, a clinical variant of the G M2 -gangliosidoses. Methods: A comprehensive physical examination, including neurological assessments, was performed to establish the current disease pattern and severity. In addition, the patients' past medical histories were reviewed. The patients' ␣-subunit mutations (␤-Hexosaminidase A genotype) were determined and correlated with their corresponding clinical findings and disease course. Results: Twenty-one patients (current mean age: 27.0 years; range: 14 -47 years) were identified.The pedigree revealed a relative with the "classic" infantile or late-onset form of Tay-Sachs disease in four (out of 18) unrelated families. The patients were predominantly male (15/21 individuals) and of Ashkenazi Jewish ancestry (15/18 families). Mean age at onset was 18.1 years; balance problems and difficulty climbing stairs were the most frequent presenting complaints. In several cases, the diagnosis was delayed (mean age at diagnosis: 27.0 years). Analysis of the ␤-hex A gene revealed the G269S mutation as the most common disease allele; found in homozygosity (N ϭ 1) or heterozygosity (N ϭ 18; including 2 sib pairs). Disease onset (age 36 years) was delayed and progression relatively slower in the homozygous G269S patient. Two siblings (ages 28 and 31 years), of non-Jewish ancestry, were compound heterozygotes (TATC1278/W474C); their clinical course is dominated by psychiatric problems. Brain imaging studies revealed marked cerebellar atrophy in all patients (N ϭ 18) tested, regardless of disease stage. Conclusions: Late-onset Tay-Sachs disease is an infrequent disorder and the diagnosis is often missed or delayed (by approximately 8 years). Early on, the majority of patients develop signs of either cerebellar or anterior motor neuron involvement. Affected individuals may also develop psychotic episodes. In most cases, the later-onset of expression results from the presence of at least one allele (usually the G269S mutation), associated with residual enzyme (␤-hexosaminidase A) activity. A positive family history is a valuable clue, enabling early diagnosis. Nonspecific cerebellar atrophy on brain imaging is another important finding. This entity should be considered among patients presenting with speech, gait, and balance problems, and those with psychiatric disorders even when focal neurologic deficits may be initially absent. Accurate diagnosis will permit appropriate genetic counseling regarding disease prognosis and reproductive risks. Genet Med 2005:7(2): 119 -123.

Purpose: To evaluate the safety and efficacy of miglustat in patients with G M2 gangliosidosis. Methods: A randomized, multicenter, openlabel, 12-month study involving patients aged 18 years or older, randomized 2:1 to miglustat (200 mg TID) or "no miglustat treatment." This study was followed by 24 months of extended treatment during which all patients received miglustat. Primary efficacy endpoints were change in eight measures of isometric muscle strength in the limbs and isometric grip strength, evaluated at baseline, and months 12 and 36. Secondary efficacy endpoints included gait, balance, disability, and other neurological assessments. Safety evaluations included adverse event reporting. Results: Thirty patients (67% male, age range 18 -56 years) with late-onset Tay-Sachs disease were enrolled; 20 were randomized to miglustat and 10 to "no miglustat treatment." Muscle and grip strength generally decreased over the study period. No differences were observed between the two groups in any efficacy measure, either during the 12-month randomized phase or the full 36 months. The most common treatment-related adverse events were decrease in weight and diarrhea. Conclusion: Miglustat treatment was not shown to lead to measurable benefits in this cohort of patients with late-onset Tay-Sachs disease. The observed safety profile was consistent with that of the approved dose (100 mg TID) in type 1 Gaucher disease. Genet Med 2009:11(6):425-433.

To determine the association between cognitive dysfunction and motor behavior in older adults, 41 cognitively normal elderly (NL), 25 nondemented patients exhibiting mild cognitive impairment (MI) and at risk for future decline to dementia, and 25 patients with mild (early) Alzheimer's disease (AD) were examined using a wide array of motor/psychomotor and cognitive assessments. The three groups were recruited from an aging and dementia research center and were composed of well-characterized physically healthy volunteers, with similar ages and gender distributions. The outcome measures included 16 motor/psychomotor tests categorized a priori into gross, fine, and complex, as well as eight cognitive tests of memory and language. Relative to the NL group, MI individuals performed poorly on cognitive, fine, and complex motor measures but not on gross motor tests; AD patients performed worse on cognitive and all motor domains. Differences in complex motor function persisted after adjustment for performance on cognitive and on less complex motor tests. Classification analyses showed similar accuracies in discriminating NL from MIand NL from ADcases for both complex motor (79% and 92% accuracy, respectively) and cognitive tests (80% and 93% accuracy, respectively). Less complex motor tests produced poorer accuracies. Among nondemented subjects, education correlated with several cognitive scores but no motor scores. These results indicate that motor impairment is an important aspect of cognitive decline in older adults. Motor/psychomotor assessments were found to be comparably sensitive to traditional tests of cognitive function in identifying persons affected by the earliest stages of AD pathology and may improve identification of at-risk nondemented elderly, especially among diversely educated individuals.

Mild cognitive impairment (MCI) is a classification reserved for nondemented elderly individuals at increased risk for future decline to dementia, compared to those with normal cognition. Cognitive tests, particularly those assessing verbal recall, have been found to be useful in the identification of elderly people with MCI. We argue that a variety of motor/psychomotor evaluations are also sensitive to MCI. Motor assessments described as complex correctly categorize normal versus MCI elderly with comparable accuracies to those obtained by cognitive tests. Unlike performance on verbally based cognitive measures, motor-test scores appear to be relatively independent of educational attainment, indicating that the use of certain motor tests may be particularly valuable in the identification of MCI among elderly with widely varying educational backgrounds.

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Healthy young and elderly adults may utilize existing intrinsic feedback and central control mechanisms to achieve accuracy during a reproduction task. Some subjects in both age groups who entered into the study with high error scores benefited from circumferential pressure by possibly relying on peripheral mechanisms. Further studies are needed to determine the effect of circumferential pressure on subjects with poor reproduction performance.

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