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R Mohs

Publications and source records attributed to R Mohs.

At least 19 recordsLinked to original sources
PubMed2001

Altered expression of a-type but not b-type synapsin isoform in the brain of patients at high risk for Alzheimer's disease assessed by DNA microarray technique.

Using a cDNA microarray representing 6794 distinct human genes, we identified candidate genes whose expression is altered in cerebral cortex of cases of early Alzheimer's disease (AD); among these was the synaptic vesicle protein synapsin II, which plays an important role in neurotransmitter release. While other candidate genes are presently under investigation in our lab, in this study we discuss the regulation of synapsin gene expression during the transition from normal cognitive function to early AD. We found a selective decrease in the expression of the synapsin splice variants I-III of the a-type isoform in the entorhinal (EC, BM36) but not visual cortex (VC, BM17) of cases characterized by the earliest clinically detectable stage of AD. In contrast, we found no changes in synapsin splice variant II of the b-type isoform. Alteration of synapsin expression at the earliest clinical stage of AD may suggest novel strategies for improved treatment.

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PubMed2001

Correlation of the clinical severity of Alzheimer's disease with an aberration in mitochondrial DNA (mtDNA).

Controversy exists about which of the well-established neurobiological abnormalities in Alzheimer's disease (AD) relate directly to the clinical disabilities. Because of an interest in the mitochondrial lesion in AD, we tested the correlation between clinical disability (measured by the Clinical Dementia Rating [CDR] scale) and an anomaly in mitochondrial DNA (mtDNA) in AD brain. Simultaneous polymerase chain reaction (PCR) amplification of the CO1 gene in mtDNA and CO1 pseudogenes in nuclear DNA (nDNA) were performed in samples from AD and non-AD brain, and the ratios of mtDNA/nDNA amplicons calculated. This approach utilizes PCR amplification of endogenous nDNA as a normalization standard for the amplification of mtDNA. We examined total DNA from the brains of Caucasian residents of a Jewish nursing home (86 AD and 26 non-AD "controls"). These patients had been closely followed clinically until death and then autopsied. In this sample, the degree of cognitive impairment in the AD patients correlated with the reduction in the amplification of the mtDNA gene (p = 0.23; p = 0.034), but not with the density of neuritic plaques (p = 0.109). These results agree with the suggestion that the well-documented impairment in brain-energy metabolism in AD may be a direct cause of the clinical disability.

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PubMed2000

Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia.

BACKGROUND: Inflammatory cytokines have been linked to Alzheimer disease (AD) neurodegeneration, but little is known about the temporal control of their expression in relationship to clinical measurements of AD dementia progression. DESIGN AND MAIN OUTCOME MEASURES: We measured inflammatory cytokine messenger RNA (mRNA) expression in postmortem brain specimens of elderly subjects at different clinical stages of dementia and neuropathological dysfunction. SETTING AND PATIENTS: Postmortem study of nursing home patients. RESULTS: In brains of cognitively normal control subjects, higher interleukin 6 (IL-6) and transforming growth factor beta1 (TGF-beta1) mRNA expression was observed in the entorhinal cortex and superior temporal gyrus compared with the occipital cortex. Compared with age-matched controls, subjects with severe/terminal dementia, but not subjects at earlier disease stages, had higher IL-6 and TGF-beta1 mRNA expression in the entorhinal cortex (P<.01) and superior temporal gyrus (P<.01). When stratified by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological criteria, IL-6 mRNA expression in both the entorhinal cortex (P<.05) and superior temporal gyrus (P<.01) correlated with the level of neurofibrillary tangles but not neuritic plaques. However, in the entorhinal cortex, TGF-beta1 mRNA did not correlate with the level of either neurofibrillary tangles or neuritic plaques. Interestingly, in the superior temporal gyrus, TGF-beta1 mRNA expression negatively correlated with neurofibrillary tangles (P<.01) and showed no relationship to the pathological features of neuritic plaques. CONCLUSIONS: The data are consistent with the hypothesis that cytokine expression may differentially contribute to the vulnerability of independent cortical regions during the clinical progression of AD and suggest that an inflammatory cytokine response to the pathological effects of AD does not occur until the late stages of the disease. These findings have implications for the design of anti-inflammatory treatment strategies. Arch Neurol. 2000;57:1153-1160

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PubMed1999

Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVE: To determine the variability in annual Mini-Mental State Examination scores of patients with Alzheimer disease enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). PATIENTS: A total of 372 patients with probable Alzheimer disease with 1 or more years of follow-up. SETTING: Twenty-one CERAD clinical sites throughout the United States. RESULTS: An average annual decline of 3.4 points in CERAD patients returning for longitudinal reassessments was close to the SD of the measurement error of 2.8 points for the Mini-Mental State Examination. There was wide variability in individual rates of decline. Even with 4 years of follow-up, 15.8% of the patients had no clinically meaningful decline in Mini-Mental State Examination score (defined as a change in initial score >3, ie, 1 SD of measurement error). Validity of measurements of the rate of change in Mini-Mental State Examination scores improved with longer observation intervals and was reliable for most patients when observations were separated by 3 or more years. CONCLUSIONS: Although the Mini-Mental State Examination is a useful screening instrument to assess level of cognitive function, it has limited value in measuring the progression of Alzheimer disease in individual patients for periods less than 3 years because of a large measurement error and substantial variation in change in annual score.

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PubMed1998

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group.

The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD.

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PubMed1997

A multicenter evaluation of new treatment efficacy instruments for Alzheimer's disease clinical trials: overview and general results. The Alzheimer's Disease Cooperative Study.

Evaluating treatment efficacy in Alzheimer's disease (AD) clinical trials requires optimal assessment methods to determine the extent and clinical meaningfulness of potential therapeutic effects of pharmacologic agents. Development of improved outcome measures for AD clinical trials is a major objective of the Alzheimer's Disease Cooperative Study (ADCS), an NIA-sponsored, multisite clinical trials consortium. The ADCS Instrument Development Project evaluated the sensitivity, reliability and validity of new or improved measures in each of five assessment domains: (a) cognition (immediate and delayed memory, praxis, attention, and executive function); (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms (agitation and other noncognitive symptoms); and (e) cognition in severely impaired patients. A total of 306 English-speaking subjects were enrolled in the study, including AD patients stratified by disease severity and cognitively normal, age-matched elderly subjects. Half were retested at 1 month and 2 months after baseline, and all received 6- and 12-month follow-up assessments. Spanish versions of these new measures are currently being evaluated. The development of this multisite study, the common methods and procedures, and a detailed description of the cohort are provided in this overview article. This multisite project demonstrates the feasibility of a consortium approach to instrument development. We were able to develop new instruments and efficiently evaluate their reliability and sensitivity to longitudinal change by capitalizing on the experience and patient resources of the participating ADCS research sites.

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PubMed1997

Multicenter evaluation of new instruments for Alzheimer's disease clinical trials: summary of results. The Alzheimer's Disease Cooperative Study.

The Instrument Development Project of the Alzheimer's Disease Cooperative Study (ADCS) evaluated new assessments in five domains: (a) cognitive function; (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms, and (e) cognition in severely impaired patients. These new instruments demonstrate excellent discrimination between normal controls and patient groups and show adequate validity and reliability. Stability of measurement and sensitivity to longitudinal change were also demonstrated in each of these areas. Examination of several domain-specific questions also contributed new information on the measurement of cognitive function with different subtasks across AD severity levels, the stability of clinical ratings of global change, and the applicability of behavioral assessment across severity levels. The success of this project enhances the state of the art in the measurement of efficacy in AD clinical trials and also provides a basis for future research on improving AD outcome measures.

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PubMed1996

Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer's disease: A CERAD analysis, Part XII.

To determine whether the age of the onset of Alzheimer's disease (AD) is related to the expression and rate of decline of this disorder, we examined the clinical and neuropsychological performance of 421 patients entered into the Consortium to Establish a Registry for Alzheimer's Disease and followed annually for up to 4 years. Statistical analyses were based on multivariable logistic regression analysis for dichotomous clinical measures and multivariable linear regression analysis for psychometric measures. All analyses examined the effect of age after controlling for gender, education, and stage of dementia. Clinical information obtained on entry into the study indicated that younger patients performed more poorly on measures of language and concentration, and older patients performed more poorly on measures of memory and orientation. On neuropsychological measures at entry, younger patients, performed more poorly on praxis and had significantly higher scores of confrontation naming. Younger age predicted a significantly faster rate of progression for all neuropsychological measures. These findings support the concept of age-related clinical subtypes of AD.

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PubMed1995

Smooth pursuit performance in patients with affective disorders or schizophrenia and normal controls: analysis with specific oculomotor measures, RMS error and qualitative ratings.

Smooth pursuit performance in schizophrenia and affective disorders has generally been found to be abnormal using a variety of measures. The purpose of this study was to assess patients with these disorders and normal controls in order to compare the different measures across diagnoses. Smooth pursuit was assessed using quantitative specific measures (gain, catch-up saccade rate and amplitude, square-wave jerk rate, number of anticipatory saccades and total time scored), as well as two global measures: root mean-square error (RMS) and qualitative rating. As previously reported, patients with schizophrenia had low gain, increased catch-up saccade rate and spent less time engaged in scoreable smooth pursuit than normal controls. Patients with affective disorders were not statistically different from controls on any of these measures, and had significantly higher gain than patients with schizophrenia. RMS error and qualitative rating measures were highly correlated (r = 0.87). In linear regression analyses, the quantitative specific measures were highly significant predictors of both RMS error and qualitative ratings (P < 0.0001). Linear regression analyses and a modelling study indicated that one quantitative specific measure, the percent of time engaged in scoreable smooth pursuit (total time scored), was most related to global ratings. However, RMS error and qualitative ratings were less sensitive than total time scored to the difference between controls and patients with schizophrenia. These data indicate two smooth pursuit performance deficits in schizophrenia: patients spend less time engaged in scoreable smooth pursuit and have low gain (accompanied by increased compensatory saccades) when the smooth pursuit is engaged.

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PubMed1995

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part XI. Clinical milestones in patients with Alzheimer's disease followed over 3 years.

The rate of cognitive decline, measured by psychometric testing, is widely used to track the progression of Alzheimer's disease (AD). As an alternative approach, we studied clinical measures as markers of the progression of dementia in 343 community-dwelling patients with probable AD enrolled in the multi-center Consortium to Establish a Registry for Alzheimer's Disease (CERAD) project. Subjects received standardized evaluations at entry and at annual follow-up. Decline on the Clinical Dementia Rating, loss of instrumental activities of daily living, failure to recall three words on the Mini-Mental State Examination (MMSE), and decline of the total MMSE score to below 10 were high-risk milestones, with cumulative frequencies exceeding 50% at 3 years. Loss of dressing and toileting activities occurred at intermediate rates, while loss of eating ability was rare. The risk of reaching clinical milestones and the annual rate of cognitive decline on the MMSE were directly correlated. Clinical milestones are useful indices of the progression of dementia in patients with AD.

Activities of Daily Living↗
PubMed1994

Eye movement impairment and schizotypal psychopathology.

OBJECTIVE: Eye movement dysfunction in relation to a smooth pursuit task has been documented in schizophrenic patients and in patients with the related personality disorder, schizotypal personality disorder. To investigate which quantitative measures are associated with the eye movement dysfunction and whether the dysfunction is more related to the psychotic-like or the deficit-like symptoms of schizotypal personality disorder, ratings of eye movements in several groups of subjects were compared. METHOD: The study groups consisted of 26 patients with schizotypal personality disorder, 42 patients with other personality disorders (22 who also had two or more schizotypal personality traits and 20 who had fewer than two), and 37 normal comparison subjects. Smooth pursuit eye tracking of sinusoidal and constant velocity targets was recorded by an infrared eye tracking system. Two raters evaluated pursuit gain and large and small saccades in the direction of the target and in the direction opposite to that of the target (quantitative ratings) and constant velocity (qualitative rating). RESULTS: Patients with schizotypal personality disorder and patients with other personality disorders and two or more schizotypal traits, but not those with fewer than two schizotypal traits, had significantly poorer qualitative ratings of tracking than the normal comparison subjects. Neither gain nor any of the saccadic measures significantly differed between groups. The number of large saccades in the direction of the target was the only quantitative variable that predicted low qualitative ratings. Qualitatively poor tracking was associated with the deficit-like, but not the psychotic-like, symptoms of schizotypal personality disorder. CONCLUSIONS: Patients with schizotypal personality disorder demonstrate qualitatively poorer tracking than comparison groups, and the impaired tracking is associated with deficit-like symptoms.

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PubMed1993

High, usual and impaired functioning in community-dwelling older men and women: findings from the MacArthur Foundation Research Network on Successful Aging.

The objective of this study is to determine the range of complex physical and cognitive abilities of older men and women functioning at high, medium and impaired ranges and to determine the psychosocial and physiological conditions that discriminate those in the high functioning group from those functioning at middle or impaired ranges. The subjects for this study were drawn from men and women aged 70-79 from 3 Established Populations for the Epidemiologic Study of the Elderly (EPESE) programs in East Boston MA, New Haven CT, and Durham County NC screened on the basis of criteria of physical and cognitive function. In 1988, 4030 men and women were screened as part of their annual EPESE interview. 1192 men and women met criteria for "high functioning". Age and sex-matched subjects were selected to represent the medium (n = 80) and low (n = 82) functioning groups. Physical and cognitive functioning was assessed from performance-based examinations and self-reported abilities. Physical function measures focused on balance, gait, and upper body strength. Cognitive exams assessed memory, language, abstraction, and praxis. Significant differences for every performance-based examination of physical and cognitive function were observed across functioning groups. Low functioning subjects were almost 3 times as likely to have an income of < or = $5000 compared to the high functioning group. They were less likely to have completed high school. High functioning subjects smoked cigarettes less and exercised more than others. They had higher levels of DHEA-S and peak expiratory flow rate. High functioning elders were more likely to engage in volunteer activities and score higher on scales of self-efficacy, mastery and report fewer psychiatric symptoms.

Activities of Daily Living↗
PubMed1993

Cognitive performance in a high-functioning community-dwelling elderly population.

BACKGROUND: The purpose of this study was to examine the role of demographic factors as predictors of cognitive performance in a high-functioning, community-dwelling elderly population. METHODS: The study cohort consisted of 1,192 community-dwelling subjects, who were selected to represent the highest third of an elderly population with respect to physical and cognitive functioning. A neuropsychological battery, including 5 cognitive performance subtests (confrontation naming, delayed recognition span, similarities, figure-copying, and incidental delayed recall) was administered to the subjects in their homes. RESULTS: A summary measure of the 5 neuropsychological subtest scores, the total cognitive score, arrayed the study group across a broad range of difficulty, creating a near-normal distribution. Education, income, and race had statistically significant associations with the total score and the individual subtests. The effect of education was the most striking finding, explaining 30% of the variance in the total score. Education was most strongly related to the abstraction (partial R2 = .11) subtest, and least related to the memory subtests, delayed recognition (R2 = .02) and delayed recall (R2 = .01). CONCLUSIONS: Demographic factors are important predictors of cognitive performance in this high-functioning cohort. Education had the strongest influence on overall cognitive performance, and particularly notable associations with subtests that depended upon the use of previously learned materials. Longitudinal follow-up, now underway, will help to determine whether high levels of education help to maintain cognitive performance with age.

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