A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.

Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated. Towards this end, we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70-95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily. Although three subjects withdrew, 11 RAPA and 14 controls completed at least 8 weeks of treatment and were included in the analysis. We monitored for changes that would indicate detrimental effects of RAPA treatment on metabolism, including both standard clinical laboratory assays (CBC, CMP, HbA1c) and oral glucose tolerance tests (OGTTs). We also monitored parameters typically associated with aging that could potentially be modified by RAPA; these included cognitive function which was assessed by three different tools: Executive Interview-25 (EXIT25); Saint Louis University Mental Status Exam (SLUMS); and Texas Assessment of Processing Speed (TAPS). In addition, physical performance was measured by handgrip strength and 40-foot timed walks. Lastly, changes in general parameters of healthy immune aging, including serum pro-inflammatory cytokine levels and blood cell subsets, were assessed. Five subjects reported potential adverse side effects; in the RAPA group, these were limited to facial rash (1 subject), stomatitis (1 subject) and gastrointestinal issues (2 subjects) whereas placebo treated subjects only reported stomatitis (1 subject). Although no other adverse events were reported, statistically significant decrements in several erythrocyte parameters including hemoglobin (HgB) and hematocrit (Hct) as well as in red blood cell count (RBC), red blood cell distribution width (RDW), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed in the RAPA-treatment group. None of these changes manifested clinically significant effects during the short duration of this study. Similarly, no changes were noted in any other clinical laboratory, cognitive, physical performance, or self-perceived health status measure over the study period. Immune parameters were largely unchanged as well, possibly due to the advanced ages of the cohort (70-93 years; mean age 80.5). RAPA-associated increases in a myeloid cell subset and in TREGS were detected, but changes in most other PBMC cell subsets were not statistically significant. Importantly, the OGTTs revealed no RAPA-induced change in blood glucose concentration, insulin secretion, and insulin sensitivity. Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a trial with a larger sample size and longer treatment duration is warranted.

Towards an aging-specific cognitive phenotype: the freedom house study.

UNLABELLED: BACKGROUND/STUDY CONTEXT: The authors have previously reported latent growth curve (LGC) models of 3-year change in multiple cognitive measures among successfully aging volunteers. In this analysis, the authors apply growth mixture modeling (GMM) to demonstrate homogeneous subsets among them with discriminable trajectories. Only one trajectory class can be interpreted as the effect of Aging Proper. The goal of the study was to describe an aging-specific cognitive phenotype (ASCP). METHODS: Five hundred forty-seven noninstitutionalized septuagenarian and octogenarian volunteers, residing in a comprehensive care retirement community, were assessed longitudinally on a comprehensive battery of brief psychometric measures. RESULTS: All variables held more than one latent class. Members of an a priori defined "Aging Proper" class were highly concordant across measures, and allowed the aging-specific cognitive phenotype (ASCP) to be examined. The ASCP was characterized by simultaneous decline in visuospatial function, coupled with improving verbal fluency. The ASCP was not associated with decline in memory task performance. CONCLUSIONS: Previously reported age-related declines in memory are more likely to represent the effects of comorbid disease and not aging per se. The ASCP is more consistent with earlier "Right Hemisphere" models of aging and could provide clues to the mechanisms underlying true aging-related cognitive changes.

Depressive symptoms predict longitudinal change in executive control but not memory.

OBJECTIVE: Depression in non-demented persons has been identified as a possible risk factor for incident Alzheimer's disease (AD). METHODS: Latent Growth Curve models were developed of baseline depressive symptoms as a predictor of longitudinal changes in cognition. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS). Memory was assessed by the California Verbal Learning Task (CVLT). Executive control function (ECF) was assessed by the Executive Interview (EXIT25) and Trail-Making Test Part B (Trails-B). Five hundred forty-seven non-institutionalized older retirees living in a single comprehensive care retirement community participated. RESULTS: Depressive symptoms were significantly associated only with the 3-year rate of decline in psychomotor speed, as measured by Trails A, and ECF, as measured by the EXIT25. Both associations withstood adjustment for age, gender, education, and baseline level of care. CONCLUSIONS: Depressive symptoms are associated with longitudinal decline in cognition. However, this association selectively involves executive control, not memory, and possibly only a subset of 'executive' functions. Although depressive symptoms may hasten conversion from mild cognitive impairment (MCI) to dementia, depression-related conversion is not likely to be mediated by evolution of the AD pathological process.

Informed consent and the cognitively impaired geriatric dental patient.

Many geriatric patients will have cognitive impairment, sometimes temporary and other times progressive. Dentists are challenged to evaluate for the presence of cognitive impairment that can affect the consent process. This review gives an overview of types of cognitive impairments, clues to recognizing these conditions, how they affect the dental consent process, and what makes an effective informed consent. When there is doubt of a patient's capacity to consent, prudence calls for stopping dental treatment and referring the patient for a medical evaluation.

Clock-drawing potentially mediates the effect of depression on mortality: replication in three cohorts.

OBJECTIVE: Previously studies have associated visuospatial tasks, particularly 'clock-drawing', with mortality. We sought to determine whether clock-drawing also mediates the association between depressive symptoms and mortality. PARTICIPANTS: Non-institutionalized Hispanic and non-Hispanic White elderly volunteers. MEASUREMENTS: Survival curves were generated as a function of baseline depressive symptom ratings. Significant models were adjusted for CLOX performance. CLOX is divided into CLOX1, a measure of executive control, and CLOX2, a measure of visuospatial skills. DESIGN: Retrospective analysis of three longitudinal cohorts. RESULTS: CLOX2 and depressive symptoms were both associated with mortality in unadjusted models. CLOX2 predicted survival independently of CLOX1 in all three cohorts. CLOX2 also attenuated, and/or mediated the association between depressive symptoms and mortality. These results withstood adjustment for age and education in all three cohorts. CONCLUSION: Regardless of the sample examined, or the measure of depressive symptoms applied, the association between depressive symptoms and mortality appears to be at least partially mediated by visuospatial skills. This finding supports our hypothesis that right hemisphere structural brain disease, particularly that involving the insula, may mediate depression's effects on mortality.

Depression and mortality in elders referred for geriatric psychiatry consultation.

OBJECTIVE: The association between depressive symptoms and mortality was assessed in a 7-year longitudinal follow-up of subjects referred for geropsychiatric consultation. METHODS: The medical records of 89 referrals were reviewed. Survival analysis was performed on subjects stratified by Geriatric Depression Scale (GDS) and residential status. RESULTS: Fifty percent of subjects with GDS > 6 (n = 28) died by 19 months versus 54 months for subjects with GDS < 7 (n = 61) (chi2 = 13.2, df = 1, P < .001). GDS, medical burden, age, and gender were independently associated with survival. CONCLUSIONS: GDS scores greater than 6 are associated with increased risk of mortality in elders referred for geropsychiatric consultation.

Cognitive predictors of mortality in elderly retirees: results from the Freedom House study.

OBJECTIVE: The objective of this longitudinal cohort study was to study the cognitive domains associated with five-year longitudinal survival among healthy, well-educated, noninstitutionalized elderly. METHODS: Survival curves were generated as a function of cross-sectional baseline cognitive test performance. RESULTS: Nonverbal tests were significantly associated with survival. This finding was markedly consistent. Several nonverbal tasks were each significantly associated with survival independently of age, gender, baseline level of care, and healthcare utilization. In a multivariate model, copying a clock made the strongest, independent contribution to survival. CONCLUSIONS: Right hemisphere integrity in general and nonverbal drawing tasks in particular have been associated with survival in conditions as diverse as Alzheimer disease, stroke, and epilepsy. This study extends this association to "normal" aging. The mechanism by which nonverbal cognitive function is related to mortality remains unclear but may be mediated by changes in right hemisphere cortical control of autonomic function. Nondemented older persons may be at risk. Clock drawing may provide a simple means of identifying them.

An empiric approach to level of care determinations: the importance of executive measures.

BACKGROUND: The ability to predict the level of care received by elderly retirees was compared in a discriminant model and using a classification tree derived from cognitive and noncognitive variables. Methods. Participants were 193 residents (mean age, 79.1+/-5.1 years) of a single, 1,500-bed, continuing care retirement community. They were given a battery of cognitive measures that included tests of general cognition, memory, and executive control function. A multivariate discriminant model of level of care was compared with a classification tree. RESULTS: Residents in congregate high-rises (n=115) differed significantly from those in apartment settings (n=78) with respect to age, Executive Interview (EXIT 25), and the Executive Clock-Drawing Task (CLOX). Only age and executive control function measures (CLOX1, EXIT 25, and Trail Making Test Part B [Trails B]) contributed independently to a discriminant model of level of care (Wilke's lambda=0.92; F [df 4,170]=3.48; p <.01). Sixty-three percent of participants were correctly classified. A classification tree derived from the same variable set was more accurate (75% correctly classified). Age, CLOX1, and EXIT 25 made the most important contributions to the model. The EXIT 25 and CLOX1 thresholds empirically derived from this model coincide with the fifth percentiles for these instruments in a young adult sample. CONCLUSIONS: Executive control function appears to be most responsible for the effect of cognition on level of care. Young adult norms may be most relevant when the effects of cognitive impairment on functional status are assessed.

Executive control mediates memory's association with change in instrumental activities of daily living: the Freedom House Study.

OBJECTIVES: To assess the relative independent contribution of changes in executive control function (ECF) and memory to changes in functional status. DESIGN: Three-year longitudinal cohort study. SETTING: A comprehensive care retirement community. PARTICIPANTS: Five hundred forty-seven noninstitutionalized people aged 70 and older. MEASUREMENTS: The California Verbal Learning Test (CVLT) and Executive Interview (EXIT25). Functional status was assessed using instrumental activities of daily living (IADLs). Latent growth curves of CVLT, EXIT25, and IADLs were modeled. The rate of change in IADLs (adjusted for baseline IADLs and cognition) was regressed on the rate of change in each cognitive measure. Models were also adjusted for baseline age, level of care, and comorbid illnesses. RESULTS: There was significant variability around the baseline means and slopes for all variables. The rate of change in EXIT25 was independently correlated with the rate of change in IADLs (correlation coefficient (r)=-0.52, P<.001). This remained significant after adjusting for baseline EXIT25 scores, IADLs, age, comorbid disease, and level of care. The EXIT25's effect on the rate of change in IADLs was stronger than those of age, baseline IADLs, comorbid disease, or level of care. The rate of change in CVLT scores was not significantly associated with the rate of change in IADLs. CONCLUSION: ECF is a strong, significant, and independent correlate of functional status in normal aging. In contrast, decline in memory, as measured using the CVLT, has no independent association with the rate of change in functional status. This suggests that amnestic mild cognitive impairment can be associated with dementia only though the subsequent or comorbid development of ECF impairment.

Normal rates of cognitive change in successful aging: the freedom house study.

We determined the rates of cognitive change associated with twenty individual measures. Participants included 547 noninstitutionalized septuagenarians and octogenarian residents of a comprehensive care retirement community who were studied over three years. Latent growth curves (LGC) of multiple cognitive measures were compared to a LGC model of the rates of change in Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL). All curves were standardized relative to each variable's baseline distribution. Baseline scores were within their expected normal age-specific ranges. Most measures showed significant rates of change over time. There was also significant variability about those rates, suggesting clinical heterogeneity. Many deteriorated over time, as did ADLs and IADLs. However, performance on some measures improved, consistent with learning effects. The rates of change in two measures, the Executive Interview and the Trail Making Test, were closely related to decline in IADLs. These results suggest that age-related cognitive decline is a dynamic longitudinal process affecting multiple cognitive domains. Heterogeneity in the rates of cognitive change may reflect the summed effects of age and comorbid conditions affecting cognition. Some measures may be ill-suited for measuring age-related changes in cognition, either because they are insensitive to change, or hindered by learning effects. Nonverbal measures appear to be particularly well suited for the prediction of age-related functional decline. These observations are relevant to the definition and diagnosis of "dementing" conditions.

Misclassification is likely in the assessment of mild cognitive impairment.

We estimated the relative frequency of isolated memory impairment versus isolated and comorbid impairment in executive control function (ECF). One hundred and ninety-three noninstitutionalized residents of a single Comprehensive Care Retirement Community (mean age 79.2 years) were investigated. The subjects were tested with multiple measures of memory and ECF. Test scores were standardized to minimize scaling effects. 'Impairment' was defined as performance < or =1.5 standard deviations below the mean for the entire sample (i.e., a z score < or =-1.5). Disability was estimated as the sum of self-reported activities of daily living and instrumental activities of daily living. The cognitive test performance was significantly associated with functional impairment, independently of age. ECF and memory measures were significantly intercorrelated. Both were significantly and independently associated with disability ratings. 6-10% of the subjects had memory impairment; 25-35% of the memory-impaired subjects had comorbid ECF impairments. An additional 4-7% of the subjects had isolated ECF impairment. A significant fraction of the cases otherwise meeting the criteria for 'mild cognitive impairment' may have comorbid ECF impairment. This raises the issue of whether they might be more properly classified as 'demented'. In addition, isolated ECF impairment may affect almost as many persons as isolated memory impairment. Isolated ECF impairment is not consistent with the natural history of preclinical Alzheimer's disease, suggests other conditions, and can be disabling, independently of age and/or memory loss.

Declining executive control in normal aging predicts change in functional status: the Freedom House Study.

OBJECTIVES: To assess the contribution of executive control function (ECF) to functional status. DESIGN: Three-year longitudinal cohort study. SETTING: A comprehensive-care retirement community. PARTICIPANTS: Five hundred forty-seven noninstitutionalized septuagenarians. MEASUREMENTS: The Mini-Mental State Examination (MMSE) and Executive Interview (EXIT25). Functional status was assessed using instrumental activities of daily living (IADLs). Latent growth curves of MMSE, EXIT25, and IADL were modeled. The rate of change in IADLs (DeltaIADL), adjusted for baseline IADLs and cognition, was regressed on the rate of change in each cognitive measure (adjusted for baseline cognition). Models were also adjusted for baseline age, level of care, and comorbid illnesses. RESULTS: Baseline test scores were within normal ranges, but mean EXIT25 scores reached the impaired range by the second follow-up. There was significant variability around the baseline means and slopes for all variables. The rate of change in EXIT25 was strongly correlated with DeltaIADL (r=-0.57, P<.001). This remained significant after adjusting for baseline EXIT25 scores, IADLs, age, comorbid disease, and level of care. The effect of the EXIT25 on DeltaIADL was stronger than those of age, baseline IADLs, comorbid disease, or level of care. The rate of change in MMSE scores was not significantly associated with DeltaIADL. CONCLUSION: ECF is a significant and independent correlate of functional status in normal aging. Traditional dementia case finding is likely to underestimate cognition-related disability. Neither a normal baseline MMSE score nor stable MMSE scores over time preclude functionally significant changes in ECF.

Executive dyscontrol in normal aging: normative data, factor structure, and clinical correlates.

Although there is ample evidence of frontal system dysfunction in old age, the clinical significance of these impairments has not been well studied. In this article, we examine the factor structure of putative executive measures in a sample of well elderly subjects. Three stable factors emerged, but only one was associated with measures of functional status. This factor was most strongly associated with relatively simple bedside executive measures that might prove useful in dementia screening. In contrast, a second factor, dominated by the Wisconsin Card Sorting Task, was weakly associated with disability. These data suggest that certain executive measures may be more relevant to functional outcomes, and hence dementia case finding, than others. Moreover, associations with functional status should not be casually extrapolated from regional frontal clinical correlations, particularly with the dorsolateral prefrontal cortex.

Decline in learning ability best predicts future dementia type: the Freedom House Study.

The authors studied longitudinal change in learning efficiency as a predictor of future dementia type among healthy, well-educated, noninstitutionalized elderly retirees. Serial assessments of memory were obtained using the California Verbal Learning Test (CVLT). Latent growth (LG) models were developed from the slopes of the subjects' performance over the first five CVLT learning trials at each of three serial administrations (e.g., cohort inception [i.e., baseline] [CVLT1], 18 months [CVLT2] and 36 months [CVLT3]). The resulting growth curves were incorporated into a higher order LG model representing the dynamic change in learning efficiency over time (DeltaCVLT). DeltaCVLT was used to predict each subject's "dementia type" (i.e., clinical state) at 36 months (e.g., no dementia, Type 1 [Alzheimer type] dementia or Type 2 [non-Alzheimer type] dementia), after adjusting for CVLT1, baseline age, and baseline dementia type. Nonlinear (logarithmic) LG models of CVLT1-CVLT3 and DeltaCVLT best fit the data. There was significant variability about both CVLT1 and DeltaCVLT, suggesting subgroups in the sample with significantly different baseline memory function, and different rates of deterioration in learning efficiency. Age, baseline dementia type, and DeltaCVLT made significant independent contributions to final dementia type. CVLT1 did not predict final dementia type independently of the other covariates. These data suggest that baseline memory performance in noninstitutionalized elderly retirees does not predict future dementia type independently of the dynamic rate of change in memory measures. Serial administrations of memory tests may help identify nondemented persons at greater or lesser risk for conversion to frank dementia in the near-term.

The patient with Parkinson's disease.

Parkinson's disease is an idiopathic, slowly progressive disorder of the central nervous system characterized by resting tremor, muscular rigidity, slow and decreased movement (bradykinesia), and postural instability. In the United States, Parkinson's disease is the fourth most common neurodegenerative disorder in the elderly, affecting an estimated half a million people. Oral health care providers can expect to be called upon to care for patients with this progressively debilitating disease. To provide competent care to patients with Parkinson's disease, clinicians must understand the disease, its treatment, and its impact on the patient's ability to undergo and respond to dental care.