Loneliness Predicts Progression of Frailty in Married and Widowed, but Not Unmarried Community Dwelling Older Adults.

BACKGROUND: Loneliness is highly prevalent among older adults and is associated with frailty. Most studies consider loneliness in isolation without consideration for structural and functional measures of social relationships - and longitudinal studies are scarce. OBJECTIVES: This study examined longitudinal associations between loneliness and frailty and analyzed how structural and functional social measures influence these associations. DESIGN: Linear mixed effects models examined longitudinal associations between loneliness and frailty assessed with the frailty index (scale 0-100). Models were adjusted for baseline age, gender, education, depressive symptoms, global cognition, and structural (e.g., social network, marital status), and functional social measures (e.g., social, cognitive, and physical activity, and social support). PARTICIPANTS: Loneliness and frailty data from 1,931 older adults without dementia at baseline from the Rush Memory and Aging Project were examined (mean age 79.6 ± 7.7 years, 74.9% female). MEASUREMENTS: Baseline loneliness assessed by the de Jong Gierveld Loneliness Scale was the predictor of interest. RESULTS: Frailty increased significantly over a mean follow-up period of 4.6 years. Effects of loneliness on frailty were modified by marital status. Loneliness predicted an additional accumulation of 0.37 and 0.34 deficits on the frailty index per year in married and widowed individuals respectively, compared to those who were not lonely (married: p=0.009, CI 0.09, 0.64; widowed: p=0.005, CI 0.1, 0.58). Loneliness did not predict frailty progression in unmarried individuals. CONCLUSIONS: Loneliness predicts frailty progression, highlighting the importance of social determinants on physical health in aging.

MIND Diet Associated with Reduced Incidence and Delayed Progression of ParkinsonismA in Old Age.

BACKGROUND: In old age, motor impairments including parkinsonian signs are common, but treatment is lacking for many older adults. In this study, we examined the association of a diet specifically developed to promote brain health, called MIND (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), to the incidence and progression of parkinsonism in older adults. METHODS: A total of 706 Memory and Aging Project participants aged 59 -97 years and without parkinsonism at baseline were assessed annually for the presence of four parkinsonian signs using a 26-item modified version of the United Parkinson's Disease Rating Scale. Incident parkinsonism was defined as the first occurrence over 4.6 years of follow-up of two or more parkinsonian signs. The progression of parkinsonism was assessed by change in a global parkinsonian score (range: 0-100). MIND, Mediterranean, and DASH diet pattern scores were computed based on a validated food frequency questionnaire including 144 food items. We employed Cox-Proportional Hazard models and linear mixed models, to examine the associations of baseline diet scores with incident parkinsonism and the annual rate of change in global parkinsonian score, respectively. RESULTS: In models adjusted for age, sex, smoking, total energy intake, BMI and depressive symptoms, higher MIND diet scores were associated with a decreased risk of parkinsonism [(HR=0.89, 95% CI 0.83-0.96)]; and a slower rate of parkinsonism progression [(ß= -0.008; SE=0.0037; p=0.04)]. The Mediterranean diet was marginally associated with reduced parkinsonism progression (ß= -0.002; SE=0.0014; p=0.06). The DASH diet, by contrast, was not associated with either outcome. CONCLUSION: The MIND diet created for brain health may be a associated with decreased risk and slower progression of parkinsonism in older adults.

Neuronal-expressed microRNA-targeted pseudogenes compete with coding genes in the human brain.

MicroRNAs orchestrate brain functioning via interaction with microRNA recognition elements (MRE) on target transcripts. However, the global impact of potential competition on the microRNA pool between coding and non-coding brain transcripts that share MREs with them remains unexplored. Here we report that non-coding pseudogene transcripts carrying MREs (PSG+MRE) often show duplicated origin, evolutionary conservation and higher expression in human temporal lobe neurons than comparable duplicated MRE-deficient pseudogenes (PSG-MRE). PSG+MRE participate in neuronal RNA-induced silencing complexes (RISC), indicating functional involvement. Furthermore, downregulation cell culture experiments validated bidirectional co-regulation of PSG+MRE with MRE-sharing coding transcripts, frequently not their mother genes, and with targeted microRNAs; also, PSG+MRE single-nucleotide polymorphisms associated with schizophrenia, bipolar disorder and autism, suggesting interaction with mental diseases. Our findings indicate functional roles of duplicated PSG+MRE in brain development and cognition, supporting physiological impact of the reciprocal co-regulation of PSG+MRE with MRE-sharing coding transcripts in human brain neurons.

Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations.

BACKGROUND: Recent genetic studies of stroke and related risk factors have identified a growing number of susceptibility loci; however, the relationship of these alleles to ischemic stroke is unknown. The challenge in finding reproducible loci of ischemic stroke susceptibility may be in part related to the etiologic heterogeneity in clinically defined stroke subtypes. In this study, we tested whether known single nucleotide polymorphisms (SNPs) associated with stroke or putative stroke risk factors are associated with neuropathologically defined micro- or macroscopic infarcts and with arteriolosclerosis. METHODS: Measures of neuropathology and genotyping were available from 755 deceased participants from the Religious Orders Study and the Rush Memory and Aging Project. All donated brains were examined by a board-certified neuropathologist using standardized protocol for the presence of microscopic infarct, macroscopic infarct and arteriolosclerosis (lipohyalinosis). In primary analysis, 74 candidate SNPs previously associated (p < 5 × 10(-8)) with ischemic stroke or known risk factors, including atrial fibrillation (AF), hypertension, diabetes, low-density lipoprotein (LDL) level and carotid artery stenosis, were evaluated for association with neuropathologic endpoints. We performed a secondary exploratory analysis to include 93 additional SNPs associated with putative ischemic stroke risk factors including SNPs associated with high-density lipoprotein (HDL), triglyceride serum levels, myocardial infarction (MI), coronary artery disease and cerebral white matter disease. Regression models relating SNPs to cerebrovascular neuropathology were adjusted for age at death, gender and cohort membership. RESULTS: The strongest associations seen for both macroscopic and microscopic infarcts were risk variants associated with diabetes. The diabetes risk variant rs7578326 located near the IRS1 locus was associated with both macroscopic (OR = 0.73, p = 0.011) and microscopic (OR = 0.71, p = 0.009) infarct pathology. Another diabetes susceptibility locus (rs12779790) located between the calcium/calmodulin-dependent protein kinase ID (CAMK1D) and cell division cycle 123 homolog (CDC123) genes is also associated with both macroscopic (OR = 1.40, p = 0.0292) and microscopic infarcts (OR = 1.43, p = 0.0285). The diabetes risk variant rs864745 within JAZF1 was associated with arteriolosclerosis (OR = 0.80, p = 0.014). We observed suggestive associations with the diabetes risk variant rs7961581 (p = 0.038; between TSPAN8 and LGR5) and rs5215 (p = 0.043; KCNJ11), the LDL risk variant rs11206510 (p = 0.045; PCSK9), as well as the AF risk locus ZFHX3. The CDKN2A/B locus (rs2383207, 9p21), identified initially as a susceptibility allele for MI and recently implicated in large vessel stroke, was associated with macroscopic infarct pathology in our autopsy cohort (OR = 1.26, p = 0.031). CONCLUSION: Our results suggest replication of the candidate CDKN2A/B stroke susceptibility locus with directly measured macroscopic stroke neuropathology, and further implicate several diabetes and other risk variants with secondary, pleiotropic associations to stroke-related pathology in our autopsy cohort. When coupled with larger sample sizes, cerebrovascular neuropathologic phenotypes will likely be powerful tools for the genetic dissection of susceptibility for ischemic stroke.

Total daily physical activity and the risk of AD and cognitive decline in older adults.

OBJECTIVE: Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. METHODS: Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical®; Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. RESULTS: During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273-0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). CONCLUSIONS: A higher level of total daily physical activity is associated with a reduced risk of AD.

Hemoglobin level in older persons and incident Alzheimer disease: prospective cohort analysis.

OBJECTIVE: To test the hypothesis that level of hemoglobin is associated with incident Alzheimer disease (AD). METHODS: A total of 881 community-dwelling older persons participating in the Rush Memory and Aging Project without dementia and a measure of hemoglobin level underwent annual cognitive assessments and clinical evaluations for AD. RESULTS: During an average of 3.3 years of follow-up, 113 persons developed AD. In a Cox proportional hazards model adjusted for age, sex, and education, there was a nonlinear relationship between baseline level of hemoglobin such that higher and lower levels of hemoglobin were associated with AD risk (hazard ratio [HR] for the quadratic of hemoglobin 1.06, 95% confidence interval [CI] 1.01-1.11). Findings were unchanged after controlling for multiple covariates. When compared to participants with clinically normal hemoglobin (n = 717), participants with anemia (n = 154) had a 60% increased hazard for developing AD (95% CI 1.02-2.52), as did participants with clinically high hemoglobin (n = 10, HR 3.39, 95% CI 1.25-9.20). Linear mixed-effects models showed that lower and higher hemoglobin levels were associated with a greater rate of global cognitive decline (parameter estimate for quadratic of hemoglobin = -0.008, SE -0.002, p < 0.001). Compared to participants with clinically normal hemoglobin, participants with anemia had a -0.061 z score unit annual decline in global cognitive function (SE 0.012, p < 0.001), as did participants with clinically high hemoglobin (-0.090 unit/year, SE 0.038, p = 0.018). CONCLUSIONS: In older persons without dementia, both lower and higher hemoglobin levels are associated with an increased hazard for developing AD and more rapid cognitive decline.

Change in frailty and risk of death in older persons.

The authors developed and validated a continuous composite measure of frailty and examined its rate of change in 832 older persons with annual evaluations for up to 8 years. In generalized estimating equation models adjusted for age, sex, and education, there was a significant increase in frailty during follow-up. In a proportional hazards model controlling for age, sex, education, and baseline frailty, each 1-unit increase in annual change in frailty was associated with an almost 5 times the risk of mortality. Using a continuous measure, the authors document that frailty is progressive in some older persons and that its rate of progression is associated with mortality.

Respiratory muscle strength predicts decline in mobility in older persons.

OBJECTIVES: To test the hypothesis that respiratory muscle strength is associated with the rate of change in mobility even after controlling for leg strength and physical activity. METHODS: Prospective study of 890 ambulatory older persons without dementia who underwent annual clinical evaluations to examine change in the rate of mobility over time. RESULTS: In a linear mixed-effect model adjusted for age, sex, and education, mobility declined about 0.12 unit/year, and higher levels of respiratory muscle strength were associated with a slower rate of mobility decline (estimate 0.043, SE 0.012, p < 0.001). Respiratory muscle strength remained associated with the rate of change in mobility even after controlling for lower extremity strength (estimate 0.036, SE 0.012, p = 0.004). In a model that included terms for respiratory muscle strength, lower extremity strength and physical activity together, all three were independent predictors of mobility decline in older persons. These associations remained significant even after controlling for body composition, global cognition, the development of dementia, parkinsonian signs, possible pulmonary disease, smoking, joint pain and chronic diseases. CONCLUSION: Respiratory muscle strength is associated with mobility decline in older persons independent of lower extremity strength and physical activity. Clinical interventions to improve respiratory muscle strength may decrease the burden of mobility impairment in the elderly.

Pulmonary function, muscle strength and mortality in old age.

Numerous reports have linked extremity muscle strength with mortality but the mechanism underlying this association is not known. We used data from 960 older persons without dementia participating in the Rush Memory and Aging Project to test two sequential hypotheses: first, that extremity muscle strength is a surrogate for respiratory muscle strength, and second, that the association of respiratory muscle strength with mortality is mediated by pulmonary function. In a series of proportional hazards models, we first demonstrated that the association of extremity muscle strength with mortality was no longer significant after including a term for respiratory muscle strength, controlling for age, sex, education, and body mass index. Next, the association of respiratory muscle strength with mortality was attenuated by more than 50% and no longer significant after including a term for pulmonary function. The findings were unchanged after controlling for cognitive function, parkinsonian signs, physical frailty, balance, physical activity, possible COPD, use of pulmonary medications, vascular risk factors including smoking, chronic vascular diseases, musculoskeletal joint pain, and history of falls. Overall, these findings suggest that pulmonary function may partially account for the association of muscle strength and mortality.

Lower extremity motor function and disability in mild cognitive impairment.

Recent findings suggest that lower extremity motor dysfunction may be a feature of mild cognitive impairment (MCI), but little is known about the nature and significance of lower extremity motor dysfunction in MCI. The aim of this study was to examine the extent to which MCI is associated with impaired gait, balance, and strength and to examine the relation of lower extremity function to disability among persons with MCI in the Rush Memory and Aging Project, a clinical-pathologic study of common chronic conditions of old age. In a series of analyses adjusted for age, sex, and education, individuals with MCI exhibited more impaired gait and balance than individuals without cognitive impairment. Because vascular factors can contribute to lower extremity motor dysfunction, the authors repeated the initial analyses including terms for vascular risk factors and vascular disease, and the associations between MCI and lower extremity motor dysfunction persisted. Moreover, among those with MCI, impairments in gait and balance were associated with an increased likelihood of disability. These findings suggest that lower extremity motor dysfunction is common and contributes to disability in MCI, but lower extremity motor dysfunction in MCI does not appear to be explained by the vascular factors examined in this study.

Physical activity and motor decline in older persons.

We tested the hypothesis that physical activity modifies the course of age-related motor decline. More than 850 older participants of the Rush Memory and Aging Project underwent baseline assessment of physical activity and annual motor testing for up to 8 years. Nine strength measures and nine motor performance measures were summarized into composite measures of motor function. In generalized estimating equation models, global motor function declined during follow-up (estimate, -0.072; SE, 0.008; P < 0.001). Each additional hour of physical activity at baseline was associated with about a 5% decrease in the rate of global motor function decline (estimate, 0.004; SE, 0.001; P = 0.007). Secondary analyses suggested that the association of physical activity with motor decline was mostly due to the effect of physical activity on the rate of motor performance decline. Thus, higher levels of physical activity are associated with a slower rate of motor decline in older persons.

Body mass index in older persons is associated with Alzheimer disease pathology.

OBJECTIVE: We examined the extent to which body mass index (BMI) in older persons is associated with common age-related neuropathologies known to contribute to dementia including Alzheimer disease (AD) pathology, cerebral infarction, and Lewy body disease. METHODS: We studied brain autopsies from 298 deceased Catholic clergy participating in the Religious Orders Study, a longitudinal clinical-pathologic investigation. BMI was assessed at annual clinical evaluations during an average follow-up of 4.9 years (SD = 2.7 years). Each person's average BMI, derived from all evaluations, was used in analyses. Multiple regression analyses were used to examine the relation of common postmortem neuropathologic findings to average BMI prior to death. RESULTS: Mean age at death was 85.7 years (SD = 6.8 years), and average BMI during the course of the study was 26.0 (SD = 5.1). A series of linear regression models was performed with average BMI as the outcome and controlling for age, sex, and education. Level of AD pathology was associated with BMI proximate to death (estimate = -1.15; SE = 0.42; p = 0.007). However, Lewy body pathology (estimate = -0.45; SE = 0.73; p = 0.53) and cerebral infarctions (estimate = -0.10; SE = 0.61; p = 0.88) were not associated with average BMI. The association of AD pathology with BMI was unchanged after controlling for dementia, chronic diseases, and physical activity. CONCLUSION: Body mass in old age is associated with Alzheimer disease pathology in persons with and without dementia.

Change in body mass index and risk of incident Alzheimer disease.

OBJECTIVE: To examine the association of change in body mass index (BMI) with risk of Alzheimer disease (AD). METHODS: Nine hundred eighteen older Catholic clergy participating in the Religious Orders Study without dementia at baseline were studied. Outcome measures were the clinical diagnosis of AD and change in cognitive function. RESULTS: During a mean follow-up of 5.5 years, 151 persons developed AD. BMI averaged 27.4 at baseline and declined in about half the participants. In a proportional hazards model adjusted for age, sex, and education, each 1-unit less of BMI at baseline was associated with about a 5% increase in the risk of AD (hazard ratio = 0.944; 95% CI = 0.908 to 0.981), and each 1-unit annual decline in BMI (about the 10th percentile) was associated with about a 35% increase in the risk of AD compared with a person experiencing no change in BMI (about the 50th percentile) (hazard ratio = 0.730; 95% CI = 0.625 to 0.852). The results were similar after controlling for chronic diseases and excluding persons who developed AD during the first 4 years of observation. Random effects models showed that the rate of cognitive decline increased by about 8% for each 1-unit less of BMI at baseline and declined an additional 40%/year in persons losing 1 unit of BMI/year compared with those with no change in BMI. CONCLUSION: Declining body mass index (BMI) is associated with increased risk of incident Alzheimer disease (AD). Loss of BMI may reflect pathologic processes that contribute to the subsequent development of AD.

Control of movement distance in Parkinson's disease.

Studies of electromyographic (EMG) patterns during movements in Parkinson's disease (PD) have often yielded contradictory results, making it impossible to derive a set of rules to explain how muscles are activated to perform different movement tasks. We sought to clarify the changes in modulation of EMG parameters associated with control of movement distance during fast movements in patients with PD. Specifically, we studied surface EMG activity during rapid elbow flexion movements over a wide range of distances (5-72 degrees) in 14 patients with relatively mild symptoms of PD and 14 control subjects of similar age, sex, height, and weight. The PD group exhibited several changes in EMG modulation including impaired modulation of agonist burst duration; increased number of agonist bursts; reduced scaling of agonist EMG magnitude in the more severely impaired subjects; and increased temporal overlap of the antagonist and agonist signals in the most severely impaired subjects. These findings suggest that progressive motor dysfunction in PD is accompanied by increasing deficits in modulating muscle activation. These results help clarify previous disparate and sometimes contradictory results of EMG patterns in subjects with PD.

Effect of age and gender in the control of elbow flexion movements.

In previous studies of rapid elbow movements in young healthy men, characteristic task-dependent changes in the patterns of muscle activation when movement speed or distance was varied have been reported. In the present study, the authors investigated whether age or gender is associated with changes in the patterns of muscle activity previously reported in young men. Arm movements of 10 healthy older and 10 healthy younger participants (5 men and 5 women in each group) were studied. Surface electromyograms (EMGs) from agonist (biceps) and antagonist (triceps) muscles, kinematic and kinetic parameters, as well as anthropometric and strength measures were recorded. All 4 groups of participants showed similar task- (distance or speed) dependent changes in biphasic EMG activity. Similar modulation of the initial rate of rise of the EMG, integrated agonist and antagonist EMG activity, as well as their relative timing were observed in all 4 groups. Those results suggest that older individuals of both genders retain the control strategies for elbow movements used by young individuals. Despite the qualitative similarities in the patterns of muscle activation, the men moved more quickly than the women, and younger participants moved more quickly than older participants. Those performance differences could not be explained in terms of differences in body size and strength alone.

The effect of changes in head posture on the patterns of muscle activity in cervical dystonia (CD).

Twelve patients with cervical dystonia (CD) and predominant rotation were studied to determine the effects of changes in head posture on the specific patterns of cervical muscle activity. Turns analysis was used to quantify muscle activity underlying head rotation, recorded simultaneously from the agonist and antagonist muscle pairs bilaterally (sternocleidomastoid [SCM] and splenius [SPL]). Muscle activity was compared between the uncompensated dystonic posture and during the maintenance of midposition. In addition, patients were separated into two groups (geste = 6; no geste = 6) based on whether they had a clinically efficacious geste to determine the effect of geste on patterns of cervical muscle activity. Muscle activity was measured during the maintenance of midposition with and without a clinical or simulated geste. Differences in muscle activity between the groups and postures were compared using repeated measure analysis of variance (ANOVA) analyses. The four muscles tested showed a significant difference in muscle activity in the uncompensated dystonic posture as a result of the increased activity in the agonist muscle pair (SCM and SPL responsible for the dystonic posture) (EMG amplitude: F[1,11] = 18.81, p = 0.0012; EMG frequency: F[1,11] = 32.07, p = 0.0001). Maintaining the head in the midposition was associated with a significant reduction in muscle activity compared with the uncompensated dystonic posture (EMG amplitude: F[1,9] = 6.36, p < 0.033; EMG frequency: F[1,9] = 10.96, p < 0.0091). This reduction in midposition muscle activity was significantly greater in the agonist muscle pair (EMG amplitude: F[1,10] = 19.70, p = 0.0013; EMG frequency: F[1,10] = 44.67, p < 0.0001). In the patients with clinically effective geste, there was no additional reduction in muscle activity observed in the midposition when they performed their geste (EMG amplitude: F[1,9] = 4.63, p = 0.060; EMG frequency: F[1,9] = 1.22, p = 0.298). These findings suggest that CD with rotation is characterized by predominantly increased agonist muscle activation. Patients with CD retain the ability to modulate this involuntary agonist muscle activity to maintain the head in the midposition. The maintenance of the midposition does not seem to be facilitated by geste.

Quantitative electromyographic analysis of changes in muscle activity following botulinum toxin therapy for cervical dystonia.

Reports of efficacy of botulinum toxin for cervical dystonia have relied on subjective reports of improvement or various clinical rating scales. We studied 19 patients with cervical dystonia using Turns analysis to determine if quantitative EMG measures of muscle activity changed following botulinum toxin injections. Before and after botulinum toxin injections, six muscles were evaluated bilaterally. Quantitative EMG analysis of active muscles injected with botulinum toxin showed a significant decline in muscle activity after botulinum toxin (F = [1,41] 55.0; p < 0.001). Significant reductions in quantitative EMG parameters were also noted in noninjected active muscles after botulinum toxin treatment (F = [1,51] 59.15; p < 0.001). The sum of EMG activity for all active muscles was calculated for each subject and showed a significant reduction after botulinum toxin injection [MANOVA: (F = [1,5] 5.69; p < 0.05]. Quantitative EMG assessment provides an objective measure of response to botulinum toxin. Decreased muscle activity in noninjected muscles may result from toxin diffusion or reflect relaxation of muscles only secondarily involved in cervical dystonia.