Nicola T. Lautenschlager

Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer Disease: A Randomized Trial

CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking. OBJECTIVE To determine whether physical activity reduces the rate of cognitive decline among older adults at risk. DESIGN AND SETTING Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. PARTICIPANTS We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment. INTERVENTION Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months. RESULTS In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly. CONCLUSIONS In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000136606.

Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study

A high percentage of patients with mild cognitive impairment (MCI) develop clinical dementia of the Alzheimer type (AD) within 1 year. The aim of this longitudinal study was to identify characteristic patterns of cerebral metabolism at baseline in patients converting from MCI to AD, and to evaluate the changes in these patterns over time. Baseline and follow-up examinations after 1 year were performed in 22 MCI patients (12 males, 10 females, aged 69.8±5.8 years); these examinations included neuropsychological testing, structural cranial magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography (PET) evaluation of relative cerebral glucose metabolic rate (rCMRglc). Individual PET scans were stereotactically normalised with NEUROSTAT software (Univ. of Michigan, Ann Arbor, USA). Subsequently, statistical comparison of PET data with an age-matched healthy control population and between patient subgroups was performed using SPM 99 (Wellcome Dept. of Neuroimaging Sciences, London, UK). After 1 year, eight patients (36%) had developed probable AD (referred to as MCIAD), whereas 12 (55%) were still classified as having stable MCI (referred to as MCIMCI). Compared with the healthy control group, a reduced rCMRglc in AD-typical regions, including the temporoparietal and posterior cingulate cortex, was detected at baseline in patients with MCIAD. Abnormalities in the posterior cingulate cortex reached significance even in comparison with the MCIMCI group. After 1 year, MCIAD patients demonstrated an additional bilateral reduction of rCMRglc in prefrontal areas, along with a further progression of the abnormalities in the parietal and posterior cingulate cortex. No such changes were observed in the MCIMCI group. In patients with MCI, characteristic cerebral metabolic differences can be delineated at the time of initial presentation, which helps to define prognostic subgroups. A newly emerging reduction of rCMRglc in prefrontal cortical areas is associated with the transition from MCI to AD.

The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease

BACKGROUND The Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging aimed to recruit 1000 individuals aged over 60 to assist with prospective research into Alzheimers disease (AD). This paper describes the recruitment of the cohort and gives information about the study methodology, baseline demography, diagnoses, medical comorbidities, medication use, and cognitive function of the participants. METHODS Volunteers underwent a screening interview, had comprehensive cognitive testing, gave 80 ml of blood, and completed health and lifestyle questionnaires. One quarter of the sample also underwent amyloid PET brain imaging with Pittsburgh compound B (PiB PET) and MRI brain imaging, and a subgroup of 10% had ActiGraph activity monitoring and body composition scanning. RESULTS A total of 1166 volunteers were recruited, 54 of whom were excluded from further study due to comorbid disorders which could affect cognition or because of withdrawal of consent. Participants with AD (211) had neuropsychological profiles which were consistent with AD, and were more impaired than participants with mild cognitive impairment (133) or healthy controls (768), who performed within expected norms for age on neuropsychological testing. PiB PET scans were performed on 287 participants, 100 had DEXA scans and 91 participated in ActiGraph monitoring. CONCLUSION The participants comprising the AIBL cohort represent a group of highly motivated and well-characterized individuals who represent a unique resource for the study of AD. They will be reassessed at 18-month intervals in order to determine the predictive utility of various biomarkers, cognitive parameters and lifestyle factors as indicators of AD, and as predictors of future cognitive decline.

Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old?

Despite recent advances in the molecular genetics of Alzheimers disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

Tau and Aβ42 protein in CSF of patients with frontotemporal degeneration

Background CSF concentrations of tau and &bgr;-amyloid protein-42 (A&bgr;42) have been extensively studied in AD. Few data are available concerning CSF levels of both proteins in patients with frontotemporal degeneration (FTD). Methods The authors investigated CSF tau and A&bgr;42 concentrations in 34 patients with FTD, 74 patients with AD, and 40 cognitively healthy control subjects. CSF levels of tau and A&bgr;42 were measured by ELISA. With use of receiver operating characteristic–derived cutoff points and linear discrimination lines, the diagnostic sensitivity and specificity of both markers were determined. Results CSF tau concentrations were significantly higher in FTD than in control subjects but were significantly lower than in AD. CSF A&bgr;42 levels were significantly lower in FTD than in control subjects but were significantly higher than in AD. In subjects with FTD, neither tau nor A&bgr;42 levels correlated with the severity of dementia. The best discrimination between the diagnostic groups was obtained by simultaneous measurement of tau and A&bgr;42, yielding a sensitivity of 90% at a specificity of 77% (FTD vs controls) and a sensitivity of 85% at a specificity of 85% (FTD vs AD). Conclusions In FTD, CSF levels of tau are elevated and A&bgr;42 levels are decreased. With use of these markers, subjects with FTD can be distinguished from control subjects and from patients with AD with reasonable accuracy.

Association between lifestyle factors and mental health measures among community-dwelling older women

Objective: To investigate the association between potentially modifiable lifestyle factors and cognitive abilities/depressive symptoms in community-dwelling women aged 70 years and over. Method: Cross-sectional study of community-dwelling women aged 70 years and over (n = 278; mean age = 74.6 years). Lifestyle variables assessed included smoking, alcohol consumption, physical activity, nutrition and education. The mental health measures of interest were depression, anxiety, quality of life and cognitive function, as assessed by the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), SF-36, and the Cambridge Cognitive Examination for Mental Disorders of the Elderly (CAMCOG), respectively. Results: Physically active women were half as likely to be depressed (BDI score ≥ 10) and anxious (BAI score ≥ 8) when compared to their physically inactive counterparts (OR = 0.5, 95% CI = 0.3–0.8 for both, adjusted for marital status and smoking in the case of depression). Having ever smoked more than 20 cigarettes per day was associated with increased risk of depression (OR = 2.8, 95% CI = 1.4–5.5, adjusted for marital status and physical activity). Moderate alcohol use was associated with increased likelihood of having a CAMCOG score within the highest 50 percentile (OR = 2.0, 95% CI = 1.1–3.5, adjusted for age and education), as was more than minimum statutory education (OR = 2.0, 95% CI = 1.1–3.5, adjusted for age and alcohol consumption). There was no obvious association between vitamin B12/folate deficiency or obesity with any of the measures of interest. Conclusions: The results of this study are consistent with the hypothesis that depression is directly associated with heavy smoking and inversely associated with physical activity. They also support the idea that non-harmful alcohol consumption is associated with better cognitive performance. Randomised clinical trials should be now designed to clarify whether management of lifestyle factors reduces the incidence of mood disorders and cognitive impairment in later life.

Smoking is associated with reduced cortical regional gray matter density in brain regions associated with incipient Alzheimer disease.

OBJECTIVES The results of observational studies suggest that smoking increases the risk of Alzheimer disease (AD). The authors designed this study to determine if older people who smoke have decreased gray matter density in brain regions associated with incipient AD. METHODS The authors recruited 39 pairs (N = 78) of smokers/never-smokers 70 to 83 years of age who were matched for age, sex, education, and handedness. Participants were free of clinically significant cognitive impairment, depression, stroke, or other serious medical conditions. Gray matter density was determined by voxel-based morphometry using statistical parametric mapping of T1-weighted magnetic resonance images. RESULTS Smokers had decreased gray matter density in the posterior cingulum and precuneus (bilateral), right thalamus, and frontal cortex (bilateral) compared with never-smokers. CONCLUSIONS Smoking is associated with decreased gray matter density in brain regions previously associated with incipient AD. Longitudinal investigations are required to clarify whether these changes are progressive in nature.

Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer’s disease

High amyloid has been associated with substantial episodic memory decline over 18 and 36 months in healthy older adults and individuals with mild cognitive impairment. However, the nature and magnitude of amyloid-related memory and non-memory change from the preclinical to the clinical stages of Alzheimers disease has not been evaluated over the same time interval. Healthy older adults (n = 320), individuals with mild cognitive impairment (n = 57) and individuals with Alzheimers disease (n = 36) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent at least one positron emission tomography neuroimaging scan for amyloid. Cognitive assessments were conducted at baseline, and 18- and 36-month follow-up assessments. Compared with amyloid-negative healthy older adults, amyloid-positive healthy older adults, and amyloid-positive individuals with mild cognitive impairment and Alzheimers disease showed moderate and equivalent decline in verbal and visual episodic memory over 36 months (ds = 0.47-0.51). Relative to amyloid-negative healthy older adults, amyloid-positive healthy older adults showed no decline in non-memory functions, but amyloid-positive individuals with mild cognitive impairment showed additional moderate decline in language, attention and visuospatial function (ds = 0.47-1.12), and amyloid-positive individuals with Alzheimers disease showed large decline in all aspects of memory and non-memory function (ds = 0.73-2.28). Amyloid negative individuals with mild cognitive impairment did not show any cognitive decline over 36 months. When non-demented individuals (i.e. healthy older adults and adults with mild cognitive impairment) were further dichotomized, high amyloid-positive non-demented individuals showed a greater rate of decline in episodic memory and language when compared with low amyloid positive non-demented individuals. Memory decline does not plateau with increasing disease severity, and decline in non-memory functions increases in amyloid-positive individuals with mild cognitive impairment and Alzheimers disease. The combined detection of amyloid positivity and objectively-defined decline in memory are reliable indicators of early Alzheimers disease, and the detection of decline in non-memory functions in amyloid-positive individuals with mild cognitive impairment may assist in determining the level of disease severity in these individuals. Further, these results suggest that grouping amyloid data into at least two categories of abnormality may be useful in determining the disease risk level in non-demented individuals.

Falls, Depression and Antidepressants in Later Life: A Large Primary Care Appraisal

Background Depression and falls are common and co-exist for older people. Safe management of each of these conditions is important to quality of life. Methods A cross-sectional survey was used to examine medication use associated with injurious and non-injurious falls in 21,900 community-dwelling adults, aged 60 years or over from 383 Australian general practices recruited for the DEPS-GP Project. Falls and injury from falls, medication use, depressive symptoms (Primary Health Questionnaire (PHQ-9)), clinical morbidity, suicidal ideation and intent, health status (SF-12 Health Survey), demographic and lifestyle information was reported in a standardised survey. Findings Respondents were 71.8 years (sd 7.7) of age and 58.4% were women. 24% 11% and 8% reported falls, fall related injury, and sought medical attention respectively. Antidepressant use (odds ratio, OR: 1.46; 95% confidence interval, 95%CI: 1.25, 1.70), questionable depression (5–14 on PHQ OR: 1.32, 95%CI: 1.13, 1.53) and clinically significant symptoms of depression (15 or more on PHQ OR: 1.70, 95%CI: 1.14, 1.50) were independently associated with multiple falls. SSRI use was associated with the highest risk of multiple falls (OR: 1.66, 95%CI: 1.36, 2.02) amongst all psychotropic medications. Similar associations were observed for injurious falls. Over 60% of those with four accumulated risk factors had multiple falls in the previous year (OR: 3.40, 95%CI: 1.79, 6.45); adjusted for other demographic and health factors. Interpretation Antidepressant use (particularly SSRIs) was strongly associated with falls regardless of presence of depressive symptoms. Strategies to prevent falls should become a routine part of the management of older people with depression.

Bone mineral density, adiposity, and cognitive functions

Cognitive decline and dementia due to Alzheimers disease (AD) have been associated with genetic, lifestyle, and environmental factors. A number of potentially modifiable risk factors should be taken into account when preventive or ameliorative interventions targeting dementia and its preclinical stages are investigated. Bone mineral density (BMD) and body composition are two such potentially modifiable risk factors, and their association with cognitive decline was investigated in this study. 164 participants, aged 34–87 years old (62.78 ± 9.27), were recruited for this longitudinal study and underwent cognitive and clinical examinations at baseline and after 3 years. Blood samples were collected for apolipoprotein E (APOE) genotyping and dual energy x-ray absorptiometry (DXA) was conducted at the same day as cognitive assessment. Using hierarchical regression analysis, we found that BMD and lean body mass, as measured using DXA were significant predictors of episodic memory. Age, gender, APOE status, and premorbid IQ were controlled for. Specifically, the List A learning from California Verbal Learning Test was significantly associated with BMD and lean mass both at baseline and at follow up assessment. Our findings indicate that there is a significant association between BMD and lean body mass and episodic verbal learning. While the involvement of modifiable lifestyle factors in human cognitive function has been examined in different studies, there is a need for further research to understand the potential underlying mechanisms.