Yonas E. Geda

Mild Cognitive Impairment: Ten Years Later

In the past 10 years, there has been a virtual explosion in the literature concerning the construct of mild cognitive impairment. The interest in this topic demonstrates the increasing emphasis on the identification of the earliest features of cognitive disorders such as Alzheimer disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiologic, neuroimaging, biomarker, neuropathological, disease mechanism, and clinical trials research. This review summarizes the progress that has been made while also recognizing the challenges that remain.

Physical Exercise as a Preventive or Disease-Modifying Treatment of Dementia and Brain Aging

A rapidly growing literature strongly suggests that exercise, specifically aerobic exercise, may attenuate cognitive impairment and reduce dementia risk. We used PubMed (keywords exercise and cognition) and manuscript bibliographies to examine the published evidence of a cognitive neuroprotective effect of exercise. Meta-analyses of prospective studies documented a significantly reduced risk of dementia associated with midlife exercise; similarly, midlife exercise significantly reduced later risks of mild cognitive impairment in several studies. Among patients with dementia or mild cognitive impairment, randomized controlled trials (RCTs) documented better cognitive scores after 6 to 12 months of exercise compared with sedentary controls. Meta-analyses of RCTs of aerobic exercise in healthy adults were also associated with significantly improved cognitive scores. One year of aerobic exercise in a large RCT of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise. Cross-sectional studies similarly reported significantly larger hippocampal or gray matter volumes among physically fit seniors compared with unfit seniors. Brain cognitive networks studied with functional magnetic resonance imaging display improved connectivity after 6 to 12 months of exercise. Animal studies indicate that exercise facilitates neuroplasticity via a variety of biomechanisms, with improved learning outcomes. Induction of brain neurotrophic factors by exercise has been confirmed in multiple animal studies, with indirect evidence for this process in humans. Besides a brain neuroprotective effect, physical exercise may also attenuate cognitive decline via mitigation of cerebrovascular risk, including the contribution of small vessel disease to dementia. Exercise should not be overlooked as an important therapeutic strategy.

Prevalence of mild cognitive impairment is higher in men The Mayo Clinic Study of Aging

Objective: We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria. Methods: We evaluated an age- and sex-stratified random sample of Olmsted County residents who were 70–89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria. Results: Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval [CI] 14.4–17.5) for any MCI, 11.1% (95% CI 9.8–12.3) for amnestic MCI, and 4.9% (95% CI 4.0–5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21–1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE ε3ε4 or ε4ε4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend <0.0001). Conclusions: Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly.

Physical Exercise, Aging, and Mild Cognitive Impairment: A Population-Based Study

BACKGROUND Physical exercise is associated with decreased risk of dementia and Alzheimer disease. OBJECTIVE To investigate whether physical exercise is associated with decreased risk of mild cognitive impairment (MCI). DESIGN Population-based case-control study. SETTING The Mayo Clinic Study of Aging, an ongoing population-based cohort study in Olmsted County, Minnesota. PARTICIPANTS A total of 1324 subjects without dementia who completed a Physical Exercise Questionnaire. MAIN OUTCOME MEASURES An expert consensus panel classified each subject as having normal cognition or MCI based on published criteria. RESULTS We compared the frequency of physical exercise among 198 subjects with MCI with that among 1126 subjects with normal cognition and adjusted the analyses for age, sex, years of education, medical comorbidity, and depression. The odds ratios for any frequency of moderate exercise were 0.61 (95% confidence interval, 0.43-0.88; P = .008) for midlife (age range, 50-65 years) and 0.68 (95% confidence interval, 0.49-0.93; P = .02) for late life. The findings were consistent among men and women. Light exercise and vigorous exercise were not significantly associated with decreased risk of MCI. CONCLUSION In this population-based case-control study, any frequency of moderate exercise performed in midlife or late life was associated with a reduced odds of having MCI.

Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging : Population-Based Study

CONTEXT Little is known about the population-based prevalence of neuropsychiatric symptoms in mild cognitive impairment (MCI). OBJECTIVE To estimate the prevalence of neuropsychiatric symptoms in MCI and normal cognitive aging in a defined population. DESIGN Cross-sectional study derived from an ongoing population-based prospective cohort study. SETTING The Mayo Clinic Study of Aging. PARTICIPANTS We studied a random sample of 1969 individuals without dementia from the target population of 9965 elderly persons residing in Olmsted County (Minnesota) on the prevalence date (October 1, 2004). Neuropsychiatric data were available for 319 of 329 subjects with MCI (97.0%) and 1590 of 1640 subjects with normal cognition (97.0%). Neurologic, cognitive, and neuropsychiatric data were obtained from the study participants. A classification of MCI, dementia, and normal cognitive aging was adjudicated by an expert consensus panel. Accordingly, 329 subjects were classified as having MCI and the remaining 1640 subjects were classified as having normal cognition. MAIN OUTCOME MEASURE Neuropsychiatric Inventory Questionnaire score. RESULTS Multivariate logistic regression analyses were conducted after adjusting for age, sex, and educational status. By considering both the odds ratio (OR) and the frequency of a symptom, the most distinguishing features between the 2 groups were apathy (OR, 4.53; 95% confidence interval [CI], 3.11-6.60; P < .001), agitation (3.60; 2.18-5.92; P < .001), anxiety (3.00; 2.01-4.48; P < .001), irritability 2.99; 2.11-4.22; P < .001), and depression (2.78; 2.06-3.76; P < .001). The OR was highest for delusion (8.12; 95% CI, 2.92-22.60; P < .001); however, it was rare in both subjects with MCI (11 of 319 [3.4%]) and those with normal cognition (6 of 1590 [0.4%]). Thus, the population attributable risk for delusion was only 2.62% compared with 14.60% for apathy. CONCLUSIONS Nonpsychotic symptoms affected approximately 50% of subjects with MCI and 25% of subjects with normal cognition. In contrast, psychotic symptoms were rare.

Assessing the Temporal Relationship Between Cognition and Gait: Slow Gait Predicts Cognitive Decline in the Mayo Clinic Study of Aging

BACKGROUND The association between gait speed and cognition has been reported; however, there is limited knowledge about the temporal associations between gait slowing and cognitive decline among cognitively normal individuals. METHODS The Mayo Clinic Study of Aging is a population-based study of Olmsted County, Minnesota, United States, residents aged 70-89 years. This analysis included 1,478 cognitively normal participants who were evaluated every 15 months with a nurse visit, neurologic evaluation, and neuropsychological testing. The neuropsychological battery used nine tests to compute domain-specific (memory, language, executive function, and visuospatial skills) and global cognitive z-scores. Timed gait speed (m/s) was assessed over 25 feet (7.6 meters) at a usual pace. Using mixed models, we examined baseline gait speed (continuous and in quartiles) as a predictor of cognitive decline and baseline cognition as a predictor of gait speed changes controlling for demographics and medical conditions. RESULTS Cross-sectionally, faster gait speed was associated with better performance in memory, executive function, and global cognition. Both cognitive scores and gait speed declined over time. A faster gait speed at baseline was associated with less cognitive decline across all domain-specific and global scores. These results were slightly attenuated after excluding persons with incident mild cognitive impairment or dementia. By contrast, baseline cognition was not associated with changes in gait speed. CONCLUSIONS Our study suggests that slow gait precedes cognitive decline. Gait speed may be useful as a reliable, easily attainable, and noninvasive risk factor for cognitive decline.

Association of Duration and Severity of Diabetes Mellitus With Mild Cognitive Impairment

BACKGROUND It remains unknown whether diabetes mellitus (DM) is a risk factor for mild cognitive impairment (MCI). OBJECTIVE To investigate the association of DM with MCI using a population-based case-control design. DESIGN Population-based case-control study. SETTING Academic research. PARTICIPANTS Our study was conducted, among subjects aged 70 to 89 years on October 1, 2004, who were randomly selected from the Olmsted County (Minnesota) population. Main Outcome Measure We administered to all participants a neurologic examination, the Clinical Dementia Rating Scale, and a neuropsychological evaluation (including 9 tests in 4 cognitive domains) to diagnose normal cognition, MCI, or dementia. We assessed history of DM, DM treatment, and DM complications by interview, and we measured fasting blood glucose levels. History of DM was also confirmed using a medical records linkage system. RESULTS We compared 329 subjects having MCI with 1640 subjects free of MCI and dementia. The frequency of DM was similar in subjects with MCI (20.1%) and in subjects without MCI (17.7%) (odds ratio [OR], 1.16; 95% confidence interval [CI], 0.85-1.57). However, MCI was associated with onset of DM before age 65 years (OR, 2.20; 95% CI, 1.29-3.73), DM duration of 10 years or longer (OR, 1.76; 95% CI, 1.16-2.68), treatment with insulin (OR, 2.01; 95% CI, 1.22-3.31), and the presence of DM complications (OR, 1.80; 95% CI, 1.13-2.89) after adjustment for age, sex, and education. Analyses using alternative definitions of DM yielded consistent findings. CONCLUSION These findings suggest an association of MCI with earlier onset, longer duration, and greater severity of DM.

Mild cognitive impairment associated with limbic and neocortical lewy body disease: a clinicopathological study

There are little data on the relationship between Lewy body disease and mild cognitive impairment syndromes. The Mayo Clinic aging and dementia databases in Rochester, Minnesota, and Jacksonville, Florida were queried for cases who were diagnosed with mild cognitive impairment between 1 January 1996 and 30 April 2008, were prospectively followed and were subsequently found to have autopsy-proven Lewy body disease. The presence of rapid eye movement sleep behaviour disorder was specifically assessed. Mild cognitive impairment subtypes were determined by clinical impression and neuropsychological profiles, based on prospective operational criteria. The diagnosis of clinically probable dementia with Lewy bodies was based on the 2005 McKeith criteria. Hippocampal volumes, rate of hippocampal atrophy, and proton magnetic resonance spectroscopy were assessed on available magnetic resonance imaging and spectroscopy scans. Eight subjects were identified; six were male. Seven developed dementia with Lewy bodies prior to death; one died characterized as mild cognitive impairment. The number of cases and median age of onset (range) for specific features were: seven with rapid eye movement sleep behaviour disorder-60 years (27-91 years), eight with cognitive symptoms-69 years (62-89 years), eight with mild cognitive impairment-70.5 years (66-91 years), eight with parkinsonism symptoms-71 years (66-92 years), six with visual hallucinations-72 years (64-90 years), seven with dementia-75 years (67-92 years), six with fluctuations in cognition and/or arousal-76 years (68-92 years) and eight dead-76 years (71-94 years). Rapid eye movement sleep behaviour disorder preceded cognitive symptom onset in six cases by a median of 10 years (2-47 years) and mild cognitive impairment diagnosis by a median of 12 years (3-48 years). The mild cognitive impairment subtypes represented include: two with single domain non-amnestic mild cognitive impairment, three with multi-domain non-amnestic mild cognitive impairment, and three with multi-domain amnestic mild cognitive impairment. The cognitive domains most frequently affected were attention and executive functioning, and visuospatial functioning. Hippocampal volumes and the rate of hippocampal atrophy were, on average, within the normal range in the three cases who underwent magnetic resonance imaging, and the choline/creatine ratio was elevated in the two cases who underwent proton magnetic resonance spectroscopy when they were diagnosed as mild cognitive impairment. On autopsy, six had neocortical-predominant Lewy body disease and two had limbic-predominant Lewy body disease; only one had coexisting high-likelihood Alzheimers disease. These findings indicate that among Lewy body disease cases that pass through a mild cognitive impairment stage, any cognitive pattern or mild cognitive subtype is possible, with the attention/executive and visuospatial domains most frequently impaired. Hippocampal volume and proton magnetic resonance spectroscopy data were consistent with recent data in dementia with Lewy bodies. All cases with rapid eye movement sleep behaviour disorder and mild cognitive impairment were eventually shown to have autopsy-proven Lewy body disease, indicating that rapid eye movement sleep behaviour disorder plus mild cognitive impairment probably reflects brainstem and cerebral Lewy body disease.

Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: A population-based study

Rapid eye movement sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies), and Parkinson disease (PD). There are no data on such risks in a population‐based sample.

Neuropsychiatric symptoms in Alzheimer's disease: Past progress and anticipation of the future

Neuropsychiatric symptoms (NPS) in Alzheimers disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimers first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimers Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimers Research and Treatment (ISTAART). The NPS‐PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome‐specific synthetic reviews and recommendations prepared by NPS‐PIA workgroups on depression, apathy, sleep, agitation, and psychosis.