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1.  Hypothyroidism and Risk of Mild Cognitive Impairment in Elderly Persons - A Population Based Study 
JAMA neurology  2014;71(2):201-207.
Association of clinical and subclinical hypothyroidism with mild cognitive impairment (MCI) is not established.
To evaluate the association of clinical and subclinical hypothyroidism with MCI in a large population based cohort.
A cross-sectional, population-based study.
Olmsted County, Minnesota.
Randomly selected participants were aged 70 to 89 years on October 1, 2004, and were without documented prevalent dementia. A total of 2,050 participants were evaluated and underwent in-person interview, neurological evaluation and neuropsychological testing to assess performance in memory, attention/executive function, visuospatial, and language domains. Subjects were diagnosed by consensus as cognitively normal, MCI or dementia according to published criteria. Clinical and subclinical hypothyroidism was ascertained from a medical records-linkage system.
Association of clinical and subclinical hypothyroidism with MCI.
Among 1904 eligible participants, the frequency of MCI was 16% in 1450 subjects with normal thyroid function, 17% in 313 subjects with clinical hypothyroidism, and 18% in 141 subjects with subclinical hypothyroidism. After adjusting for covariates (age, gender, education, education years, sex, ApoE ε 4, depression, diabetes, hypertension, stroke, BMI and coronary artery disease) we found no significant association between clinical or subclinial hypothyroidism and MCI [OR 0.99 (95% CI 0.66–1.48) and OR 0.88 (95% CI 0.38–2.03) respectively]. No effect of gender interaction was seen on these effects. In stratified analysis, the odds of MCI with clinical and subclinical hypothyroidisn among males was 1.02 (95%CI, 0.57–1.82) and 1.29 (95%CI 0.68–2.44), among females was 1.04 (95% 0.66–1.66) and 0.86 (95% CI 0.37–2.02) respectively.
In this population based cohort of eldery, neither clinical nor subclinical hypothyrpodism was associated with MCI. Our findings need to be validated in a separate settings using the published criteria for MCI and also confirmed in a longitudinal study.
PMCID: PMC4136444  PMID: 24378475
2.  Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal 
Neurology  2014;82(4):317-325.
To estimate rates of progression from mild cognitive impairment (MCI) to dementia and of reversion from MCI to being cognitively normal (CN) in a population-based cohort.
Participants (n = 534, aged 70 years and older) enrolled in the prospective Mayo Clinic Study of Aging were evaluated at baseline and every 15 months to identify incident MCI or dementia.
Over a median follow-up of 5.1 years, 153 of 534 participants (28.7%) with prevalent or incident MCI progressed to dementia (71.3 per 1,000 person-years). The cumulative incidence of dementia was 5.4% at 1 year, 16.1% at 2, 23.4% at 3, 31.1% at 4, and 42.5% at 5 years. The risk of dementia was elevated in MCI cases (hazard ratio [HR] 23.2, p < 0.001) compared with CN subjects. Thirty-eight percent (n = 201) of MCI participants reverted to CN (175.0/1,000 person-years), but 65% subsequently developed MCI or dementia; the HR was 6.6 (p < 0.001) compared with CN subjects. The risk of reversion was reduced in subjects with an APOE ε4 allele (HR 0.53, p < 0.001), higher Clinical Dementia Rating Scale–Sum of Boxes (HR 0.56, p < 0.001), and poorer cognitive function (HR 0.56, p < 0.001). The risk was also reduced in subjects with amnestic MCI (HR 0.70, p = 0.02) and multidomain MCI (HR 0.61, p = 0.003).
MCI cases, including those who revert to CN, have a high risk of progressing to dementia. This suggests that diagnosis of MCI at any time has prognostic value.
PMCID: PMC3929198  PMID: 24353333
3.  Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study 
Neurology  2014;82(1):70-76.
We determined whether head trauma was associated with amyloid deposition and neurodegeneration among individuals who were cognitively normal (CN) or had mild cognitive impairment (MCI).
Participants included 448 CN individuals and 141 individuals with MCI from the Mayo Clinic Study of Aging who underwent Pittsburgh compound B (PiB)-PET, fluorodeoxyglucose-PET, and MRI. Head trauma was defined as a self-reported brain injury with at least momentary loss of consciousness or memory. Regression models examined whether head trauma was associated with each neuroimaging variable (assessed as continuous and dichotomous measures) in both CN and MCI participants, controlling for age and sex.
Among 448 CN individuals, 74 (17%) self-reported a head trauma. There was no difference in any neuroimaging measure between CN subjects with and without head trauma. Of 141 participants with MCI, 25 (18%) self-reported a head trauma. MCI participants with a head trauma had higher amyloid levels (by an average 0.36 standardized uptake value ratio units, p = 0.002).
Among individuals with MCI, but not CN individuals, self-reported head trauma with at least momentary loss of consciousness or memory was associated with greater amyloid deposition, suggesting that head trauma may be associated with Alzheimer disease–related neuropathology. Differences between CN individuals and individuals with MCI raise questions about the relevance of head injury–PET abnormality findings in those with MCI.
PMCID: PMC3873622  PMID: 24371306
4.  Association of diabetes with amnestic and nonamnestic mild cognitive impairment 
Type 2 diabetes may increase the risk of amnestic mild cognitive impairment (aMCI) through Alzheimer's disease (AD)-related and vascular pathology and may also increase the risk of nonamnestic MCI (naMCI) through vascular disease mechanisms. We examined the association of type 2 diabetes with mild cognitive impairment (MCI) and MCI subtype (aMCI and naMCI) overall and by sex.
Participants were Olmsted County, Minnesota residents (70 years and older) enrolled in a prospective, population-based study. At baseline and every 15 months thereafter, participants were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of normal cognition, MCI, and dementia by a consensus panel. Type 2 diabetes was ascertained from the medical records of participants at baseline.
Over a median 4.0 years of follow-up, 348 of 1450 subjects developed MCI. Type 2 diabetes was associated (hazard ratio [95% confidence interval]) with MCI (1.39 [1.08–1.79]), aMCI (1.58 [1.17–2.15]; multiple domain: 1.58 [1.01–2.47]; single domain: 1.49 [1.09–2.05]), and the hazard ratio for naMCI was elevated (1.37 [0.84–2.24]). Diabetes was strongly associated with multiple-domain aMCI in men (2.42 [1.31–4.48]) and an elevated risk of multiple domain naMCI in men (2.11 [0.70–6.33]), and with single domain naMCI in women (2.32 [1.04–5.20]).
Diabetes was associated with an increased risk of MCI in elderly persons. The association of diabetes with MCI may vary with subtype, number of domains, and sex. Prevention and control of diabetes may reduce the risk of MCI and Alzheimer's disease.
PMCID: PMC3830601  PMID: 23562428
Mild cognitive impairment; Risk factors; Type 2 diabetes; Incidence; Cohort studies; Population-based studies; Sex differences; Diabetic retinopathy; Diabetic neuropathy
5.  Association of Lifetime Intellectual Enrichment with Cognitive Decline in the Older Population 
JAMA neurology  2014;71(8):1017-1024.
Intellectual lifestyle enrichment throughout life is increasingly viewed as a protective strategy against commonly observed cognitive decline in the elderly.
To investigate the association of lifetime intellectual enrichment with baseline cognitive performance and rate of cognitive decline in a non-demented elderly population and to estimate difference (in years) associated with lifetime intellectual enrichment to the onset of cognitive impairment.
Prospective analysis of subjects enrolled in the Mayo Clinic Study of Aging (MCSA), a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We studied 1995 non-demented (1718 cognitively normal, 277 MCI) participants in MCSA who completed intellectual lifestyle measures at baseline and underwent at least one follow-up visit.
We studied the effect of lifetime intellectual enrichment by separating the variables into two non-overlapping principal components: education/occupation-score and mid/late-life cognitive activity measure based on self-report questionnaires. A global cognitive Z-score served as our summary cognition measure. We used linear mixed-effects models to investigate the associations of demographic and intellectual enrichment measures with global cognitive Z-score trajectories.
Baseline cognitive performance was lower in older subjects and in those with lower education/occupation, lower mid/late-life cognitive activity, apolipoprotein E4 (APOE) genotype, and in men. The interaction between the two intellectual enrichment measures was significant such that the beneficial effect of mid/late-life cognitive activity on baseline cognitive performance was reduced with increasing education/occupation. Only baseline age, mid/late-life cognitive activity, and APOE4 genotype were significantly associated with longitudinal change in cognitive performance from baseline. For APOE4 carriers with high lifetime intellectual enrichment (75th percentile of both education/occupation and mid/late-life cognitive activity), the onset of cognitive impairment was about 8.7 years later compared with low lifetime intellectual enrichment (25th percentile of both education/occupation and mid/late-life cognitive activity) in an 80 year old subject.
Higher levels of education/occupation were associated with higher levels of cognition. Higher levels of mid/late-life leisure activity were also associated with higher levels of cognition, but the slope of this relationship slightly increased over time. Lifetime intellectual enrichment might delay the onset of cognitive impairment and be used as a successful preventive intervention to reduce the impending dementia epidemic.
PMCID: PMC4266551  PMID: 25054282
Mayo Clinic proceedings  2013;88(11):10.1016/j.mayocp.2013.08.012.
To investigate the association of chronic obstructive pulmonary disease (COPD) with mild cognitive impairment (MCI) and MCI sub-types, amnestic MCI (a-MCI) and non-amnestic MCI (na-MCI), in a population-based study of elderly.
Patients and Methods
Participants included 1,927 individuals, aged 70 to 89 years, enrolled in the population-based, Mayo Clinic Study of Aging. Participants were evaluated with a nurse assessment, neurological evaluation, and neuropsychological testing and the diagnosis of MCI was made according to the standardized criteria by a consensus panel. COPD was identified by the review of medical records. The study was conducted from October 1, 2004, through July 31, 2007. The associations of COPD, and disease duration with MCI, and its subtypes were evaluated using logistic regression models adjusted for potential covariates.
Of 1,927 subjects, 288 had COPD (men vs women 17.9% vs 11.8%, p<0.001). As compared to subjects without COPD, the subjects with COPD had higher prevalence of MCI (27.1% vs 14.6%, p<0.001). The odds ratio (OR) of MCI was almost two times higher in subjects with COPD (OR =1.90, 95 %CI =1.35 – 2.65), with a similar effect in men and women. The OR for MCI increased from 1.67 (97% CI, 1.00 – 2.69) in subjects with COPD duration of ≤ 5 years to 2.08 (95% CI, 1.36 – 3.14) in subjects > 5 years.
This population-based study suggests that COPD is associated with increased odds of having MCI and its sub-types. There was a dose-response association with duration of COPD, after controlling for the potential covariates.
PMCID: PMC3875365  PMID: 24182702
7.  Diabetes and Elevated HbA1c levels are Associated with Brain Hypometabolism but not Amyloid Accumulation 
Dysfunctional insulin signaling may affect brain metabolism or amyloid deposition. We investigated the associations of type 2 diabetes with amyloid accumulation measured using 11C-Pittsburgh Compound B (PiB) and brain hypometabolism measured using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET).
We studied a sample of non-demented participants from the population-based Mayo Clinic Study of Aging. All subjects underwent MRI, amyloid PET and FDG PET. Alzheimer’s disease (AD) signature and region of interest (ROI) measures for PiB retention ratio and FDG ratio were measured. Diabetes was assessed from the Rochester Epidemiology Project medical records-linkage system.
Among 749 participants (median age 79.0 years; 56.5% male, 81.0% cognitively normal; 20.6% diabetics), FDG hypometabolism (FDG ratio < 1.31) in the AD signature meta-ROI was more common in diabetics (48.1%) than in non-diabetics (28.9%; p <0.001). The median FDG ratio was lower in diabetics vs. non-diabetics in the AD signature meta-ROI (1.32 vs. 1.40, p < 0.001), and in the angular (1.40 vs. 1.48, p < 0.001) and posterior cingulate gyri ROIs (1.63 vs. 1.72, p < 0.001). The odds ratio (OR [95% confidence interval]) for abnormal AD signature FDG hypometabolism was elevated (OR, 2.28 [1.56, 3.33]) in diabetics vs. non-diabetics after adjustment for age, sex, and education, and after additional adjustment for Apolipoprotein ε4 allele, glycemic level, and cognitive status (OR, 1.69 [1.10, 2.60]). However, AD signature PiB retention ratio was similar in diabetics vs. non-diabetics (OR, 1.03 [0.71, 1.51]; p = 0.87). In post-hoc analyses in non-diabetics, a 1% increase in HBA1c was associated with greater AD signature hypometabolism in cognitively normal subjects (OR, 1.93 [1.03, 3.62; p = 0.04]) and in the total cohort (OR 1.59 [0.92, 2.75; p = 0.10).
Diabetes and poor glycemic control in non-diabetics may enhance glucose hypometabolism in AD signature regions. These factors should be investigated in longitudinal studies for their role in detecting onset of symptoms in AD.
PMCID: PMC4011952  PMID: 24652830
Diabetes; cerebral glucose metabolism; FDG- and PiB-PET imaging; hemoglobin A1c; amyloid accumulation
8.  Neuropsychiatric symptoms in Alzheimer’s disease: Past progress and anticipation of the future 
Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s 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.
PMCID: PMC3766403  PMID: 23562430
Neuropsychiatric symptoms; Behavioral and psychological symptoms of dementia; Agitation/aggression; Sleep disorders; Depression; Apathy; Psychosis; Delusions; Hallucinations; Dementia; Alzheimer’s disease; Mild cognitive impairment; Mild Behavioral Impairment
9.  Risk factors for dementia with Lewy bodies 
Neurology  2013;81(9):833-840.
To determine the risk factors associated with dementia with Lewy bodies (DLB).
We identified 147 subjects with DLB and sampled 2 sex- and age-matched cognitively normal control subjects for each case. We also identified an unmatched comparison group of 236 subjects with Alzheimer disease (AD). We evaluated 19 candidate risk factors in the study cohort.
Compared with controls, subjects with DLB were more likely to have a history of anxiety (odds ratio; 95% confidence interval) (7.4; 3.5–16; p < 0.0001), depression (6.0; 3.7–9.5; p < 0.0001), stroke (2.8; 1.3–6.3; p = 0.01), a family history of Parkinson disease (PD) (4.6; 2.5–8.6; p < 0.0001), and carry APOE ε4 alleles (2.2; 1.5–3.3; p < 0.0001), but less likely to have had cancer (0.44; 0.27–0.70; p = 0.0006) or use caffeine (0.29; 0.14–0.57; p < 0.0001) with a similar trend for alcohol (0.65; 0.42–1.0; p = 0.0501). Compared with subjects with AD, subjects with DLB were younger (72.5 vs 74.9 years, p = 0.021) and more likely to be male (odds ratio; 95% confidence interval) (5.3; 3.3–8.5; p < 0.0001), have a history of depression (4.3; 2.4–7.5; p < 0.0001), be more educated (2.5; 1.1–5.6; p = 0.031), have a positive family history of PD (5.0; 2.4–10; p < 0.0001), have no APOE ε4 alleles (0.61; 0.40–0.93; p = 0.02), and to have had an oophorectomy before age 45 years (7.6; 1.5–39; p = 0.015).
DLB risk factors are an amalgam of those for AD and PD. Smoking and education, which have opposing risk effects on AD and PD, are not risk factors for DLB; however, depression and low caffeine intake, both risk factors for AD and PD, increase risk of DLB more strongly than in either.
PMCID: PMC3908463  PMID: 23892702
10.  Assessing the Temporal Relationship Between Cognition and Gait: Slow Gait Predicts Cognitive Decline in the Mayo Clinic Study of Aging 
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.
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.
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.
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.
PMCID: PMC3712358  PMID: 23250002
Gait speed; Cognition; Longitudinal; Cohort study.
11.  Criteria for Mild Cognitive Impairment Due to Alzheimer’s Disease in the Community 
Annals of neurology  2013;74(2):199-208.
The newly proposed National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known.
The Mayo Clinic Study of Aging (MCSA) is a population-based longitudinal study of non-demented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI 1) to assess the applicability of the criteria in both settings and to assess their outcomes.
In the MCSA, 14% and in ADNI 1 16% of subjects were biomarker negative. In addition, 14% of the MCSA and 12% of ADNI 1 subjects had evidence for amyloid deposition only, while 43% of MCSA and 55% of ADNI 1 subjects had evidence for amyloid deposition plus neurodegeneration (MRI atrophy, FDG PET hypometabolism or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model, e.g., 29% of MCSA subjects and 17% of the ADNI 1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone.
The NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings however, a sizeable proportion of subjects had conflicting biomarkers which may be very important and need to be explored.
PMCID: PMC3804562  PMID: 23686697
12.  Depressive Symptoms in Healthy Apolipoprotein E ε4 Carriers and Noncarriers: A Longitudinal Study 
The Journal of clinical psychiatry  2013;74(12):1256-1261.
To determine if symptoms of depression accelerate in cognitively normal apolipoprotein E (APOE) ε4 carriers as compared to noncarriers.
Six hundred thirty-three cognitively and functionally normal members of the Arizona APOE Cohort aged 21–86 years underwent neuropsychological testing every 1 to 2 years that included the Hamilton Depression Rating Scale, the Beck Depression Inventory, the Geriatric Depression Scale, and the Personality Assessment Inventory. We estimated the longitudinal change on these measures using mixed models that simultaneously modeled cross-sectional and longitudinal effects of age on depression scores by APOE status and the interaction between the two. We also estimated incident depression on the basis of accepted clinical cut-scores on depression measures and use of depression medications.
The mean length of follow-up was 7.7 years. Comparing APOE ε4 carriers with noncarriers revealed no significant longitudinal difference in the rate of change or slope of change on any depression scale or subscale. There was also no difference in incident depression or antidepressant drug use between the carrier and noncarrier groups.
These data fail to support a relationship between APOE genotype and longitudinal change in depression symptoms, suggesting that depression symptoms may not be intrinsic to the early preclinical phase of Alzheimer’s disease.
PMCID: PMC4097601  PMID: 24434095
Individuals with mild cognitive impairment (MCI) are at high risk of developing dementia and/or Alzheimer’s disease (AD). Among persons with MCI, depression and anxiety have been associated with an increased risk of incident dementia. We examined whether neuropsychiatric symptoms in MCI increased the risk of incident dementia (all-cause) and incident AD.
Longitudinal cohort study followed annually (median 1.58 years)
National Alzheimer’s Coordinating Center (NACC) database combining clinical data from 29 Alzheimer’s Disease Centers (ADCs).
1821 participants with MCI
1) Progression to dementia (all-cause) or AD, 2) Neuropsychiatric Inventory Questionnaire (NPI-Q), 3) Geriatric Depression Scale (GDS), 4) Clinical Dementia Rating Global Score and Sum of Boxes (CDR-Sum) 5) Mini-Mental State Exam (MMSE). The association of covariates with risk of incident dementia or AD was evaluated with hazard ratios (HR) determined by Cox proportional-hazards models adjusted for age, ethnicity, CDR-Sum, and MMSE.
527 participants (28.9%) progressed to dementia and 454 (24.9%) to AD. Baseline GDS>0 was associated with increased risk of incident dementia (HR 1.47, 95% CI 1.17, 1.84) and AD (HR 1.45, 95% CI 1.14, 1.83). Baseline NPI>0 was associated with increased risk of incident dementia (HR 1.37. 95% CI 1.12, 1.66) and AD (HR 1.35,95% CI 1.09, 1.66).
Neuropsychiatric symptoms in MCI are associated with significantly increased risk of incident dementia and AD. Neuropsychiatric symptoms may be among the earliest symptoms of preclinical stages of AD and targeting them therapeutically might delay transition to dementia.
PMCID: PMC3428504  PMID: 23567400
14.  A Prospective Study of Chronic Obstructive Pulmonary Disease and Risk of Mild Cognitive Impairment 
JAMA neurology  2014;71(5):581-588.
Previous studies suggest cross-sectional associations between a diagnosis of chronic obstructive pulmonary disease (COPD) and mild cognitive impairment (MCI). However, few studies have assessed whether COPD, a potentially modifiable factor, is associated with an increased risk of MCI and if the relation is specific to type of MCI.
To investigate whether a diagnosis of COPD, and COPD duration, is associated with an increased risk of incident MCI, and MCI subtypes (amnestic MCI (a-MCI) and non-amnestic MCI (na-MCI)).
Mayo Clinic Study on Aging, a prospective population-based cohort study.
Olmsted County, Minnesota.
The study included 1425 cognitively normal individuals aged 70–89 years, who were randomly selected from Olmsted County, MN, on October 1, 2004, using the medical records linkage system.
At baseline and every 15 months thereafter, participants were assessed with a nurse interview, neurological examination, and neuropsychological testing. A diagnosis of COPD was confirmed via medical record chart review. A baseline diagnosis of COPD and disease duration were examined as risk factors for MCI and MCI-subtypes using Cox proportional hazards models and adjusting for demographic variables and medical comorbidities, using age as the time scale.
Incident MCI, amnestic MCI, non-amnestic MCI
Of 1425 cognitively normal subjects at baseline, 370 developed incident MCI. The median duration of follow-up was 5.1 years (Interquartile Range [IQR], 3.8–5.4 years). COPD significantly increased the risk of na-MCI by 83% (HR 1.83; 95% CI, 1.04–3.23), but not any MCI or a-MCI in multivariate analyses. There was a dose-response relationship such that individuals with COPD duration of 5 years or longer at baseline had the greatest risk of both MCI (HR 1.58, 95% CI:1.04, 2.40) and na-MCI (HR 2.58, 95% CI:1.32–5.06).
COPD was associated with an increased risk of MCI, particularly na-MCI. There was a dose-response relationship between COPD duration and risk of MCI. These findings highlight the importance of COPD as a risk factor for MCI and may provide a substrate for early intervention to prevent or delay the onset and progression of MCI, particularly na-MCI.
PMCID: PMC4020948  PMID: 24637951
15.  Mild Cognitive Impairment in Older Adults 
Current psychiatry reports  2012;14(4):320-327.
Mild cognitive impairment (MCI) is the intermediate stage between the cognitive changes of normal aging and dementia. Individuals with MCI show cognitive impairment greater than expected for their age, but otherwise are functioning independently and do not meet the criteria for dementia. MCI is important because it constitutes a high risk group for dementia. Ideally, prevention strategies should target individuals who are not even symptomatic. Indeed, the field is now moving towards identification of asymptomatic individuals who have underlying Alzheimer’s disease (AD) pathology that can be detected by using biomarkers and neuroimaging technologies. To this effect, the Alzheimer’s Association and the National Institute on Aging have developed a new classification scheme that has categorized AD into a preclinical phase (research category), MCI due to AD, and dementia of Alzheimer’s type. On the other hand, there are also ongoing researches to understand high risk groups for non-Alzheimer’s dementia as well.
PMCID: PMC3963488  PMID: 22773365
Aging; Mild cognitive impairment; Neuropsychiatric symptoms; Dementia; Dementia of Alzheimer’s type; Cognitive Impairment No dementia; Benign and malignant forgetfulness; Age-associated memory impairment; Age-associated cognitive decline; Mild neurocognitive decline; Age-associated memory impairment; Questionable dementia; Asymptomatic Alzheimer’s disease
16.  Cardiac Disease Increases Risk of Non-amnestic Mild Cognitive Impairment: Stronger impact in women 
JAMA neurology  2013;70(3):374-382.
Non-amnestic mild cognitive impairment (naMCI), a putative precursor of vascular and other non-Alzheimer’s disease dementias, is hypothesized to have a vascular etiology. We investigated the association of cardiac disease with amnestic (aMCI) and non-amnestic (naMCI) MCI.
A prospective, population-based, cohort study with a median 4.0 years of follow-up.
Olmsted County, Minnesota.
Participants were evaluated at baseline and every 15 months using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing. A diagnosis of normal cognition, MCI, or dementia was made by consensus. Cardiac disease at baseline was assessed from the participant’s medical records.
Main outcome measures
Incident MCI, aMCI, naMCI.
Among 1,450 subjects free of MCI or dementia at baseline, 366 developed MCI. Cardiac disease was associated with an increased risk of naMCI (hazard ratio [HR] 95% confidence interval; 1.77 [1.16–2.72]). However, the association varied by sex (P for interaction = .02). Cardiac disease was associated with an increased risk of naMCI (HR, 3.07 [1.58–5.99]) in women, but not in men (HR, 1.16 [0.68–1.99]. Cardiac disease was not associated with any MCI or aMCI.
Cardiac disease is an independent risk factor for naMCI, within sex comparisons showed a stronger association in women. Prevention and management of cardiac disease and vascular risk factors may reduce the risk of naMCI.
PMCID: PMC3734560  PMID: 23358884
17.  Recognition of Facial Emotional Expression in Amnestic Mild Cognitive Impairment 
We examined whether recognition of facial emotional expression would be affected in amnestic mild cognitive impairment (aMCI). A total of 50 elderly persons met the initial inclusion criteria, 10 were subsequently excluded (Geriatric Depression Score >5). 22 subjects were classified with aMCI based on published criteria (single domain aMCI [SD-aMCI], n = 10; multiple domain aMCI [MD-aMCI], n = 12); 18 subjects were cognitively normal. All underwent standard neurological and neuropsychological evaluations as well as tests of facial emotion recognition (FER) and famous faces identification (FFI). Among normal controls, FFI was negatively correlated with MMSE and positively correlated with executive function. Among patients with aMCI, FER was correlated with attention/speed of processing. No other correlations were significant. In a multinomial logistic regression model adjusted for age, sex, and education, a poorer score on FER, but not on FFI, was associated with greater odds of being classified as MD-aMCI (odds ratio [OR], 3.82; 95% confidence interval [CI], 1.05–13.91; p = 0.042). This association was not explained by memory or global cognitive score. There was no association between FER or FFI and SD-aMCI (OR, 1.13; 95% CI, 0.36–3.57; p = 0.836). Therefore, FER, but not FFI, may be impaired in MD-aMCI. This implies that in MD-aMCI, the tasks of FER and FFI may involve segregated neurocognitive networks.
PMCID: PMC3918473  PMID: 22954669
assessment of cognitive disorders/dementia; cognitive aging; emotion; mild cognitive impairment; neuropsychiatric symptoms
18.  A purpose “driven” life: Is it potentially neuroprotective? 
Archives of neurology  2010;67(8):1010-1011.
PMCID: PMC3918477  PMID: 20697053
19.  Successful Aging: Definitions and Prediction of Longevity and Conversion to Mild Cognitive Impairment 
To examine alternative models of defining and characterizing successful aging.
A retrospective cohort study
Olmsted County, MN.
560 community-dwelling non-demented adults, aged 65 years and older.
Three models were developed. Each model examined subtests in four cognitive domains: memory, attention/executive function, language, and visual-spatial skills. A composite domain score was generated for each of the four domains. In Model 1, a global z-score was further generated from the four cognitive domains, and subjects with mean global z-score in the top 10% were classified as “successful agers” whereas those in the remaining 90% were classified as “typical agers”. In Model 2, subjects with all 4 domain scores above the 50th percentile were classified as “successful agers.” In Model 3, a primary neuropsychological variable was selected from each domain, and subjects whose score remained above minus 1 SD compared to norms for young adults were labeled successful agers. Validation tests were conducted to determine the ability of each model to predict survival and conversion to mild cognitive impairment (MCI).
Model 1 showed 65% lower mortality in successful agers compared to typical agers, and also a 25% lower conversion rate to MCI.
Model 1 was most strongly associated with longevity and cognitive decline; as such, it can be useful in investigating various predictors of successful aging, including plasma level, APOE genotype, and neuroimaging measurements.
PMCID: PMC3918503  PMID: 21606901
successful aging; optimal aging; longevity; cognitive decline
20.  Caloric Intake, Aging, and Mild Cognitive Impairment: A Population-Based Study 
In a population-based case-control study, we examined whether moderate and high caloric intakes are differentially associated with the odds of having mild cognitive impairment (MCI). The sample was derived from the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Non-demented study participants aged 70–92 years (1,072 cognitively normal persons and 161 subjects with MCI) reported their caloric consumption within 1 year of the date of interview by completing a Food Frequency Questionnaire. An expert consensus panel classified each subject as either cognitively normal or having MCI based on published criteria. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age, sex, education, depression, medical comorbidity, and body mass index. We also conducted stratified analyses by apolipoprotein E ε4 genotype status. Analyses were conducted in tertiles of caloric intake: 600 to <1,526 kcals per day (reference group); 1,526 to 2,143 kcals per day (moderate caloric intake group); and >2,143 kcals per day (high caloric intake group). In the primary analysis, there was no significant difference between the moderate caloric intake group and the reference group (OR 0.87, 95% CI 0.53–1.42, p = 0.57). However, high caloric intake was associated with a nearly two-fold increased odds of having MCI (OR 1.96, 95% CI 1.26–3.06, p = 0.003) as compared to the reference group. Therefore, high caloric intake was associated with MCI but not moderate caloric intake. This association is not necessarily a cause-effect relationship.
PMCID: PMC3578975  PMID: 23234878
aging; APOE ε4 genotype; caloric intake; mild cognitive impairment; population-based
21.  Indicators of amyloid burden in a population-based study of cognitively normal elderly 
Neurology  2012;79(15):1570-1577.
Secondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs.
A total of 483 cognitively normal (CN) individuals, aged 70–92 years, from the population-based Mayo Clinic Study of Aging, underwent Pittsburgh compound B (PiB)–PET imaging. Logistic regression determined whether age, sex, APOE genotype, family history, or cognitive performance was associated with odds of a PiB retention ratio >1.4 and >1.5. Area under the receiver operating characteristic curve (AUROC) evaluated the discrimination between PiB-positive and -negative subjects. For each characteristic, we determined the number needed to screen in each age group (70–79 and 80–89) to identify 100 participants with PiB >1.4 or >1.5.
A total of 211 (44%) individuals had PiB >1.4 and 151 (31%) >1.5. In univariate and multivariate models, discrimination was modest (AUROC ∼0.6–0.7). Multivariately, age and APOE best predicted odds of PiB >1.4 and >1.5. Subjective memory complaints were similar to cognitive test performance in predicting PiB >1.5. Indicators of PiB positivity varied with age. Screening APOE ε4 carriers alone reduced the number needed to screen to enroll 100 subjects with PIB >1.5 by 48% in persons aged 70–79 and 33% in those aged 80–89.
Age and APOE genotype are useful predictors of the likelihood of significant amyloid accumulation, but discrimination is modest. Nonetheless, these results suggest that inexpensive and noninvasive measures could significantly reduce the number of CN individuals needed to screen to enroll a given number of amyloid-positive subjects.
PMCID: PMC3475629  PMID: 22972644
22.  Mild Cognitive Impairment: A Subset of Minor Neurocognitive Disorder? 
The field of aging and dementia is increasingly preoccupied with identification of the asymptomatic phenotype of Alzheimer disease (AD). A quick glance at historical landmarks in the field indicates that the agenda and priorities of the field have evolved over time. The initial focus of research was dementia. In the late 1980s and 1990s, dementia researchers reported that some elderly persons are neither demented nor cognitively normal. Experts coined various terms to describe the gray zone between normal cognitive aging and dementia, including mild cognitive impairment (MCI). Advances made in epidemiologic, neuroimaging, and biomarkers research emboldened the field to seriously pursue the avenue of identifying asymptomatic AD. Accurate “diagnosis” of the phenotype has also evolved over time. For example, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Task Force is contemplating to use the terms major and minor neurocognitive disorders. The six papers published in this edition of the journal pertain to MCI which is envisaged to become a subset of minor neurocognitive disorders. These six studies have three points in common: 1) All of them are observational studies; 2) They have generated useful hypotheses or made important observations without necessarily relying on expensive biomarkers; and 3) Based on the new National Institute on Aging and the Alzheimer’s Association guidelines, all the studies addressed the symptomatic phase of AD. Questionnaire-based observational studies will continue to be useful until such a time that validated biomarkers, be it chemical or neuroimaging, become widely available and reasonably affordable.
PMCID: PMC3644585  PMID: 22935926
23.  Longitudinal Stability of Subsyndromal Symptoms of Depression in Individuals with Mild Cognitive Impairment: Relationship to Conversion to Dementia after Three Years 
To evaluate the degree to which longitudinal stability of subsyndromal symptoms of depression (SSD) is associated with conversion to dementia in patients with Mild Cognitive Impairment (MCI).
Data from 405 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed. Participants were evaluated at baseline and 12 month intervals over three years. Participants were designated as MCI Converters if dementia was diagnosed within 3 years or as Cognitively Stable MCI if dementia was not diagnosed during this interval. SSD were evaluated utilizing the 15-item Geriatric Depression Scale (GDS). Endorsement of specific SSD at baseline and the stability of SSD over 36 months were compared between the two MCI groups.
Baseline symptom endorsement and stability of total GDS scores did not differentiate MCI groups. Worsening of 4 individual items from the GDS over time (memory problems, feelings of helplessness, loss of interest, and preference for staying at home) differentiated MCI converters from cognitively stable MCI (p <0.05 for all). However, only increased endorsement of memory symptoms over time was associated with progression to dementia after controlling for other clinical variables (p=0.05).
SSD in MCI participants largely consist of cognitive symptoms and activity limitations and the stability of SSD over time differentiated the MCI groups better than baseline endorsement of symptoms. However, the only significant predictor of conversion to dementia was increased endorsement of memory problems, which likely represents insight into cognitive problems more than depressive symptomatology in MCI individuals.
PMCID: PMC3685477  PMID: 21744390
subsyndromal depression; longitudinal stability; mild cognitive impairment; insight; dementia
Our objective was to document the clinical and imaging features of Othello's syndrome (delusional jealousy).
The study design was a retrospective case series of 105 patients with Othello's syndrome that were identified by using the Electronic Medical Record system of Mayo Clinic.
The average age at onset of Othello's syndrome was 68 (25–94) years with 61.9% of patients being male. Othello's syndrome was most commonly associated with a neurological disorder (73/105) compared with psychiatric disorders (32/105). Of the patients with a neurological disorder, 76.7% had a neurodegenerative disorder. Seven of eight patients with a structural lesion associated with Othello's syndrome had right frontal lobe pathology. Voxel-based morphometry showed greater grey matter loss predominantly in the dorsolateral frontal lobes in the neurodegenerative patients with Othello's compared to matched patients with neurodegenerative disorders without Othello's syndrome. Treatment success was notable for patients with dopamine agonist induced Othello's syndrome in which all six patients had improvement in symptoms following decrease in medication.
This study demonstrates that Othello's syndrome occurs most frequently with neurological disorders. This delusion appears to be associated with dysfunction of the frontal lobes, especially right frontal lobe.
PMCID: PMC3144984  PMID: 21518145
Othello's Syndrome; Right frontal lobe; Delusions; Dementia
25.  Probable REM Sleep Behavior Disorder Increases Risk for Mild Cognitive Impairment and Parkinson’s Disease: A Population-Based Study 
Annals of Neurology  2012;71(1):49-56.
REM 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) or Parkinson’s disease (PD). There is no data on such risk in a population-based sample.
Cognitively normal subjects aged 70–89 in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15 month intervals. In a Cox Proportional Hazards Model, we measured the risk of developing MCI, dementia, PD among the exposed (pRBD+) and unexposed (pRBD−) cohorts.
Forty-four subjects with pRBD+ at enrollment (median duration of pRBD features was 7.5 years), and 607 pRBD− subjects, were followed prospectively for a median of 3.8 years. Fourteen of the pRBD+ subjects developed MCI and one developed PD (15/44=34% developed MCI / PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD+ subjects were at increased risk of MCI / PD [Hazard Ratio (HR) 2.2, 95% Confidence Interval (95%CI) 1.3 – 3.9; p=0.005]. Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI / PD (HR 1.05 per 10 years, 95%CI 0.84 – 1.3; p=0.68).
In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI / PD over four years.
PMCID: PMC3270692  PMID: 22275251
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism; synuclein

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