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1.  Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal 
Neurology  2014;82(4):317-325.
Objective:
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.
Methods:
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.
Results:
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).
Conclusions:
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.
doi:10.1212/WNL.0000000000000055
PMCID: PMC3929198  PMID: 24353333
2.  Association of diabetes with amnestic and nonamnestic mild cognitive impairment 
Background
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.
Methods
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.
Results
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]).
Conclusions
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.
doi:10.1016/j.jalz.2013.01.001
PMCID: PMC3830601  PMID: 23562428
Mild cognitive impairment; Risk factors; Type 2 diabetes; Incidence; Cohort studies; Population-based studies; Sex differences; Diabetic retinopathy; Diabetic neuropathy
3.  Practice effects and longitudinal cognitive change in normal aging vs. incident mild cognitive impairment and dementia in the Mayo Clinic Study of Aging 
The Clinical neuropsychologist  2013;27(8):10.1080/13854046.2013.836567.
The objective of this study was to examine practice effects and longitudinal cognitive change in a population based cohort classified as clinically normal at their initial evaluation. We examined 1390 individuals with a median age of 78.1 years and re-evaluated them up to four times at approximate 15 month intervals, with an average follow-up time of five years. Of the 1390 participants, 947 (69%) individuals remained cognitively normal, 397 (29%) progressed to mild cognitive impairment (MCI), and 46 (3%) to dementia. The stable normal group showed an initial practice effect in all domains which was sustained in memory and visuospatial reasoning. There was only a slight decline in attention and language after visit 3. We combined individuals with incident MCI and dementia to form one group representing those who declined. The incident MCI/dementia group showed an unexpected practice effect in memory from baseline to visit 2, with a significant decline thereafter. This group did not demonstrate practice effects in any other domain and showed a downward trajectory in all domains at each evaluation. Modeling cognitive change in an epidemiologic sample may serve as a useful benchmark for evaluating cognitive change in future intervention studies.
doi:10.1080/13854046.2013.836567
PMCID: PMC3869900  PMID: 24041121
Cognition; memory; practice effects; mild cognitive impairment; Alzheimer’s disease
4.  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.
doi:10.1093/gerona/gls256
PMCID: PMC3712358  PMID: 23250002
Gait speed; Cognition; Longitudinal; Cohort study.
5.  Criteria for Mild Cognitive Impairment Due to Alzheimer’s Disease in the Community 
Annals of neurology  2013;74(2):199-208.
Objective
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.
Methods
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.
Results
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.
Interpretation
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.
doi:10.1002/ana.23931
PMCID: PMC3804562  PMID: 23686697
6.  MRI and MRS predictors of mild cognitive impairment in a population-based sample 
Neurology  2013;81(2):126-133.
Objective:
To investigate MRI and proton magnetic resonance spectroscopy (MRS) predictors of mild cognitive impairment (MCI) in cognitively normal older adults.
Methods:
Subjects were cognitively normal older adults (n = 1,156) who participated in the population-based Mayo Clinic Study of Aging MRI/MRS study from August 2005 to December 2010 and had at least one annual clinical follow-up. Single-voxel MRS was performed from the posterior cingulate gyri, and hippocampal volumes and white matter hyperintensity volumes were quantified using automated methods. Brain infarcts were assessed on MRI. Cox proportional hazards regression, with age as the time scale, was used to assess the effect of MRI and MRS markers on the risk of progression from cognitively normal to MCI. Linear mixed-effects models were used to assess the effect of MRI and MRS markers on cognitive decline.
Results:
After a median follow-up of 2.8 years, 214 participants had progressed to MCI or dementia (estimated incidence rate = 6.1% per year; 95% confidence interval = 5.3%–7.0%). In univariable modeling, hippocampal volume, white matter hyperintensity volume, and N-acetylaspartate/myo-inositol were significant predictors of MCI in cognitively normal older adults. In multivariable modeling, only decreased hippocampal volume and N-acetylaspartate/myo-inositol were independent predictors of MCI. These MRI/MRS predictors of MCI as well as infarcts were associated with cognitive decline (p < 0.05).
Conclusion:
Quantitative MRI and MRS markers predict progression to MCI and cognitive decline in cognitively normal older adults. MRS may contribute to the assessment of preclinical dementia pathologies by capturing neurodegenerative changes that are not detected by hippocampal volumetry.
doi:10.1212/WNL.0b013e31829a3329
PMCID: PMC3770173  PMID: 23761624
7.  Cardiac Disease Increases Risk of Non-amnestic Mild Cognitive Impairment: Stronger impact in women 
JAMA neurology  2013;70(3):374-382.
Objective
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.
Design
A prospective, population-based, cohort study with a median 4.0 years of follow-up.
Setting
Olmsted County, Minnesota.
Participants
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.
Results
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.
Conclusion
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.
doi:10.1001/jamaneurol.2013.607
PMCID: PMC3734560  PMID: 23358884
8.  What is the quality of life in the oldest old? 
International psychogeriatrics / IPA  2011;23(6):1003-1010.
Background
Maintaining and improving quality of life has become a major focus in geriatric medicine, but the oldest old have received limited attention in clinical investigations. We aimed to investigate the relationship between self-perceived and caregiver-perceived quality of life (QOL), cognitive functioning, and depressive symptoms in the oldest old.
Methods
This IRB-approved prospective study recruited community dwellers aged 90–99 years old. Collected data included neurological evaluation, DSM III-R criteria for dementia, Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), Geriatric Depression Scale (GDS), Record of Independent Living (ROIL), and QOL assessment using the Linear Analogue Self Assessment (LASA).
Results
Data on 144 subjects (56 cognitively normal (normal), 13 mild cognitive impairment (MCI), 41 dementia (DEM), 34 dementia with stroke and parkinsonism (DEMSP)) over a three-year period were analyzed. Mean ages ranged from 93 to 94 years, and the majority were female with at least high school education. Overall functional ability was higher in groups without dementia (p < 0.0001). All subjects reported high overall QOL (range 6.76–8.3 out of 10), regardless of cognitive functioning. However, caregivers perceived the subjects’ overall QOL to be lower with increasing severity of cognitive impairment (p < 0.0001). Lower GDS scores correlate with higher self-perceived overall QOL (ρ = −0.38, p < 0.0001).
Conclusions
In our community sample of the oldest old, there was a fairly high level of overall QOL, whether or not cognitive impairment exists. Individuals perceive their QOL better than caregivers do, and the difference in subjects’ and caregivers’ perception is more pronounced for the groups with dementia. QOL is more strongly correlated with depressive symptoms than with dementia severity.
doi:10.1017/S1041610210002462
PMCID: PMC3924179  PMID: 21281556
geriatric; well being; cognition; depression; dementia; stroke; parkinsonism; MCI
9.  Successful Aging: Definitions and Prediction of Longevity and Conversion to Mild Cognitive Impairment 
Objectives
To examine alternative models of defining and characterizing successful aging.
Design
A retrospective cohort study
Setting
Olmsted County, MN.
Participants
560 community-dwelling non-demented adults, aged 65 years and older.
Measurements
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).
Results
Model 1 showed 65% lower mortality in successful agers compared to typical agers, and also a 25% lower conversion rate to MCI.
Conclusion
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.
doi:10.1097/JGP.0b013e3181f17ec9
PMCID: PMC3918503  PMID: 21606901
successful aging; optimal aging; longevity; cognitive decline
10.  An Operational Approach to NIA-AA Criteria for Preclinical Alzheimer’s Disease 
Annals of neurology  2012;71(6):765-775.
Objective
A workgroup commissioned by the Alzheimer’s Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer’s disease (AD). We performed a preliminary assessment of these guidelines.
Methods
We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis and 18fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cut-points. A group of 450 cognitively normal (CN) subjects from a population based sample was used to develop cognitive cut-points and to assess population frequencies of the different preclinical AD stages using different cut-point criteria.
Results
The new criteria subdivide the preclinical phase of AD into stages 1–3. To classify our CN subjects, two additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected Non-AD Pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cut-points corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0; 16% stage 1; 12 % stage 2; 3% stage 3; and 23% SNAP.
Interpretation
This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1–3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving just 3% unclassified. Future longitudinal validation of the criteria will be important.
doi:10.1002/ana.22628
PMCID: PMC3586223  PMID: 22488240
11.  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.
Objective
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.
Methods
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.
Results
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).
Interpretation
In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI / PD over four years.
doi:10.1002/ana.22655
PMCID: PMC3270692  PMID: 22275251
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism; synuclein
12.  Engaging in Cognitive Activities, Aging and Mild Cognitive Impairment: A Population-Based Study 
We investigated whether engaging in cognitive activities is associated with mild cognitive impairment (MCI) in a cross-sectional study derived from an ongoing population-based study of normal cognitive aging and MCI in Olmsted County, Minnesota. A random sample of 1321 non-demented study participants ages 70 to 89 (n = 1124 cognitively normal persons and n = 197 subjects with MCI) was interviewed about the frequency of cognitive activities carried out in late life (within one year of the date of interview). Computer activities [OR (95% CI) = 0.50 (0.36, 0.71); p < .0001)], craft activities such as knitting, quilting, etc. [0.66 (0.47, 0.93); p = 0.019)], playing games [0.65 (0.47, 0.90); p = 0.010)], and reading books [0.67 (0.49, 0.94); p = 0.019)] were associated with decreased odds of having MCI. Social activities such as traveling were marginally significant [0.71 (0.51, 1.00); p = 0.050)]. Even though the point estimates for reading magazines, playing music, artistic activities, and group activities were associated with reduced odds of having MCI, none reached statistical significance. We could not expect to observe any difference between the two groups on the variable of reading newspapers since almost identical proportions of the two groups (97.4% of normals and 97.5% of the MCI group) were engaged in reading newspapers on a regular basis.
doi:10.1176/appi.neuropsych.23.2.149
PMCID: PMC3204924  PMID: 21677242
cognitive activities; aging; mild cognitive impairment
13.  Predicting functional decline in behavioural variant frontotemporal dementia 
Brain  2011;134(2):432-448.
Behavioural variant frontotemporal dementia is characterized by a change in comportment. It is associated with considerable functional decline over the course of the illness albeit with sometimes dramatic variability among patients. It is unknown whether any baseline features, or combination of features, could predict rate of functional decline in behavioural variant frontotemporal dementia. The aim of this study was to investigate the effects of different baseline clinical, neuropsychological, neuropsychiatric, genetic and anatomic predictors on the rate of functional decline as measured by the Clinical Dementia Rating Sum of Boxes scale. We identified 86 subjects with behavioural variant frontotemporal dementia that had multiple serial Clinical Dementia Rating Sum of Boxes assessments (mean 4, range 2–18). Atlas-based parcellation was used to generate volumes for specific regions of interest at baseline. Volumes were utilized to classify subjects into different anatomical subtypes using the advanced statistical technique of cluster analysis and were assessed as predictor variables. Composite scores were generated for the neuropsychological domains of executive, language, memory and visuospatial function. Behaviours from the brief questionnaire form of the Neuropsychiatric Inventory were assessed. Linear mixed-effects regression modelling was used to determine which baseline features predict rate of future functional decline. Rates of functional decline differed across the anatomical subtypes of behavioural variant frontotemporal dementia, with faster rates observed in the frontal dominant and frontotemporal subtypes. In addition, subjects with poorer performance on neuropsychological tests of executive, language and visuospatial function, less disinhibition, agitation/aggression and night-time behaviours at presentation, and smaller medial, lateral and orbital frontal lobe volumes showed faster rates of decline. In many instances, the effect of the predictor variables observed across all subjects was also preserved within anatomical subtypes. Furthermore, some of the predictor variables improved our prediction of rate of functional decline after anatomical subtype was taken into account. In particular, age at onset was a highly significant predictor but only after adjusting for subtype. We also found that although some predictor variables, for example gender, Mini-Mental State Examination score, and apathy/indifference, did not affect the rate of functional decline; these variables were associated with the actual Clinical Dementia Rating Sum of Boxes score estimated for any given time-point. These findings suggest that in behavioural variant frontotemporal dementia, rate of functional decline is driven by the combination of anatomical pattern of atrophy, age at onset, and neuropsychiatric characteristics of the subject at baseline.
doi:10.1093/brain/awq348
PMCID: PMC3030765  PMID: 21252111
frontotemporal dementia; behaviour; functional decline; brain volumes; mixed effects models
14.  Prominent Phenotypic Variability Associated with Mutations in Progranulin 
Neurobiology of aging  2007;30(5):739-751.
Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer’s disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.
doi:10.1016/j.neurobiolaging.2007.08.022
PMCID: PMC3164546  PMID: 17949857
Frontotemporal dementia; FTDP-17; Progranulin; PGRN; MRI
15.  Vegetables, Unsaturated Fats, Moderate Alcohol Intake, and Mild Cognitive Impairment 
Background/Aims
To investigate associations of the Mediterranean diet (MeDi) components and the MeDi score with mild cognitive impairment (MCI).
Methods
Participants (aged 70–89 years) were clinically evaluated to assess MCI and dementia, and completed a 128-item food frequency questionnaire.
Results
163 of 1,233 nondemented persons had MCI. The odds ratio of MCI was reduced for high vegetable intake [0.66 (95% CI = 0.44–0.99), p = 0.05] and for high mono-plus polyunsaturated fatty acid to saturated fatty acid ratio [0.52 (95% CI = 0.33–0.81), p = 0.007], adjusted for confounders. The risk of incident MCI or dementia was reduced in subjects with a high MeDi score [hazard ratio = 0.75 (95% CI = 0.46–1.21), p = 0.24].
Conclusion
Vegetables, unsaturated fats, and a high MeDi score may be beneficial to cognitive function.
doi:10.1159/000305099
PMCID: PMC2889256  PMID: 20502015
Mild cognitive impairment; Dietary intake; Moderate alcohol intake; Unsaturated fatty acids; Mediterranean diet; Longitudinal; Prevalence studies; Incidence studies; Population-based
16.  Mild Cognitive Impairment: Ten Years Later 
Archives of neurology  2009;66(12):1447-1455.
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’s disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiological, 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.
doi:10.1001/archneurol.2009.266
PMCID: PMC3081688  PMID: 20008648
Mild cognitive impairment; Alzheimer’s disease; Imaging; Cognitive decline
17.  Metabolic Syndrome, Inflammation, and Non-Amnestic Mild Cognitive Impairment in Older Persons: A Population-Based Study 
The metabolic syndrome (MetS) is more strongly associated with cognitive impairment in the presence of inflammation. This suggests that the association of MetS with mild cognitive impairment (MCI) may vary with the etiology and the subtype of MCI. This study investigated the association between MetS with or without inflammation and MCI (amnestic [a-MCI] and non-amnestic [na-MCI]). We studied a randomly selected sample of 1969 subjects (ages 70 to 89 years) from Olmsted County, MN, using the Clinical Dementia Rating Scale, a neurological evaluation, and neuropsychological testing. Data for participants were reviewed for a diagnosis of normal cognition, MCI, or dementia. Clinical components of MetS were ascertained by interview and confirmed from the medical records; biochemical measurements were assayed from a blood draw. We compared 88 na-MCI cases and 241 a-MCI cases with 1640 cognitively normal subjects. MetS was not associated with either na-MCI or a-MCI. High C-reactive protein (CRP highest tertile vs lowest tertile) was associated with na-MCI (odds ratio [OR] = 1.85; 95% confidence interval [CI] = 1.05, 3.24) but not with a-MCI, after adjusting for sex, age, and years of education. The combination of MetS and high CRP (compared to no Mets and lowest CRP tertile) was associated with na-MCI (OR = 2.31; 95% CI = 1.07, 5.00), but not with a-MCI (OR = 0.96; 95% CI = 0.59, 1.54). The combined presence of MetS and high levels of inflammation is associated with na-MCI in this elderly cohort, and suggests etiologic differences in MCI subtypes.
doi:10.1097/WAD.0b013e3181a4485c
PMCID: PMC2837096  PMID: 19568151
metabolic syndrome; insulin resistance; mild cognitive impairment; C-reactive protein; inflammation; cross-sectional study
18.  Physical Exercise and Mild Cognitive Impairment: A Population-Based Study 
Archives of neurology  2010;67(1):80-86.
Objective
Physical exercise was found to be associated with a decreased risk of dementia and Alzheimer disease. We investigated whether physical exercise is also associated with 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, USA.
Participants
1324 non-demented subjects who completed a questionnaire on physical exercise.
Main Outcome Measures
An expert consensus panel classified each subject as either cognitively normal or affected by MCI using information from a Clinical Dementia Rating Scale administered to the subject and to an informant, a neurological evaluation, and neuropsychological testing to assess 4 cognitive domains.
Results
We compared the frequency of physical exercise in 198 subjects with MCI to the frequency in 1126 cognitively normal subjects and adjusted analyses for age, sex, years of education, medical comorbidity, and depression. The odds ratio (OR) for any frequency of moderate-intensity exercise was 0.61 (95% confidence interval [CI], 0.43–0.88; P=.008) for exercise in midlife (aged 50–65 years), and 0.68 (95% CI, 0.49–0.93; P=.02) for exercise in late life. The findings were consistent in men and women. Light exercise and vigorous exercise were not significantly associated with MCI.
Conclusions
In this population-based case-control study, any frequency of moderate-intensity exercise carried out in either midlife or late life was associated with a reduced OR of MCI.
doi:10.1001/archneurol.2009.297
PMCID: PMC2919839  PMID: 20065133
19.  Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study 
Brain  2009;132(11):2932-2946.
The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Ward's clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one subtype showing grey matter loss in the frontal lobes as well as loss of the temporal lobes (frontotemporal subtype) and the other subtype showing loss relatively restricted to the frontal lobes (frontal-dominant subtype). These four subtypes differed on clinical measures of executive function, episodic memory and confrontation naming. There were also associations between the four subtypes and genetic or pathological diagnoses which were obtained in 48% of the cohort. The clusters did not differ in behavioural severity as measured by the Neuropsychiatric Inventory; supporting the original classification of the behavioural variant of frontotemporal dementia in these subjects. Our findings suggest behavioural variant of frontotemporal dementia can therefore be subdivided into four different anatomical subtypes.
doi:10.1093/brain/awp232
PMCID: PMC2768663  PMID: 19762452
behavioural variant frontotemporal dementia; atrophy; cluster analysis; voxel-based morphometry
20.  COMPARATIVE DIAGNOSTIC UTILITY OF DIFFERENT MR MODALITIES IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE 
This study compares diagnostic accuracy of magnetic resonance (MR)-based hippocampal volumetry, single voxel (SV) 1H MR Spectroscopy (MRS) and MR diffusion weighted imaging (DWI) measurements in discriminating patients with amnestic mild cognitive impairment (MCI), Alzheimer’s disease (AD) and normally aging elderly. Sixty-one normally aging elderly, 24 MCI, and 22 AD patients underwent MR-based hippocampal volumetry, 1H MRS, and DWI. 1H MRS voxels were placed over both of the posterior cingulate gyri and N-acetyl aspartate (NAA) / creatine (Cr), myoinositol (MI) /Cr and NAA /MI ratios were obtained. Apparent diffusion coefficient (ADC) maps were derived from DWI and hippocampal borders were traced to measure hippocampal ADC. At 80% specificity, the most sensitive single measurement to discriminate MCI (79 %) and AD (86 %) from controls was hippocampal volumes. The most sensitive single measurement to discriminate AD from MCI was posterior cingulate gyrus NAA /Cr (67 %). At high specificity (>85 –90%) combinations of MR measures had superior diagnostic sensitivity compared to any single MR measurement for the AD vs. control and control vs. MCI comparisons. The MR measures that best discriminate more from less affected individuals along the cognitive continuum from normal to AD vary with disease severity. Selection of imaging measures used for clinical assessment or monitoring efficiency of therapeutic intervention should be tailored to the clinical stage of the disease.
PMCID: PMC2796574  PMID: 12411762
Alzheimer’s disease; mild cognitive impairment; 1H MRS; diffusion weighted imaging; hippocampal volumetry; MRI
21.  Abnormal TDP-43 immunoreactivity in AD modifies clinicopathological and radiological phenotype 
Neurology  2008;70(19 Pt 2):1850-1857.
Background
TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately 1/4 of subjects with pathologically confirmed Alzheimer's disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine if subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging or pathological features compared to subjects with AD without abTDP-43 immunoreactivity.
Methods
Eighty-four subjects were identified that had a pathological diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data was collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared to age and gender matched controls.
Results
Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death, and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared to controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathological predictor of abTDP-43 immunoreactivity.
Conclusions
The presence of abTDP-43 immunoreactivity is associated with a modified AD clinicopathological and radiological phenotype.
doi:10.1212/01.wnl.0000304041.09418.b1
PMCID: PMC2779031  PMID: 18401022
22.  DWI PREDICTS FUTURE PROGRESSION TO ALZHEIMER’S DISEASE IN AMNESTIC MILD COGNITIVE IMPAIRMENT 
Neurology  2005;64(5):902-904.
This study tests if measures of hippocampal water diffusivity at baseline can predict future progression to Alzheimer’s Disease (AD) in amnestic mild cognitive impairment (aMCI). Higher baseline hippocampal diffusivity was associated with a greater hazard of progression to AD in aMCI (p=0.002). MR diffusion weighted imaging (DWI) may help identify patients with aMCI who will progress to AD as well or better than structural MRI measures of hippocampal atrophy.
doi:10.1212/01.WNL.0000153076.46126.E9
PMCID: PMC2771335  PMID: 15753434
23.  1H MR SPECTROSCOPY IN COMMON DEMENTIAS 
Neurology  2004;63(8):1393-1398.
Objective
To determine the 1H MR spectroscopic (MRS) findings and inter-group differences among common dementias: Alzheimer's disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD).
Methods
We consecutively recruited 206 normal elderly, 121 patients with AD, 41 with FTLD, 20 with DLB, and 8 with VaD. We evaluated the 1H MRS metabolite ratio changes in common dementias with respect to normal, and also differences among the common dementias.
Results
N-acetylaspartate/Creatine (NAA/Cr) was lower than normal in patients with AD, FTLD, and VaD. Myo-inositol (mI)/Cr was higher than normal in patients with AD and FTLD. Choline (Cho)/Cr was higher than normal in patients with, AD, FTLD, and DLB. There were no metabolite differences between patients with AD and FTLD, nor between patients with DLB and VaD. NAA /Cr was lower in patients with AD and FTLD than DLB. MI /Cr was higher in patients with AD and FTLD than VaD. MI /Cr was also higher in patients with FTLD than DLB.
Conclusions
NAA/Cr levels are decreased in dementias that are characterized by neuron loss such as AD, FTLD, and VaD. MI/Cr levels are elevated in dementias that are pathologically characterized by gliosis such as AD and FTLD. Cho/Cr levels are elevated in dementias that are characterized by a profound cholinergic deficit such as AD and DLB.
PMCID: PMC2766798  PMID: 15505154
24.  Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer’s disease 
Neurobiology of aging  2006;28(9):1330-1339.
Magnetic Resonance (MR)- based volume measurements of atrophy are potential markers of disease progression in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Longitudinal changes in 1H MR spectroscopy (1H MRS) metabolite markers have not been characterized in aMCI subjects. Our objective was to determine the longitudinal 1H MRS metabolite changes in patients with aMCI, and AD, and to compare 1H MRS metabolite ratios and ventricular volumes in tracking clinical disease progression in AD. The neuronal integrity marker N-acetylaspartate/Creatine ratio declined in aMCI and AD patients compared to cognitively normal elderly. The changein 1H MRS metabolite ratios correlated with clinical progression about as strongly as the rate of ventricular expansion, suggesting that 1H MRS metabolite ratios may be useful markers for the progression of AD. Choline/Creatine ratio declined in stable aMCI, compared to converter aMCI patients and cognitively normal elderly, which may be related to a compensatory mechanism in aMCI patients who did not to progress to AD.
doi:10.1016/j.neurobiolaging.2006.06.018
PMCID: PMC2766807  PMID: 16860440
1H MR spectroscopy; 1H MRS; imaging; Alzheimer’s disease; mild cognitive impairment; serial; longitudinal; N-acetylaspartate; choline
25.  1H Magnetic Resonance Spectroscopy, Cognitive Function, and Apolipoprotein E Genotype in Normal Aging, Mild Cognitive Impairment and Alzheimer’s Disease 
The aim of this study was to examine the associations of Apolipoprotein E (APOE) genotype, metabolic changes in the posterior cingulate detected by 1H magnetic resonance spectroscopy (MRS), and neuropsychologic measures of memory and cognition both in normally aging elderly, and in patients with mild cognitive impairment (MCI) and AD. We studied 67 controls, 18 MCI and 33 AD patients. We used the Dementia Rating Scale total score (DRSTOT) as a measure of general cognitive function and the total learning from the Auditory Verbal Learning Test (AVTOT) as a measure of memory performance. No differences were noted on 1H MRS metabolite ratios or cognitive measures across APOE genotype within control and patient groups.. In controls, age was a significant predictor of both cognitive test scores, and NAA/Cr was a univariate associate of DRSTOT. All three 1H MRS metabolite ratios, N-acetylaspartate (NAA)/Creatine (Cr), myoinositol (MI)/Cr, and NAA/MI, were univariate associates of AVTOT and DRSTOT scores in the combined MCI and AD group. In stepwise regression analyses in the combined patient group only NAA/MI entered the model. These data suggest NAA/Cr could be a modest predictor of general cognitive function in both healthy elderly and impaired patients, while MI/Cr is a more specific marker for neuropsychologic dysfunction associated with neurodegenerative disease. Among 1H MRS measurements, the NAA/MI ratio maybe the most efficient predictor of memory and cognitive function in patients with MCI and AD.
PMCID: PMC2766804  PMID: 12405545
1HMRS; Cognition; Aging; Mild Cognitive Impairment; Alzheimer’s Disease

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