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.
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.
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.
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.
To investigate whether demographic (age and education) adjustments for the Mini-Mental State Examination (MMSE) attenuate mean score discrepancies between African American and Caucasian adults, and to determine whether demographically-adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African American adults when compared to unadjusted MMSE scores.
Community-dwelling adults participating in the Mayo Clinic Alzheimer’s Disease Patient Registry (ADPR) and Alzheimer’s Disease Research Center (ADRC).
Three thousand two hundred fifty-four adults (2819 Caucasian, 435 African American) aged 60 and older.
MMSE at study entry.
African American adults obtained significantly lower unadjusted MMSE scores (23.0 ± 7.4) compared to Caucasian adults (25.3 ± 5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly-derived weights. However, controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. Among African American adults, an age- and education-adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia.
Age, dementia severity at study entry, and quality of educational experience are important explanatory factors to understand the existing discrepancies in MMSE performance between Caucasian and African American adults. Our findings support the use of unadjusted MMSE scores when screening African American elders for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.
MMSE; African American; ethnicity; dementia; cognition
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.
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism; synuclein
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.
cognitive activities; aging; mild cognitive impairment
KIBRA SNP rs17070145 was identified in a GWAS of memory performance, with some but not all follow-up studies confirming association of its T allele with enhanced memory. This allele was associated with reduced Alzheimer's disease (AD) risk in one study, which also found overexpression of KIBRA in memory-related brain regions of ADs. We genotyped rs17070145 and 14 additional SNPs in 2571 LOADs vs. 2842 controls, including African-Americans. We found significantly reduced risk for rs17070145 T allele in the older African-American subjects (p=0.007) and a suggestive effect in the older Caucasian series. Meta-analysis of this allele in >8000 subjects from our and published series showed a suggestive protective effect (p=0.07). Analysis of episodic memory in control subjects did not identify associations with rs17070145, though other SNPs showed significant associations in one series. KIBRA showed evidence of overexpression in the AD temporal cortex (p=0.06) but not cerebellum. These results suggest a modest role for KIBRA as a cognition and AD risk gene, and also highlight the multifactorial complexity of its genetic associations.
Alzheimer's disease; Association studies in genetics; Case control studies
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.
frontotemporal dementia; behaviour; functional decline; brain volumes; mixed effects models
The Dementia Rating Scale (DRS) is a widely used measure of global cognition, with age- and education-corrected norms derived from a cross-sectional sample of adults participating in Mayo's Older Americans Normative Studies (MOANS). In recent years, however, studies have indicated that cross-sectional normative samples of older adults represent an admixture of individuals who are indeed cognitively normal (i.e., disease-free) and individuals with incipient neurodegenerative disease. Theoretically, the “contamination” of cross-sectional normative samples with cases of preclinical dementia can lead to underestimation of the test mean and overestimation of the variance, thus reducing the clinical utility of the norms. Robust norming, in which dementia cases are removed from the normative cohort through longitudinal follow-up, is an alternative approach to norm development. The current study presents a reappraisal of the original MOANS DRS norms, provides robust and expanded norms based on a sample of 894 adults age 55 and over, and critically evaluates the benefits of robust norming.
Dementia Rating Scale; DRS; Alzheimer's disease; Robust; Norms
To investigate associations of the Mediterranean diet (MeDi) components and the MeDi score with mild cognitive impairment (MCI).
Participants (aged 70–89 years) were clinically evaluated to assess MCI and dementia, and completed a 128-item food frequency questionnaire.
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].
Vegetables, unsaturated fats, and a high MeDi score may be beneficial to cognitive function.
Mild cognitive impairment; Dietary intake; Moderate alcohol intake; Unsaturated fatty acids; Mediterranean diet; Longitudinal; Prevalence studies; Incidence studies; Population-based
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.
Mild cognitive impairment; Alzheimer’s disease; Imaging; Cognitive decline
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.
metabolic syndrome; insulin resistance; mild cognitive impairment; C-reactive protein; inflammation; cross-sectional study
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).
Population-based case-control study.
The Mayo Clinic Study of Aging, an ongoing population-based cohort study in Olmsted County, Minnesota, USA.
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.
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.
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.
Mono- and polyunsaturated fatty acids (MUFA, PUFA) have been associated with a reduced risk of dementia. The association of these fatty acids with mild cognitive impairment (MCI) is not fully established. The objective of the study was to investigate the cross-sectional association of dietary fatty acids with MCI in a population-based sample. Participants aged ≥ 70 years on October 1, 2004, were evaluated using the Clinical Dementia Rating Scale (participant and informant), a neurological evaluation, and neuropsychological testing. A panel of nurses, physicians, and neuropsychologists reviewed the data for each participant in order to establish a diagnosis of MCI, normal cognition, or dementia by consensus. Participants also completed a 128-item food-frequency questionnaire. Among 1,233 non-demented subjects, 163 (13.2%) had MCI. The odds ratio (OR) of MCI decreased with increasing PUFA and MUFA intake. Compared to the lowest tertile, the OR (95% confidence interval) for the upper tertiles were 0.44 (0.29–0.66; p for trend = 0.0004) for total PUFA; 0.44 (0.30–0.67; p for trend = 0.0004) for omega-6 fatty acids; 0.62 (0.42–0.91; p for trend = 0.012) for omega-3 fatty acids; and 0.56 (0.38–0.83; p for trend = 0.01) for (MUFA+PUFA):saturated fatty acid ratio after adjustment for age, sex, number of years of education, and caloric intake. In this study, higher intake of PUFA and MUFA was associated with a reduced likelihood of MCI among elderly persons in the population-based setting.
Cross-sectional studies; dietary fats; polyunsaturated fatty acids; monounsaturated fatty acids; population-based; mild cognitive impairment
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.
behavioural variant frontotemporal dementia; atrophy; cluster analysis; voxel-based morphometry
The Mayo Cognitive Factor Scores were derived from a “core battery” consisting of the WAIS-R, WMS-R, and Auditory Verbal Learning Test. The present study sought to clarify the factor structure of an expanded neuropsychological battery in normal elderly controls. Confirmatory factor analysis was performed on the WAIS-III, WRAT-3 Reading, Boston Naming Test, Controlled Oral Word Association Test, Category Fluency, Rey-Osterrieth Complex Figure, Visual Form Discrimination, and Trail Making Test A & B. A base four-factor model consistent with the WAIS-III factor structure was utilized. Only one novel five factor model differentiating processing and motor speed tests improved upon this base model. Other models did not, including a factor for executive function, division of construction/visuospatial ability, or “hold”/“no hold” language abilities.
Scores on the Boston Naming Test (BNT) are frequently lower for African American when compared to Caucasian adults. Although demographically-based norms can mitigate the impact of this discrepancy on the likelihood of erroneous diagnostic impressions, a growing consensus suggests that group norms do not sufficiently address or advance our understanding of the underlying psychometric and sociocultural factors that lead to between-group score discrepancies. Using item response theory and methods to detect differential item functioning (DIF), the current investigation moves beyond comparisons of the summed total score to examine whether the conditional probability of responding correctly to individual BNT items differs between African American and Caucasian adults. Participants included 670 adults age 52 and older who took part in Mayo's Older Americans and Older African Americans Normative Studies. Under a 2-parameter logistic IRT framework and after correction for the false discovery rate, 12 items where shown to demonstrate DIF. Six of these 12 items (“dominoes,” “escalator,” “muzzle,” “latch,” “tripod,” and “palette”) were also identified in additional analyses using hierarchical logistic regression models and represent the strongest evidence for race/ethnicity-based DIF. These findings afford a finer characterization of the psychometric properties of the BNT and expand our understanding of between-group performance.
Boston Naming Test; Item response theory; Differential item functioning; Ethnicity; Race; Bias
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.
Alzheimer’s disease; mild cognitive impairment; 1H MRS; diffusion weighted imaging; hippocampal volumetry; MRI
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.
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.
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.
The presence of abTDP-43 immunoreactivity is associated with a modified AD clinicopathological and radiological phenotype.
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.
To determine the annualized rates of volumetric change of the hippocampus and temporal horn in cognitively normal elderly control subjects and individually matched patients with Alzheimer's disease (AD). To test the hypothesis that these rates were different .
Cross-sectional studies consistently reveal cerebral atrophy in elderly non-demented subjects compared to healthy young adults, and greater atrophy in patients with AD relative to elderly controls. However, rates of atrophy are most accurately estimated by performing serial measurements in the same individuals.
Magnetic resonance imaging (MRI)-based volume measurements of the hippocampi and temporal horns were performed in 24 cognitively normal subjects ages 70–89 years who were individually matched with respect to gender and age with 24 patients with AD. Each subject underwent an MRI scanning protocol twice, separated by 12 months or more.
The mean annualized rate of hippocampal volume loss among controls was −1.55% ± 1.38%/year and the temporal horns increased in volume by 6.15% ± 7.69%/year. These rates were significantly greater among AD patients: hippocampus −3.98% ± 1.92%/year, P <.001; temporal horn 14.16% ± 8.47%/year, P = .002.
A statistically significant yearly decline in hippocampal volume and increase in temporal horn volume was identified in elderly controls who represent typical aging individuals. These rates were approximately 2◻ times greater in patients with AD than in individually age and gender matched controls.
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).
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.
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.
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.
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.
1H MR spectroscopy; 1H MRS; imaging; Alzheimer’s disease; mild cognitive impairment; serial; longitudinal; N-acetylaspartate; choline
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.
1HMRS; Cognition; Aging; Mild Cognitive Impairment; Alzheimer’s Disease
Functional MRI (fMRI) shows changes in multiple regions in amnestic MCI (aMCI). The concept of MCI recently evolved to include non-amnestic syndromes so little is known about fMRI changes in these individuals. This study investigated activation during visual complex scene encoding and recognition in 29 cognitively normal (CN) elderly, 19 individuals with aMCI and 12 individuals with non-amnestic MCI (naMCI). During encoding CN activated an extensive network that included bilateral occipital-parietal-temporal cortex, precuneus, posterior cingulate, thalamus, insula, and medial, anterior, and lateral frontal regions. Amnestic MCI activated an anatomic subset of these regions. Non-amnestic MCI activated an even smaller anatomic subset. During recognition, CN activated the same regions observed during encoding except the precuneus. Both MCI groups again activated a subset of the regions activated by CN. During encoding, CN had greater activation than aMCI and naMCI in bilateral temporo-parietal and frontal regions. During recognition, CN had greater activation than aMCI in predominantly temporo-parietal regions bilaterally while CN had greater activation than naMCI in larger areas involving bilateral temporo-parietal and frontal regions. The diminished parietal and frontal activation in naMCI may reflect compromised ability to perform non-memory (i.e., attention/executive, visuospatial function) components of the task.
Magnetic resonance imaging; Neuropsychology; Frontal Lobe; Parietal Lobe; Temporal Lobe; Dementia
Little is known about the population-based prevalence of neuropsychiatric symptoms in mild cognitive impairment (MCI).
To estimate the prevalence of neuropsychiatric symptoms in MCI and normal cognitive aging in a defined population.
Cross-sectional study derived from an ongoing population-based prospective cohort study.
The Mayo Clinic Study of Aging.
We studied a random sample of 1969 non-demented participants out of the target population of 9965 elderly persons residing in Olmsted County on the prevalence date (October 1, 2004). Neuropsychiatric data were available on 319 of the 329 MCI subjects (97.0%) and on 1590 of the 1640 cognitively normal subjects (97.0%).
Neurological, cognitive, and neuropsychiatric data were gathered from the study participants. A classification of normal cognitive aging, MCI, and dementia was adjudicated by an expert consensus panel. Accordingly, 329 subjects were classified as having MCI and the remaining 1640 subjects were classified as cognitively normal.
Main Outcome Measure
The Neuropsychiatric Inventory Questionnaire (NPI-Q).
Multi-variable logistic regression analyses were conducted, after adjusting for age, sex, and education. By taking into consideration both the odds ratio and the frequency of a symptom, the most distinguishing features between the 2 groups were apathy (odds ratio [OR], 4.53; 95% confidence interval [95% CI], 3.11–6.60; P<.001), agitation (OR, 3.60; 95% CI, 2.18–5.92; P<.001), anxiety (OR, 3.00; 95% CI, 2.01–4.48; P<.001), irritability (OR, 2.99; 95% CI, 2.11–4.22; P<.001), and depression (OR, 2.78; 95% CI, 2.06–3.76; P<.001). Delusion had the highest OR (8.12; 95% CI, 2.92–22.60; P<.001); however, it was rare in both cognitively normal subjects (6/1590=0.4%) and MCI (11/319=3.4%). Thus, the population attributable risk for delusion was only 2.62% as compared to 14.60% for apathy.
Non-psychotic symptoms affected approximately 50% of subjects with MCI and 25% of cognitively normal subjects. By contrast, psychotic symptoms were rare.
A variety of anatomic and functional neuroimaging findings are associated with Alzheimer's Disease (AD). One of the strongest imaging associations identified is between AD and hippocampal atrophy. The ∈4 allele of the apolipoprotein E (APOE) gene increases the risk of developing AD and lowers the mean age of onset of the disease. The purpose of this paper was to assess the association between hippocampal volume and APOE polymorphisms in elderly control subjects and patients with probable AD. We performed magnetic resonance imaging-based volume measurements of the hippocampus in 125 cognitively normal elderly controls and 62 patients with probable AD. APOE genotyping was performed using standard methods.
Hippocampal volumes were significantly smaller in AD cases than in control subjects (p <0.001). Hippocampal volumes did not differ significantly within either clinical group on the basis of APOE genotype. Both the ∈4 allele of APOE (p = 0.006) and hippocampal atrophy (p <0.001) were significantly but independently associated with AD.
Alzheimer's Disease; Dementia; MRI; Quantitative MRI; Hippocampus