Recommendations for the diagnosis of preclinical Alzheimer disease (AD) have been formulated by a workgroup of the National Institute on Aging and Alzheimer's Association. Three stages of preclinical ...AD were described. Stage 1 is characterized by abnormal levels of β-amyloid. Stage 2 represents abnormal levels of β-amyloid and evidence of brain neurodegeneration. Stage 3 includes the features of stage 2 plus subtle cognitive changes. Stage 0, not explicitly defined in the criteria, represents subjects with normal biomarkers and normal cognition. The ability of the recommended criteria to predict progression to cognitive impairment is the crux of their validity.
Using previously developed operational definitions of the 3 stages of preclinical AD, we examined the outcomes of subjects from the Mayo Clinic Study of Aging diagnosed as cognitively normal who underwent brain MRI or (18)Ffluorodeoxyglucose and Pittsburgh compound B PET, had global cognitive test scores, and were followed for at least 1 year.
Of the 296 initially normal subjects, 31 (10%) progressed to a diagnosis of mild cognitive impairment (MCI) or dementia (27 amnestic MCI, 2 nonamnestic MCI, and 2 non-AD dementias) within 1 year. The proportion of subjects who progressed to MCI or dementia increased with advancing stage (stage 0, 5%; stage 1, 11%; stage 2, 21%; stage 3, 43%; test for trend, p < 0.001).
Despite the short follow-up period, our operationalization of the new preclinical AD recommendations confirmed that advancing preclinical stage led to higher proportions of subjects who progressed to MCI or dementia.
We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria.
We evaluated an age- and sex-stratified random sample of ...Olmsted County residents who were 70-89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria.
Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval CI 14.4-17.5) for any MCI, 11.1% (95% CI 9.8-12.3) for amnestic MCI, and 4.9% (95% CI 4.0-5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21-1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE epsilon3epsilon4 or epsilon4epsilon4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend <0.0001).
Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly.
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.
Although incidence rates for mild cognitive impairment (MCI) have been reported, few studies were specifically designed to measure the incidence of MCI and its subtypes using published criteria. We ...estimated the incidence of amnestic MCI (aMCI) and nonamnestic MCI (naMCI) in men and women separately.
A population-based prospective cohort of Olmsted County, MN, residents ages 70-89 years on October 1, 2004, underwent baseline and 15-month interval evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychological testing. A panel of examiners blinded to previous diagnoses reviewed data at each serial evaluation to assess cognitive status according to published criteria.
Among 1,450 subjects who were cognitively normal at baseline, 296 developed MCI. The age- and sex-standardized incidence rate of MCI was 63.6 (per 1,000 person-years) overall, and was higher in men (72.4) than women (57.3) and for aMCI (37.7) than naMCI (14.7). The incidence rate of aMCI was higher for men (43.9) than women (33.3), and for subjects with ≤12 years of education (42.6) than higher education (32.5). The risk of naMCI was also higher for men (20.0) than women (10.9) and for subjects with ≤12 years of education (20.3) than higher education (10.2).
The incidence rates for MCI are substantial. Differences in incidence rates by clinical subtype and by sex suggest that risk factors for MCI should be investigated separately for aMCI and naMCI, and in men and women.
To test the hypothesis that the atrophy rate measured from serial MRI studies is associated with time to subsequent clinical conversion to a more impaired state in both cognitively healthy elderly ...subjects and in subjects with amnestic mild cognitive impairment (MCI).
Ninety-one healthy elderly patients and 72 patients with amnestic MCI who met inclusion criteria were identified from the Mayo Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry. Atrophy rates of four different brain structures--hippocampus, entorhinal cortex, whole brain, and ventricle--were measured from a pair of MRI studies separated by 1 to 2 years. The time of the second scan marked the beginning of the clinical observation period.
During follow-up, 13 healthy patients converted to MCI or Alzheimer disease (AD), whereas 39 MCI subjects converted to AD. Among those healthy at baseline, only larger ventricular annual percent volume change (APC) was associated with a higher risk of conversion (hazard ratio for a 1-SD increase 1.9, p = 0.03). Among MCI subjects, both greater ventricular volume APC (hazard ratio for a 1-SD increase 1.7, p < 0.001) and greater whole brain APC (hazard ratio for a 1-SD increase 1.4, p = 0.007) increased the risk of conversion to AD. Both ventricular APC (hazard ratio for a 1-SD increase 1.59, p = 0.001) and whole brain APC (hazard ratio for a 1-SD increase 1.32, p = 0.009) provided additional predictive information to covariate-adjusted cross-sectional hippocampal volume at baseline about the risk of converting from MCI to AD.
Higher whole brain and ventricle atrophy rates 1 to 2 years before baseline are associated with an increased hazard of conversion to a more impaired state. Combining a measure of hippocampal volume at baseline with a measure of either whole brain or ventricle atrophy rates from serial MRI scans provides complimentary predictive information about the hazard of subsequent conversion from mild cognitive impairment to Alzheimer disease. However, overlap among those who did vs those who did not convert indicate that these measures are unlikely to provide absolute prognostic information for individual patients.
Right temporal frontotemporal dementia (FTD) is an anatomic variant of FTD associated with relatively distinct behavioral and cognitive symptoms. We aimed to determine whether right temporal FTD is a ...homogeneous clinical, imaging, and pathologic/genetic entity.
In this case-control study, 101 subjects with FTD were identified. Atlas-based parcellation generated temporal, frontal, and parietal grey matter volumes which were used to identify subjects with a right temporal dominant atrophy pattern. Clinical, neuropsychological, genetic, and neuropathologic features were reviewed. The subjects with right temporal FTD were grouped by initial clinical diagnosis and voxel-based morphometry was used to assess grey matter loss in the different groups, compared to controls, and each other.
We identified 20 subjects with right temporal FTD. Twelve had been initially diagnosed with behavioral variant FTD (bvFTD), and the other 8 with semantic dementia (SMD). Personality change and inappropriate behaviors were more frequent in the bvFTD group, while prosopagnosia, word-finding difficulties, comprehension problems, and topographagnosia were more frequent in the SMD group. The bvFTD group showed greater loss in frontal lobes than the SMD group. The SMD group showed greater fusiform loss than the bvFTD group. All 8 bvFTD subjects with pathologic/genetic diagnosis showed abnormalities in tau protein (7 with tau mutations), while all three SMD subjects with pathology showed abnormalities in TDP-43 (p = 0.006).
We have identified 2 subtypes of right temporal variant frontotemporal dementia (FTD) allowing further differentiation of FTD subjects with underlying tau pathology from those with TDP-43 pathology.
To correlate different methods of measuring rates of brain atrophy from serial MRI with corresponding clinical change in normal elderly subjects, patients with mild cognitive impairment (MCI), and ...patients with probable Alzheimer disease (AD).
One hundred sixty subjects were recruited from the Mayo Clinic Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry Studies. At baseline, 55 subjects were cognitively normal, 41 met criteria for MCI, and 64 met criteria for AD. Each subject underwent an MRI examination of the brain at the time of the baseline clinical assessment and then again at the time of a follow-up clinical assessment, 1 to 5 years later. The annualized changes in volume of four structures were measured from the serial MRI studies: hippocampus, entorhinal cortex, whole brain, and ventricle. Rates of change on several cognitive tests/rating scales were also assessed. Subjects who were classified as normal or MCI at baseline could either remain stable or convert to a lower-functioning group. AD subjects were dichotomized into slow vs fast progressors.
All four atrophy rates were greater among normal subjects who converted to MCI or AD than among those who remained stable, greater among MCI subjects who converted to AD than among those who remained stable, and greater among fast than slow AD progressors. In general, atrophy on MRI was detected more consistently than decline on specific cognitive tests/rating scales. With one exception, no differences were found among the four MRI rate measures in the strength of the correlation with clinical deterioration at different stages of the disease.
These data support the use of rates of change from serial MRI studies in addition to standard clinical/psychometric measures as surrogate markers of disease progression in AD. Estimated sample sizes required to power a therapeutic trial in MCI were an order of magnitude less for MRI than for change measures based on cognitive tests/rating scales.
To determine the relationship between β-amyloid (Aβ) load as measured by (11)C-Pittsburgh compound B (PiB) PET and cognitive function in cognitively normal older adults.
We studied 408 cognitively ...normal older adults who participated in the population-based Mayo Clinic Study of Aging (MCSA) from January 2009 through March 2011. The participants underwent PiB PET and neuropsychometric testing within 6 months. The association between PiB retention and cognitive function was measured by partial correlation and an interaction with APOE status was tested using linear regression after adjusting for age, sex, and education.
Higher PiB retention was associated with cognitive performance (Spearman partial r = -0.18; p < 0.01), specifically the memory, language, attention/executive, and visual-spatial processing domains in the whole group of participants. The association between PiB retention and cognition was modified by the APOE status on linear regression analysis even after controlling for the differences in the distribution of PiB values among APOE ε4 carriers and noncarriers (p = 0.02). Cognitive performance was associated with the Aβ deposition in the frontal, temporal, and parietal lobe association cortices in APOE ε4 carriers on SPM analysis (p < 0.001).
There is a modest association between PiB retention and cognitive function in cognitively normal older adults and this relationship between Aβ load and cognitive function is modified by APOE status. Whereas Aβ load is associated with greater cognitive impairment in APOE ε4 carriers, the cognitive function in APOE ε4 noncarriers is influenced less by the Aβ load, suggesting that APOE isoforms modulate the harmful effects of Aβ on cognitive function.
To determine the patterns of diffusivity associated with cognitive domain functions in older adults without dementia.
We studied older adults without dementia (n = 220) who underwent ...neuropsychometric testing and a diffusion tensor imaging (DTI) examination at 3 T in a cross-sectional study. Memory, language, attention/executive function, and visual-spatial processing domains were assessed within 4 months of the MRI examination. A fluid-attenuated inversion recovery-based DTI sequence that enabled uncontaminated cortical diffusion measurements was performed. Associations between cortical mean diffusivity (MD) and cognitive function were tested using voxel-based regression analysis. Association between tract diffusivity and cognitive function was tested with regions of interest drawn on color-coded fractional anisotropy (FA) maps.
Memory function was associated with the medial temporal lobe cortical MD on voxel-based analysis (p < 0.001, corrected for multiple comparisons), and inferior longitudinal fasciculus and posterior and anterior cingulum FA on tract-based analysis (p < 0.001). Language function was associated with the left temporal lobe cortical MD (p < 0.001, corrected for multiple comparisons), inferior longitudinal fasciculus, fornix, and posterior cingulum FA (p < 0.05). Attention and executive function was associated with the posterior and anterior cingulum FA, and visual-spatial function was associated with posterior cingulum FA (p < 0.01).
Specific cognitive domain functions are associated with distinct patterns of cortical and white matter diffusivity in elderly with no dementia. Posterior cingulum tract FA was associated with all 4 cognitive domain functions, in agreement with the hypothesis that the posterior cingulate cortex is the main connectivity hub for cognitive brain networks. Microstructural changes identified on DTI may be associated with neurodegenerative pathologies underlying cognitive changes in older adults without dementia.
Neuropathology of Cognitively Normal Elderly KNOPMAN, D S; PARISI, J E; SALVIATI, A ...
Journal of neuropathology and experimental neurology,
2003-November, Letnik:
62, Številka:
11
Journal Article
Recenzirano
Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum limit for Alzheimer-type pathology in cognitively intact individuals might aid in defining more ...precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed, cognitively normal elderly individuals (24 women, 15 men; age range 74–95, median 85 years). Neuropathological changes of the Alzheimer type were quantified by determining neurofibrillary tangle (NFT) staging by the method of Braak and Braak and by quantification of the abundance of diffuse, cored, and neuritic plaque burden using the scheme developed by the Consortium to Establish a Registry for Alzheimer Disease (CERAD). Vascular, Lewy body, and argyrophilic grain pathology were also assessed. We found 34 subjects (87%) with a Braak stage <IV; 32 subjects (82%) with less than moderate numbers of cored plaques and 37 subjects (95%) with less than moderate numbers of tau-positive neuritic plaques. Many subjects had moderate or frequent diffuse plaques (n = 19, 49%). By the National Institute on Aging-Reagan Institute (NIA-RI) criteria, none of our cases met criteria for high “likelihood” of AD. Four met NIA-RI criteria for intermediate “likelihood.” Seven cases met CERAD criteria for possible AD. Nineteen met Khachaturian criteria for AD. Only 1 subject had neocortical Lewy bodies. Small, old infarcts were common, but no subjects had more than 2 of these and none had a single large infarction. Thus, the majority of individuals who are cognitively normal near the time of their death have minimal amounts of tau-positive neuritic pathology (Braak stage <IV and neuritic plaques <6 per ×100 field in the most affected neocortical region). The few subjects with more severe AD pathology can be expected based on incidence rates of AD in the very elderly.
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