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1.  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
2.  Brain Injury Biomarkers Are Not Dependent on β-amyloid in Normal Elderly 
Annals of neurology  2013;73(4):472-480.
Background
The new criteria for preclinical Alzheimer’s Disease (AD) proposed 3 stages: abnormal levels of β-amyloid (stage 1); stage 1 plus evidence of brain injury (stage 2); and stage 2 plus subtle cognitive changes (stage 3). However, a large group of subjects with normal β-amyloid biomarkers have evidence of brain injury; we labeled them as “suspected non-Alzheimer pathway” (sNAP) group. The characteristics of the sNAP group are poorly understood.
Methods
Using the preclinical AD classification, 430 cognitively normal subjects from the Mayo Clinic Study of Aging who underwent brain MR, 18fluorodeoxyglucose (FDG) and Pittsburgh compound B (PiB) positron emission tomography (PET) were evaluated with FDG PET regional volumetrics, MR regional brain volumetrics, white matter hyperintensity (WMH) volume and number of infarcts. We examined cross-sectional associations across AD preclinical stages, those with all biomarkers normal, and the sNAP group.
Results
The sNAP group had a lower proportion (14%) with APOE ε4 genotype than the preclinical AD stages 2 + 3. The sNAP group did not show any group differences compared to stages 2 + 3 of the preclinical AD group on measures of FDG PET regional hypometabolism, MR regional brain volume loss, cerebrovascular imaging lesions, vascular risk factors, imaging changes associated with α-synucleinopathy or physical findings of parkinsonism.
Conclusions
Cognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of β-amyloid, were indistinguishable on a variety of imaging markers, clinical features and risk factors. The initial appearance of brain injury biomarkers that occurs in cognitively normal persons with preclinical AD may not depend on β-amyloidosis.
doi:10.1002/ana.23816
PMCID: PMC3660408  PMID: 23424032
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
3.  Anatomy of Disturbed Sleep in Pallido-Ponto-Nigral Degeneration 
Annals of neurology  2011;69(6):1014-1025.
Objective
Pallido-ponto-nigral degeneration (PPND), caused by an N279K mutation of the MAPT gene, is 1 of a family of disorders collectively referred to as frontotemporal dementia and parkinsonism linked to chromosome 17. This study aims to characterize the nature of the sleep disturbance in PPND and compare these findings to those in other progressive neurological illnesses. Pathological findings are also provided.
Methods
Ten subjects were recruited from the PPND kindred; 5 affected and 5 unaffected. The subjects underwent clinical assessment, polysomnography, and wrist actigraphy. Available sleep-relevant areas (pedunculopontine/laterodorsal tegmentum, nucleus basalis of Meynert, thalamus, and locus ceruleus) of affected subjects were analyzed postmortem.
Results
The affected group's total sleep time was an average of 130.8 minutes compared to 403.6 minutes in the control group (p < 0.01). Initial sleep latency was significantly longer in affected subjects (range, 58–260 minutes vs 3–34 minutes). Affected subjects also had an increase in stage I sleep (8.5% vs 1%), and less stage III/IV sleep (8.5% vs 17%). At the time of autopsy, all cases had severe neuronal tau pathology in wake-promoting nuclei, as well as decreases in thalamic cholinergic innervations. There was no difference in orexinergic fiber density in nucleus basalis of Meynert or locus ceruleus compared to controls.
Interpretation
The PPND kindred showed severe sleep disturbance. Sleep abnormalities are common in neurodegenerative illnesses, but this is the first study of sleep disorders in PPND. Unlike most neurodegenerative conditions, PPND is characterized by decreased total sleep time, increased sleep latency, and decreased sleep efficiency, without daytime hypersomnolence.
doi:10.1002/ana.22340
PMCID: PMC3905604  PMID: 21681797
4.  Effect of Lifestyle Activities on AD Biomarkers and Cognition 
Annals of neurology  2012;72(5):730-738.
Objectives
To investigate the effect of intellectual and physical activity on biomarkers of Alzheimer’s disease (AD) pathophysiology and cognition in a non-demented elderly population. The biomarkers evaluated were brain Aβ-amyloid load via PIB-PET, neuronal dysfunction via FDG-PET and neurodegeneration via Structural-MRI.
Methods
We studied 515 non-demented (428 cognitively normal and 87 MCI) participants in the population based Mayo Clinic Study of Aging who completed a 3T MRI, PET scans, APOE genotype, had lifestyle activity measures and cognition data available. The imaging measures computed were global PiB-PET uptake; global FDG-PET and MRI based hippocampal volume. We consolidated activity variables into lifetime intellectual, current intellectual and current physical activities. We used a global cognitive Z-score as a measure of cognition. We applied two independent methods – partial correlation analysis adjusted for age and gender and path analysis using structural equations to evaluate the associations between lifestyle activities, imaging biomarkers and global cognition.
Results
None of the lifestyle variables correlated with the biomarkers and the path associations between lifestyle variables and biomarkers were not significant (p>0.05). On the other hand, all the biomarkers were correlated with global cognitive Z-score (p<0.05) and the path associations between (lifetime and current) intellectual activities and global Z-score were significant (p<0.01).
Interpretation
Intellectual and physical activity lifestyle factors were not associated with AD biomarkers but intellectual lifestyle factors explained variability in the cognitive performance in this non-demented population. This study provides evidence that lifestyle activities may delay the onset of dementia but do not significantly influence the expression of AD pathophysiology.
doi:10.1002/ana.23665
PMCID: PMC3539211  PMID: 23280791
Alzheimer’s disease; Imaging biomarkers; Lifestyle Activities
5.  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
6.  Beta-amyloid burden is not associated with rates of brain atrophy 
Annals of neurology  2008;63(2):204-212.
Objective
To test the hypothesis that beta-amyloid (Aβ) burden is associated with rates of brain atrophy.
Methods
Forty-five subjects who had been prospectively studied, died, and had an autopsy diagnosis of low, intermediate, or high probability of Alzheimer's disease that had two volumetric head MRI scans were identified. Compact, as well as total (compact + diffuse) Aβ burden was measured using a computerized image analyzer with software program to detect the proportion of grey matter occupied by Aβ. Visual ratings of Aβ burden were also performed. The boundary-shift integral (BSI) was used to calculate change over time in whole brain and ventricular volume. All BSI results were annualized by adjusting for scan interval. Demographics, cognitive measures, clinical diagnoses, apolipoprotein E genotype, neurofibrillary tangle pathology, and vascular lesion burden were determined.
Results
There was no correlation between compact or total Aβ burden, or visual Aβ ratings, and rates of brain loss or ventricular expansion in all subjects. However, significant correlations were observed between rates of brain loss and age, Braak stage, and change over time in cognitive measures. These features also correlated with rates of ventricular expansion. The rates of brain loss and ventricular expansion were greater in demented compared to non-demented subjects.
Interpretation
These findings suggest that rate of brain volume loss is not determined by the amount of insoluble Aβ in the grey matter.
doi:10.1002/ana.21223
PMCID: PMC2735194  PMID: 17894374

Results 1-6 (6)