An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease

Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Annals of Neurology (Impact Factor: 9.98). 06/2012; 71(6):765-75. DOI: 10.1002/ana.22628
Source: PubMed


A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer 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 (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria.
The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 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 cutpoints 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 only 3% unclassified. Future longitudinal validation of the criteria will be important.

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    • "Finally, we summed up the volume of both hippocampi as we were not primarily interested in lateralization-specific effects and normalized each subject's hippocampal volume with estimated total intracranial volume (eTIV). The normalized hippocampal volume (HVn) was calculated as the residual from a linear regression between hippocampal volume (y) and total intracranial volume (x) (Jack et al., 2012), resulting in the regression formula y (mm³) = 5101 + 1.51 * 10 -3 * eTIV + ε. "
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    ABSTRACT: Objective: Paired associative stimulation (PAS) is a widely used transcranial magnetic stimulation (TMS) paradigm to induce synaptic long-term potentiation (LTP)-like plasticity in the intact human brain. The PAS effect is reduced in Alzheimer's dementia (AD) but has not yet been assessed in patients with mild cognitive impairment (MCI). Methods: PAS was assessed in a group of 24 MCI patients and 24 elderly controls. MCI patients were further stratified by their cognitive profile as well as hippocampal atrophy and Apolipoprotein E (ApoE) genotype. Results: There was no difference in PAS effects between MCI patients and healthy controls. MCI patients tended to show a higher response rate and an average PAS effect. PAS effects were not correlated with markers of disease severity or ApoE genotype but were more pronounced in individuals with shorter sleep duration and in MCI subjects with higher ratings of subjective alertness. Conclusions: Contrary to our initial hypothesis, there was no clear difference in PAS between MCI patients and healthy controls. Significance: Our results argue against a continuous reduction of LTP-like plasticity along the spectrum of clinical MCI when stratified by MCI-subtype, APOE genotype or hippocampus atrophy.
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 08/2015; DOI:10.1016/j.clinph.2015.08.010 · 3.10 Impact Factor
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    • "We hypothesized that asymmetry in olfactory function could be an early predictor of AD and, hence, that it could distinguish between MCI and age-matched healthy controls. Crucially, we selected a uniform population of MCI patients with positive amyloid PET, a biomarker currently considered as the hallmark of AD patients at a predemential stage of the disease [47] and compared them with a group of healthy, amyloid-negative age-matched controls . Furthermore, we also compared the MCI group to a group of patients presenting with a primary olfactory dysfunction (post-viral olfactory loss). "
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    ABSTRACT: Background: Olfactory dysfunction is associated with Alzheimer's disease (AD), and already present at pre-dementia stage. Objectives: Based on the assumption that early neurodegeneration in AD is asymmetrical and that olfactory input is primarily processed in the ipsilateral hemisphere, we assessed whether unirhinal psychophysical and electrophysiological assessment of olfactory function can contribute to the diagnostic workup of mild cognitive impairment (MCI). Methods: Olfactory function of 13 MCI patients with positive amyloid PET, 13 aged-matched controls (AC) with negative amyloid PET and 13 patients with post-infectious olfactory loss (OD)was assessed unirhinally using (1) psychophysical testing of olfactory detection, discrimination and identification performance and (2) the recording of olfactory event-related brain potentials. Time-frequency analysis was used to enhance the signal-to-noise ratio of the electrophysiological responses. Psychophysical and electrophysiological assessment of auditory and trigeminal chemosensory function served as controls. Results: As compared to AC and OD, MCI patients exhibited a significant asymmetry of olfactory performance. This asymmetry efficiently discriminated between MCI and AC (sensitivity: 85%, specificity: 77%), as well as MCI and OD (sensitivity: 85%, specificity: 70%). There was also an asymmetry of the electrophysiological responses, but not specific for MCI. In both MCI and OD, olfactory stimulation of the best nostril elicited significantly more activity than stimulation of the worse nostril, between 3-7.5 Hz and 1.2-2.0 s after stimulus onset. Trigeminal and auditory psychophysical testing did not show any difference between groups. Conclusion: MCI patients exhibit a marked asymmetry of behavioral olfactory function, which could be useful for the diagnostic workup of MCI.
    Journal of Alzheimer's disease: JAD 07/2015; 47(1):253-270. DOI:10.3233/JAD-141494 · 4.15 Impact Factor
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    • "A strength of the present study was the use of individual test scores and actuarial neuropsychological criteria to operationalize subtle cognitive decline within the same conceptual framework we have previously used to define MCI [27]. This method of defining subtle cognitive decline may improve diagnostic consistency and reliability compared to the use of " self-complaint of memory decline or subtle neurobehavioral changes, " [1] which has been shown to cloud rather than clarify diagnosis [43], or the use of composite scores [9] [34] [35] in which sensitive and insensitive test performances are averaged together, with the result that the composite score's sensitivity to subtle cognitive decline is likely reduced. A direction for future research will be to examine individual neuropsychological markers of subtle cognitive decline against different methods of constructing composite scores (e.g., principle components analysis, item response theory) [44] to determine which method most reliably predicts progression. "
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    ABSTRACT: The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alonewas most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.
    Journal of Alzheimer's disease: JAD 07/2015; 47(1):231-242. DOI:10.3233/JAD-150128 · 4.15 Impact Factor
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