Curtis Taylor

Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer's disease risk groups.

To assess the ability of resting-state functional magnetic resonance imaging to distinguish known risk factors for AD, we evaluated 17 cognitively normal individuals with a family history of AD and at least one copy of the apolipoprotein e4 allele compared to 12 individuals who were not carriers of the APOE4 gene and did not have a family history of AD. Blood oxygen level dependent fMRI was performed evaluating encoding-associated signal and resting-state default mode network signal differences between the two risk groups. Neurocognitive testing revealed that the high risk group performed worse on category fluency testing, but the groups were equivalent on all other cognitive measures. During encoding of novel face-name pairs, there were no regions of encoding-associated BOLD activations that were different in the high risk group. Encoding-associated deactivations were greater in magnitude in the low risk group in the medial and right lateral parietal cortex, similar to findings in AD studies. The resting-state DMN analysis demonstrated nine regions in the prefrontal, orbital frontal, temporal and parietal lobes that distinguished the two risk groups. Resting-state DMN analysis could distinguish risk groups with an effect size of 3.35, compared to an effect size of 1.39 using encoding-associated fMRI techniques. Imaging of the resting state avoids performance related variability seen in activation fMRI, is less complicated to acquire and standardize, does not require radio-isotopes, and may be more effective at identifying functional pathology associated with AD risk compared to non-resting fMRI techniques.

Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment

Objective: To investigate the neurocognitive measures that best predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD). Methods: We evaluated 539 participants with aMCI from the Alzheimers Disease Cooperative Study clinical drug trial of donepezil, vitamin E, or placebo. During the study period of 36 months, 212 aMCI participants progressed to AD. Using progression from aMCI to AD within 36 months as the dependent variable, a generalized linear model was fit to the data using the least absolute shrinkage and selection operator. Independent variables included in this analysis were age, sex, education, APOE-e4 (APOE4) status, family history of dementia, Mini-Mental State Examination score, Digits Backwards (Wechsler Memory Scale), Maze Time and Errors, Number Cancellation, Delayed Recall of Alzheimers Disease Assessment Scale Word List, New York University Paragraph Recall Test (Immediate and Delayed), Boston Naming Test, Category Fluency, Clock Drawing Test, and the Alzheimers Disease Assessment Scale–Cognitive subscale (ADAS-cog). Results: The model that best predicted progression from aMCI to AD over 36 months included APOE4 status, the Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), and the ADAS-cog total score. When APOE4 was removed from the analysis the resulting model had a similar estimated predictive accuracy as the full model. As determined by cross-validation, the estimated predictive accuracy of the final model was 80%. Conclusion: Progression from amnestic mild cognitive impairment to Alzheimer disease in this cohort was best determined by combining four common, easily administered, cognitive measures.

Volumetric MRI vs clinical predictors of Alzheimer disease in mild cognitive impairment

Objective: To compare volumetric MRI of whole brain and medial temporal lobe structures to clinical measures for predicting progression from amnestic mild cognitive impairment (MCI) to Alzheimer disease (AD). Methods: Baseline MRI scans from 129 subjects with amnestic MCI were obtained from participants in the Alzheimers Disease Cooperative Study groups randomized, placebo-controlled clinical drug trial of donepezil, vitamin E, or placebo. Measures of whole brain, ventricular, hippocampal, and entorhinal cortex volumes were acquired. Participants were followed with clinical and cognitive evaluations until formal criteria for AD were met, or completion of 36 months of follow-up. Logistic regression modeling was done to assess the predictive value of all MRI measures, risk factors such as APOE genotype, age, family history of AD, education, sex, and cognitive test scores for progression to AD. Least angle regression modeling was used to determine which variables would produce an optimal predictive model, and whether adding MRI measures to a model with only clinical measures would improve predictive accuracy. Results: Of the four MRI measures evaluated, only ventricular volumes and hippocampal volumes were predictive of progression to AD. Maximal predictive accuracy using only MRI measures was obtained by hippocampal volumes by themselves (60.4%). When clinical variables were added to the model, the predictive accuracy increased to 78.8%. Use of MRI measures did not improve predictive accuracy beyond that obtained by cognitive measures alone. APOE status, MRI, or demographic variables were not necessary for the optimal predictive model. This optimal model included the Delayed 10-word list recall, New York University Delayed Paragraph Recall, and the Alzheimers Disease Assessment Scale–Cognitive Subscale total score. Conclusion: In moderate stages of amnestic mild cognitive impairment, common cognitive tests provide better predictive accuracy than measures of whole brain, ventricular, entorhinal cortex, or hippocampal volumes for assessing progression to Alzheimer disease.

Cerebral perfusion and oxygenation differences in Alzheimer's disease risk.

Functional MRI has demonstrated differences in response to memory performance based on risk for Alzheimers disease (AD). The current study compared blood oxygen level dependent (BOLD) functional MRI response with arterial spin labeling (ASL) perfusion response during an associative encoding task and resting perfusion signal in different risk groups for AD. Thirteen individuals with a positive family history of AD and at least one copy of the apolipoprotien E epsilon4 (APOE4) gene (high risk) were compared to ten individuals without these risk factors (low risk). In the medial temporal lobes (MTLs) the high risk group had an elevated level of resting perfusion, and demonstrated decreased fractional BOLD and perfusion responses to the encoding task. However, there was no difference in the absolute cerebral blood flow during the task. These data demonstrate that individuals with increased risk for Alzheimers disease have elevated MTL resting cerebral blood flow, which significantly influences apparent differences in BOLD activations. BOLD activations should be interpreted with caution, and do not necessarily reflect differences in neuronal activation.

Neuropsychiatric symptoms and regional neocortical atrophy in mild cognitive impairment and Alzheimer's disease.

Background: To assess the relationship between regional neocortical atrophy and psychotic symptoms in adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods: Rates of change in regional neocortical atrophy as measured by longitudinal magnetic resonance imaging scans and the occurrence of psychotic symptoms and/or the long-term use of antipsychotic medications in 389 outpatients with MCI or AD in Alzheimer’s Disease Neuroimaging Initiative. Results: Atrophy rate of 3 specific neocortical regions, lateral frontal, lateral parietal, and anterior cingulate gyrus, was significantly associated with the onset of psychosis including delusions, agitation, wandering, and hallucinations and/or the need for chronic antipsychotic medications. Atrophy rate of the lateral frontal lobe correlated most significantly with onset of psychotic symptoms or need for chronic antipsychotic medications. Conclusions: Psychosis was associated with volume loss in specific regions of the lateral frontal and parietal lobes as well as anterior cingulate gyrus.

Comparison of the Memory Performance Index With Standard Neuropsychological Measures of Cognition

The Mild Cognitive Impairment Screen (MCIS) is a computer-based cognitive assessment designed for clinical and research use in detecting amnestic mild cognitive impairment (aMCI). Performance on the MCIS is reported as the Memory Performance Index (MPI). However, the comparability between the MPI and traditional neuropsychological tests in detecting aMCI, and in differentiating it from Alzheimer’s disease (AD) and normal aging has not been examined. A cross-sectional study was conducted to assess the validity of the MPI relative to standard neuropsychological measures. Participants included 12 individuals diagnosed with aMCI, 49 with mild AD, and 25 healthy elderly. The MCIS significantly discriminated among aMCI, AD, and healthy elderly controls. The MCIS is effective in detecting aMCI, and in discriminating it from cognitive changes observed in AD and normal aging. The MCIS may be a valuable tool in the identification of elderly at high risk for dementia due to its ease-of-use and brief administration time.

P2-171: Clinical predictors of progression to Alzheimer’s disease in amnestic mild cognitive impairment

for early treatment of the disease. Identifying individuals at higher risk of developing AD is also beneficial. The term mild cognitive impairment (MCI) has gained importance over the past years when predicting progression from MCI into dementia and AD. Today there is no clinical method to determine which patients with MCI that will progress into AD, except for very long follow-up. Thus, there is a clinical need for diagnostic biomarkers to identify incipient AD in patients with MCI. Recently, a peptide pattern of a quintet of A peptides truncated at the C-terminal (A 1-37/38/39/40 and 42) was found in CSF from patients with AD, where the relative order of abundance differed in absolute and relative terms. Objective(s): The aim of the present study was to analyze the peptide pattern of C-terminally truncated A peptides in CSF from patients with MCI at baseline, and to investigate whether the peptide pattern could be used to discriminate between those patients who preceded into AD and those who did not. Methods: Cerebrospinal fluid levels of A 1-37/38/39/40 and 42 were analyzed on Western blot. The study was designed to have a blind approach where the clinical diagnosis after 4-6 years follow-up was kept blind until analysis and prediction according to outcome of the analysis was set. The ratio between A 1-42 and A 1-40 was also used to analytically discriminate between those patients who had proceeded into AD and those who still remained MCI. Conclusions: This novel finding suggests that analyzing the peptide pattern consisting of C-terminally truncated A -peptides is a good way of predicting AD in patients with MCI. Results: Using the peptide pattern when predicting AD in patients with MCI gave a positive predictive value (PPV) 73 % (CI 61-85) and a negative predictive value (NPV) 96 % (CI 91-101).