Abnormal Cerebral Perfusion Profile in Older Adults with HIV-Associated Neurocognitive Disorder: Discriminative Power of Arterial Spin-Labeling.

BACKGROUND AND PURPOSE: The aging HIV-infected (HIV+) population has increased vascular comorbidities, including stroke, and increased cognitive deficits compared with the general population. Arterial spin-labeling is a technique to measure cerebral blood flow and is more sensitive than regional volume loss in assessing neurodegenerative diseases and cognitive aging. Previous studies have found global cerebral perfusion abnormalities in the HIV+ participants. In this study, we evaluated the specific regional pattern of CBF abnormalities in older HIV+ participants using quantitative whole-brain arterial spin-labeling. MATERIALS AND METHODS: CBF data from the UCSF HIV Over 60 Cohort and the Alzheimer Disease Neuroimaging Initiative were retrospectively evaluated to identify 19 HIV+ older adults, all with plasma viral suppression (including 5 with HIV-associated neurocognitive disorder); 13 healthy, age-matched controls; and 19 participants with early mild cognitive impairment. CBF values were averaged by ROI and compared among the 3 groups using generalized linear models. RESULTS: When we accounted for age, education, sex, and vascular risk factors, the HIV+ participants demonstrated alterations in regional cerebral perfusion, including hypoperfusion of bilateral temporal, parietal, and occipital brain regions compared with both clinically healthy participants and those with mild cognitive impairment. Arterial spin-labeling showed reasonable test characteristics in distinguishing those with HIV-associated neurocognitive disorder from healthy controls and participants with mild cognitive impairment. CONCLUSIONS: This study found specific CBF patterns associated with HIV status despite viral suppression-data that should animate further investigations into the pathobiologic basis of vascular and cognitive abnormalities in HIV-associated neurocognitive disorders.

CSF protein biomarkers predicting longitudinal reduction of CSF ß-amyloid42 in cognitively healthy elders.

ß-amyloid (Aß) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aß1-42 (Aß42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aß metabolism predict the development of Aß plaques, assessed by longitudinal CSF Aß42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aß42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal Aß42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aß metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aß42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aß42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aß42 reduction only in subjects with normal baseline Aß42, and not in subjects with reduced baseline Aß42. We conclude that baseline CSF proteins related to Aß metabolism, microglia activity or synapses predict longitudinal Aß42 reduction in cognitively healthy elders. The finding that some proteins only predict Aß42 reduction in subjects with normal baseline Aß42 suggest that they predict future development of the brain Aß pathology at the earliest stages of AD, prior to widespread development of Aß plaques.

Impact of methodologic choice for automatic detection of different aspects of brain atrophy by using temporal lobe epilepsy as a model.

BACKGROUND AND PURPOSE: VBM, DBM, and cortical thickness measurement techniques are commonly used automated methods to detect structural brain changes based on MR imaging. The goal of this study was to demonstrate the pathology detected by the 3 methods and to provide guidance as to which method to choose for specific research questions. This goal was accomplished by 1) identifying structural abnormalities associated with TLE with (TLE-mts) and without (TLE-no) hippocampal sclerosis, which are known to be associated with different types of brain atrophy, by using these 3 methods; and 2) determining the aspect of the disease pathology identified by each method. MATERIALS AND METHODS: T1-weighted MR images were acquired for 15 TLE-mts patients, 14 TLE-no patients, and 33 controls on a high-field 4T scanner. Optimized VBM was carried out by using SPM software, DBM was performed by using a fluid-flow registration algorithm, and cortical thickness was analyzed by using FS-CT. RESULTS: In TLE-mts, the most pronounced volume losses were identified in the ipsilateral hippocampus and mesial temporal region, bilateral thalamus, and cerebellum, by using SPM-VBM and DBM. In TLE-no, the most widespread changes were cortical and identified by using FS-CT, affecting the bilateral temporal lobes, insula, and frontal and occipital lobes. DBM revealed 2 clusters of reduced volume complementing FS-CT analysis. SPM-VBM did not show any significant volume losses in TLE-no. CONCLUSIONS: These results demonstrate that the 3 methods detect different aspects of brain atrophy and that the choice of the method should be guided by the suspected pathology of the disease.

Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects.

OBJECTIVE: To determine whether elderly normal APOE E2 (APOE2) carriers exhibit slower rates of hippocampal atrophy and memory decline compared to APOE3/3 carriers. We also determined whether APOE2 carriers have less Alzheimer pathology as reflected by CSF biomarkers. METHODS: We included longitudinal data from 134 cognitively normal individuals (27 APOE2/2 or E2/3, 107 APOE3/3) from the Alzheimer's Disease Neuroimaging Initiative, a prospective cohort study. A linear mixed-effects model was used to determine how APOE2 affected rates of hippocampal atrophy and cognitive change over time. In a subsample of 72 individuals who also underwent CSF analysis, an ordinary least-squares regression was used to determine whether CSF ß-amyloid (Aß), total tau, and phosphorylated tau-181 (p-tau) differed by APOE2 status. RESULTS: APOE2 carriers demonstrated slower rates of hippocampal atrophy (p = 0.004). The mean rate of hippocampal atrophy among APOE2 carriers was -33 mm(3)/year (95% confidence interval -65 to +0.4), or -0.5%/year, compared to -86 mm(3)/year (95% confidence interval -102 to -71), or -1.3%/year, in the APOE3/3 group. No differences in the rates of episodic memory (p = 0.23) or overall cognitive change (p = 0.90) were detected. In the CSF subsample, APOE2 carriers had higher levels of CSF Aß (p = 0.01), lower p-tau (p = 0.02), and marginally lower tau (p = 0.12). CONCLUSION: A slower rate of hippocampal atrophy in normal APOE2 carriers is consistent with the lower risk of Alzheimer disease in these individuals. We hypothesize that the slower atrophy rate is related to decreased preclinical Alzheimer pathology.