Arterial spin labeling (ASL) magnetic resonance imaging uses arterial blood water as an endogenous tracer to measure cerebral blood flow (CBF). In this review, based on ASL studies in the resting state, we discuss state-of-the-art technical and data processing improvements in ASL, and ASL CBF changes in normal aging, mild cognitive impairment (MCI), Alzheimer's disease (AD), and other types of dementia. We propose that vascular and AD risk factors should be considered when evaluating CBF changes in aging, and that other validated biomarkers should be used as inclusion criteria or covariates when evaluating CBF changes in MCI and AD. With improvements in hardware and experimental design, ASL is proving to be an increasingly promising tool for exploring pathogenetic mechanisms, early detection, monitoring disease progression and pharmacological response, and differential diagnosis of AD.

Objective-The view that everyday function is preserved in mild cognitive impairment may be problematic. The objectives of this study were to determine the magnitude of impairment in everyday function in patients with mild cognitive impairment and Alzheimer's disease using a novel sensitive performance-based measure (the UCSD Performance-Based Skills Assessment; UPSA), contrast it with use of an informant-based measure (the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory; ADCS-ADL), and model the relationship between cognitive measures and the performance-based measure.Method-Fifty cognitively normal elders, 26 patients who met criteria for amnestic mild cognitive impairment, and 22 patients who suffered from mild to moderate Alzheimer's disease were assessed on the UPSA, the ADCS-ADL, and a battery of neurocognitive tests.Results-Patients with mild cognitive impairment had significant impairments on the UPSA but not on the ADCS-ADL. The magnitude of the effect size between the cognitively healthy and the mild cognitive impairment group for the UPSA was large (d=0.86). A strong and significant relationship was observed between cognitive performances in speed (R 2 =0.37), episodic memory (R 2 =0.10), and semantic processing (R 2 =0.03) and UPSA score using multiple regression models. The psychometric properties of the UPSA were acceptable, as were its sensitivity and specificity in contrasts between cognitively normal elders and patients with mild cognitive impairment and between the latter group and patients with Alzheimer's disease.Conclusions-These findings indicate that performance-based measures of function may be a sensitive tool in studies of Alzheimer's disease and mild cognitive impairment and suggest the need for a reconceptualization of the relationship between cognition and function in mild cognitive impairment so that they can be usefully aligned.Mild cognitive impairment is a less-than-benign diagnosis because it is associated with an elevated risk of incident Alzheimer's disease and more rapid cognitive decline (1,2). The rate of conversion from mild cognitive impairment to Alzheimer's disease may be 10%-12% per year (3). Neuropathologically, mild cognitive impairment (in many but not all cases) appears to be a transitional state of evolving Alzheimer's disease (4,5 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript imaging using the amyloid binding ligand carbon-11-PIB has suggested that the amyloid burden in mild cognitive impairment is intermediate between healthy comparison subjects and patients with Alzheimer's disease (6,7). By recommended diagnostic criteria, individuals with mild cognitive impairment have an impairment of 1.5 standard deviations in episodic memory but essentially preserved everyday function (8,9).Several lines of evidence suggest that the diagnostic criterion relating to function may be problematic. First, neuropsychiatric conditions with associated cognitive impairments are also reliably associated with sequelae in ...

Objective: To determine whether cognitive impairment in Parkinson disease (PD) and Alzheimer disease (AD) derives from the same network pathology.Methods: We analyzed 18 F-fluorodeoxyglucose PET scans from 40 patients with AD and 40 agematched healthy controls from the Alzheimer's Disease Neuroimaging Initiative and scanned an additional 10 patients with AD and 10 healthy controls at The Feinstein Institute for Medical Research to derive an AD-related metabolic pattern (ADRP) analogous to our previously established PD cognition-related pattern (PDCP) and PD motor-related pattern (PDRP). We computed individual subject expression values for ADRP and PDCP in 89 patients with PD and correlated summary scores for cognitive functioning with network expression. We also evaluated changes in ADRP and PDCP expression in a separate group of 15 patients with PD scanned serially over a 4-year period.Results: Analysis revealed a significant AD-related metabolic topography characterized by covarying metabolic reductions in the hippocampus, parahippocampal gyrus, and parietal and temporal association regions. Expression of ADRP, but not PDCP, was elevated in both AD groups and correlated with worse cognitive summary scores. Patients with PD showed slight ADRP expression, due to topographic overlap with the network underlying PD motor-related pattern degeneration, but only their PDCP expression values increased as cognitive function and executive performance declined. Longitudinal data in PD disclosed an analogous dissociation of network expression. Conclusions:Cognitive dysfunction in PD is associated with a specific brain network that is largely spatially and functionally distinct from that seen in relation to AD. Cognitive impairment is commonly observed in patients with Parkinson disease (PD), even early in the clinical course, 1,2 but its cause remains unclear. The postmortem observation of amyloid-b plaques and tau neurofibrilliary tangles, pathologic hallmarks of Alzheimer disease (AD), in individuals with PD and dementia has led to the hypothesis that the cognitive changes in PD are caused by comorbid AD.3-5 Many patients with PD have substantial cognitive loss without forming plaques and tangles, however, and the severity of neuropsychological deficits in patients with PD with coexisting cortical Lewy body and AD-like pathology correlates only with From the Center for Neurosciences (P.J.M., M.N., W

Aim: To analyze age-related cerebral blood flow (CBF) using arterial spin labeling (ASL) MRI in healthy subjects with multivariate principal component analysis (PCA).Methods: 50 healthy subjects (mean age 45.8 ± 18.5 years, range 21–85) had 3D structural MRI and pseudo-continuous ASL MRI at resting state. The relationship between CBF and age was examined with voxel-based univariate analysis using multiple regression and two-sample t-test (median age 41.8 years as a cut-off). An age-related CBF pattern was identified using multivariate PCA.Results: Age correlated negatively with CBF especially anteriorly and in the cerebellum. After adjusting by global value, CBF was relatively decreased with aging in certain regions and relatively increased in others. The age-related CBF pattern showed relative reductions in frontal and parietal areas and cerebellum, and covarying increases in temporal and occipital areas. Subject scores of this pattern correlated negatively with age (R2 = 0.588; P < 0.001) and discriminated between the older and younger subgroups (P < 0.001).Conclusion: A distinct age-related CBF pattern can be identified with multivariate PCA using ASL MRI.

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Objectives Alterations in miRNA expression in post-mortem brain tissue or peripheral blood have been linked to schizophrenia. Cerebrospinal fluid might provide an in vivo biomarker more directly reflecting functional changes in the brain. The goals of this study were to determine the feasibility of detecting miRNAs in cerebrospinal fluid and to compare miRNA levels in cerebrospinal fluid versus blood. Methods Four healthy volunteers and four patients with psychotic disorders underwent lumbar puncture and a blood draw. Expression of 378 validated microRNAs was assessed from each biofluid type for each subject using microarray technology. Five miRNAs were chosen for validation with qPCR. Results A substantial number of microRNAs (n=95) were exclusively or predominately detected in CSF. Levels of 35 miRNAs detected in both CSF and blood samples in all subjects were poorly correlated. Conclusions The investigation of microRNAs in CSF can help advance the understanding of psychiatric diseases and particularly schizophrenia.

Background Proton magnetic resonance spectroscopy (1H-MRS) studies on healthy aging have reported inconsistent findings and have not systematically taken into account the possible modulatory effect of APOE genotype. We aimed to quantify brain metabolite changes in healthy subjects in relation to age and the presence of the APOE E4 genetic risk factor for Alzheimer's disease. Additionally, we examined these measures in relation to cognition. Methods We studied a cohort of 112 normal adults between 50 and 86 years old who were genotyped for APOE genetic polymorphism. Measurements of 1H-MRS metabolites were obtained in the posterior cingulate and precuneus region. Measures of general cognitive functioning, memory, executive function, semantic fluency, and speed of processing were also obtained. Results General linear model analysis demonstrated that older APOE E4 carriers had significantly higher choline/creatine and myoinositol/creatine ratios than APOE E3 homozygotes. Structural equation modeling resulted in a model with an excellent goodness of fit and in which the APOE × age interaction and APOE status each had a significant effect on 1H-MRS metabolites (choline/creatine and myo-inositol/creatine). Furthermore, the APOE × age variable modulation of cognition was mediated by 1H-MRS metabolites. Conclusions In a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased in APOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers.