Faculty Bibliography

OBJECTIVES: This brain imaging study examines whether cognitively normal (NL) individuals with 2 parents affected by late-onset Alzheimer disease (LOAD) show evidence of more extensive Alzheimer disease pathology compared with those who have a single parent affected by LOAD. METHODS: Fifty-two NL individuals received MRI, (11)C-Pittsburgh compound B (PiB)-PET, and (18)F-fluoro-2-deoxyglucose (FDG)-PET. These included 4 demographically balanced groups (n = 13/group, aged 32-72 years, 60% female, 30% APOE epsilon4 carriers) of NL individuals with maternal (FHm), paternal (FHp), and maternal and paternal (FHmp) family history of LOAD, and with negative family history (FH-). Statistical parametric mapping, voxel-based morphometry, and z-score mapping were used to compare MRI gray matter volumes (GMVs), partial volume-corrected PiB retention, and FDG metabolism across FH groups and vs FH-. RESULTS: NL FHmp showed more severe abnormalities in all 3 biomarkers vs the other groups regarding the number of regions affected and magnitude of impairment. PiB retention and hypometabolism were most pronounced in FHmp, intermediate in FHm, and lowest in FHp and FH-. GMV reductions were highest in FHmp and intermediate in FHm and FHp vs FH-. In all FH+ groups, amyloid-beta deposition exceeded GMV loss and hypometabolism exceeded GMV loss (p < 0.001), while amyloid-beta deposition exceeded hypometabolism in FHmp and FHp but not in FHm. CONCLUSIONS: These biomarker findings show a "LOAD parent-dose effect" in NL individuals several years, if not decades, before possible clinical symptoms.

In hypertension (HTN), cerebral blood flow regulation limits are changed, and the threshold for blood pressure (BP) at which perfusion is safely maintained is higher. This shift may increase the brain's vulnerability to lower BP in subjects with vascular disease. We investigated whether longitudinal reduction in mean arterial pressure (MAP) was related to changes in cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease in a group of cognitively healthy elderly with and without HTN. The relationships among MAP, memory decline, and hippocampal atrophy were also examined. Seventy-seven subjects (age 63.4 +/- 9.4, range 44-86 years; education 16.9 +/- 2.1, range 10-22 years; 60% women) were assessed twice, 2 +/- 0.5 years apart. At both time points, all subjects underwent full medical and neuropsychological evaluations, lumbar punctures, and magnetic resonance imaging examinations. Twenty-five subjects had HTN. Hyper- and normotensive subjects did not differ in their CSF biomarkers, hippocampal volumes (HipVs), or memory scores at baseline. In the entire study group, the increase in tau phosphorylated at threonine 181 (p-tau181) was associated with a decline in verbal episodic memory (beta = -0.30, p = 0.01) and HipV reduction (beta = -0.27, p = 0.02). However, longitudinal decrease in MAP was related to memory decline (beta = 0.50, p = 0.01) and an increase in p-tau181 (beta = -0.50, p = 0.01) only in subjects with HTN. Our findings suggest that the hypertensive group may be sensitive to BP reductions.

Background: The pathophysiological process of Alzheimer's disease (AD) begins many years before the emergence of clinical symptoms (preclinical AD). A hypothetical biomarker progression in the pathogenesis of AD has been suggested, beginning with the deposition of amyloid-beta (Abeta) and followed by increases in neurofibrillary tangles, synaptic loss, hippocampal atrophy, and lastly, cognitive impairment. Objective: We explored the effect of several risk factors for AD on the pattern of AD biomarker expression in normal subjects. Methods: AD biomarker evidence was examined at baseline in 96 cognitively normal elderly subjects with none or at least one of the following: ApoE4+ allele, a maternal history of AD (mFHx), sleep-disordered breathing (SDB), and longitudinal evidence of decline to mild cognitive impairment or AD (decliners) at follow-up. Results: Decliners and ApoE4+ subjects presented with expected reduced cerebrospinal fluid Abeta42, elevated P-tau and T-tau. In addition, decliners had fluorodeoxyglucose positron emission tomography hypometabolism in the medial temporal lobe. Individuals with mFHx demonstrated no Abeta42 effect, but had elevations in P-tau and T-tau. SDB was found to be associated with elevated Abeta42, P-tau and T-tau, as well as with reduced medial temporal lobe glucose metabolic rates. Conclusion: Our results indicate a heterogeneous biomarker expression, suggesting diversity of AD pathways in at-risk presymptomatic subjects. (c) 2013 S. Karger AG, Basel.

Background: Behavioral and psychological symptoms of dementia (BPSD) and associated disturbances in Alzheimer's disease (AD) are a source of distress and burden for spouses, professional caregivers, and others with responsibilities for the care of individuals with AD. BPSD with behavioral disturbances are also associated with more rapid institutionalization and increased morbidity and mortality for persons with AD. Objectives: In this review and commentary, we discuss the history of the development of BPSD and behavioral disturbance assessments, which are distinct from those evaluating cognitive and functional symptoms of AD. In particular, we review the informant-based Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the related, potentially more sensitive, BEHAVE-AD Frequency-Weighted Severity Scale (BEHAVE-AD-FW), and the direct subject evaluation-based Empirical BEHAVE-AD Rating Scale (E-BEHAVE-AD). The kinds of medications that alleviate behavioral symptoms on these measures as well as the problems and possibilities for further advances with these medications are discussed. Finally, the importance of distinguishing BPSD and behavioral disturbance remediation in AD from the treatment of cognitive decline and other aspects of AD is emphasized in the context of appropriate assessment methodology. The objective of this paper is to provide a framework for further advances in the treatment of BPSD and associated behavioral disturbances in AD and, consequently, a framework for continuing improvements in the lives of individuals with AD and those who share the burden of the disease with the AD person. (c) 2014 S. Karger AG, Basel.

Late-Life Major Depression (LLMD) is a complex heterogeneous disorder that has multiple pathophysiological mechanisms such as medical comorbidity, vascular-related factors and Alzheimer's disease (AD). There is an association between LLMD and AD, with LLMD possibly being a risk factor for, or early symptom of AD and vascular dementia. Whether depression is an etiologic risk factor for dementia, or part of the dementia prodrome remains controversial. AD has a long prodromal period with the neuropathologic features of the disease preceding the onset of clinical symptoms by as much as 15-20 years. Clinicopathological studies have provided robust support for the importance of Abeta42 in the pathogenesis of AD, but several other risk factors have also been identified. Given the relationship between Abeta42 and AD, a potential relationship between Abeta42 and LLMD would improve the understanding of the association between LLMD and AD. We reviewed 15 studies that analyzed the relationship between soluble Abeta42 and LLMD. For studies looking at plasma and/or cerebrospinal fluid (CSF) levels of Abeta42, the relationship between LLMD and soluble Abeta42 was equivocal, with some studies finding elevated Abeta42 levels associated with LLMD and others finding the opposite, decreased levels of Abeta42 associated with LLMD. It may be that there is poor reliability in the diagnosis of depression in late life, or variability in the criteria and the scales used, or subtypes of depression in late life such as early vs. late onset depression, vascular-related depression, and preclinical/comorbid depression in AD. The different correlations associated with each of these factors would be causing the inconsistent results for soluble Abeta42 levels in LLMD, but it is also possible that these patterns derive from disease stage-dependent differences in the trajectory of CSF Abeta42 during older age, or changes in neuronal activity or the sleep/wake cycle produced by LLMD that influence Abeta42 dynamics.

Background: Glucose hypometabolism measured with FDG-PET in the medial temporal lobe (MTL) has been associated with longitudinal cognitive decline in normal elderly. Other studies find the temporal lobe may be relevant in the regulation of normal breathing, such that apneas and dyspnea are elicited with lesions and electrical stimulation in this region. Our recent work has shown that sleep-disordered breathing (S

Background: A great deal of current research is aiming to better understand what happens to brains affected by Alzheimer's disease, both structurally and metabolically. However, little is known about how the brain ages in the cognitively normal adult population. There is also a limited understanding as to how glucose metabolism and brain atrophy interact in the normal human brain. To our knowledge, this study is the first to longitudinally analyze measures of atrophy and metabolism in both MRI and FDG-PET in cognitively normal subjects. Methods: 45 cognitively normal subjects were studied longitudinally over a span of at least 1.5 years (average = 5.99 years). Each had at least two structural MRIs and 2 FDG-PET scans. Free Surfer was used to analyze ventricle and intracranial volume. This was turned into an intracranial volume ratio to get a normalized picture of brain atrophy. A hippocampal masking technique (HipMask) was used to analyze the FDG-PET scans for changes in metabolic rates in regions normally affected by Alzheimer's disease (precuneus/posterior cingulate, hippocampus, inferior parietal lobe), as well as regions affected by normal aging (prefrontal cortex and cerebellum). Results: Mixed model analysis indicates that ventricle enlargement occurs in the cognitively normal adult brain as early as adult middle age (t = 7.050, p < .001), with a particular acceleration after the age of 65 (t = 2.878, p = .004). However, the mixed model results did not show any evidence of a concomitant decrease in rate with age, nor any acceleration, in regional metabolism after controlling for brain atrophy. Conclusions: Our results show that brain atrophy increases over the adult lifespan. These changes appear to accelerate over time. However, metabolically, we did not find any significant results with regard to change over time. This is in contrast to Alzheimer's disease, where literature has shown metabolic decreases in frontal and parietal regions, particularly in precuneus/posterior cingulate. Our !

Introduction: Our previous work in cognitively normal elderly shows sleep-disordered breathing (S

RATIONALE: Previous studies have shown that sleep-disordered breathing (S