During the past 10 years, there has been a rapidly growing number of pharmaceutical industry-sponsored drug trials for treatment of Alzheimer disease (AD) and other neurodegenerative diseases. As public awareness and concerns about AD have grown, so has interest in developing drug therapies for retarding symptom progression, delaying onset, and ultimately curing the disease. Ethical debate on the use of placebo control trials in AD research has come of age in the United States with the availability of treatments approved by the Food and Drug Administration. The experts and the public agree that more effective therapies are necessary, and new therapeutic options are being developed as rapidly as possible. The arguments on each side of the debate are provocative and important but do not provide unequivocal justification for either the abandonment or the maintenance of placebo-controlled trials in all AD research. Clinical trials differ with respect to scientific and practical goals, and these factors inherently affect the ethical priorities of each study. We present these contrasting points of view to delineate some of the issues rather than to make specific recommendations other than to urge that all clinical trials in AD should be designed with careful consideration of the ethical issues surrounding the use of placebo controls. As new and more effective treatments emerge, the ethical framework for placebo use in AD studies will require frequent re-examination. To make wise choices, patients, caregivers, physicians, and ethicists (among others) must have a voice in this continuing discussion.

Introduction

The aim was to examine associations between midlife cardiovascular health (CVH) and 20-year cognitive decline among blacks and whites.

Methods

Midlife CVH metrics (American Heart Association's Life's Simple 7) were calculated and examined in relation to midlife and 20-year change in cognitive function among 13,270 whites and blacks from the Atherosclerosis Risk in Communities Cohort Study. We used linear mixed models to estimate adjusted associations of midlife CVH with midlife cognitive status and change.

Results

Higher midlife (Life's Simple 7) scores and individual metrics, particularly blood pressure and glucose, were associated with better midlife cognition and reduced 20-year decline. Midlife CVH 20-year neuroprotection was more pronounced among whites than blacks.

Discussion

Better midlife CVH was associated with higher midlife and reduced decline in cognitive function 20 years later. However, the benefits of midlife CVH on cognition were stronger for whites than for blacks. Our findings suggest that improved midlife CVH may promote enduring cognitive health.

Background

Bone marrow-derived progenitor cells survey the vasculature and home to sites of tissue injury where they can promote repair and regeneration. It has been hypothesized that these cells may play a protective role neurodegenerative and vascular cognitive impairment.

Objective

To evaluate progenitor cell levels in older adults with and without mild cognitive impairment (MCI), and to relate circulating levels to memory, brain volume, white matter lesion volume, and cerebral perfusion.

Method

Thirty-two older adults, free of stroke and cardiovascular disease, were recruited from the community and evaluated for diagnosis of MCI versus cognitively normal (CN). Participants underwent brain MRI and blood samples were taken to quantify progenitor reserve using flow cytometry (CD34+, CD34+CD133+, and CD34+CD133+CD309+ cells).

Results

Participants with MCI (n = 10) exhibited depletion of all CPC markers relative to those who were CN (n = 22), after controlling for age, sex, and education. Post-hoc age, sex, and education matched comparisons (n = 10 MCI, n = 10 CN) also revealed the same pattern of results. Depletion of CD34+ cells correlated with memory performance, left posterior cortical thickness, and bilateral hippocampal perfusion. Participants exhibited low levels of vascular risk and white matter lesion burden that did not correlate with progenitor levels.

Conclusions

Circulating progenitor cells are associated with cognitive impairment, memory, cortical atrophy, and hippocampal perfusion. We hypothesize that progenitor depletion contributes to, or is triggered by, cognitive decline and cortical atrophy. Further study of progenitor cell depletion in older adults may benefit efforts to prevent or delay dementia.

Background

Diabetes predicts late-life dementia, but the association with rate of cognitive decline is inconsistent and has rarely been examined in non-white populations, despite the high prevalence of diabetes in African Americans. We evaluated the effect of diabetes on cognitive decline in middle-aged African Americans and whites.

Methods

Atherosclerosis Risk in Communities (ARIC) Brain MRI Study participants (n = 1,886, mean age = 60, 49% African American) underwent assessments of verbal memory, processing speed, and verbal fluency four times over 14 years. Using race-stratified mixed linear effects models, we examined cognitive change for participants with prevalent (baseline) diabetes and incident (diagnosed after baseline) diabetes versus those without diabetes.

Results

African Americans had more advanced diabetes, as indicated by fasting blood glucose levels, anti-diabetes medication use, and cardiovascular risk profiles. African Americans with prevalent diabetes experienced 41% greater annual decline in processing speed scores (p = 0.048) and 50% greater annual decline in verbal fluency scores (p = 0.042) than those without diabetes; incident diabetes was not associated with cognitive decline. Among whites, diabetes was not associated with cognitive decline.

Conclusions

Prevalent diabetes was associated with greater cognitive decline in middle-aged African Americans, possibly reflecting adverse effects of longer duration and more advanced diabetes.

Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer's disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer's disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer's pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer's disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure--analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity 'overload' that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both.

Introduction

Clinical and MRI measurements can track disease progression in PSP, but many have not been extensively evaluated in multicenter clinical trials. We identified optimal measures to capture clinical decline and predict disease progression in multicenter PSP trials.

Methods

Longitudinal clinical rating scales, neuropsychological test scores, and volumetric MRI data from an international, phase 2/3 clinical trial of davunetide for PSP (intent to treat population, n = 303) were used to identify measurements with largest effect size, strongest correlation with clinical change, and best ability to predict dropout or clinical decline over one year as measured by PSP Rating Scale (PSPRS).

Results

Baseline cognition as measured by Repeatable Battery for Assessing Neuropsychological Status (RBANS) was associated with attrition, but had only a small effect. PSPRS and Clinical Global Impression (CGI) had the largest effect size for measuring change. Annual change in CGI, RBANS, color trails, and MRI midbrain and ventricular volumes were most strongly correlated with annual PSPRS and had the largest effect sizes for detecting annual change. At baseline, shorter disease duration, more severe depression, and lower performance on RBANS and executive function tests were associated with faster worsening of the PSPRS in completers. With dropouts included, SEADL, RBANS, and executive function tests had significant effect on PSPRS trajectory of change.

Conclusion

Baseline cognitive status and mood influence the rate of disease progression in PSP. Multiple clinical, neuropsychological, and volumetric MRI measurements are sensitive to change over one year in PSP and appropriate for use in multicenter clinical trials.

Introduction

Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD).

Methods

We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium.

Results

The CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0. The CDR®-SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®-SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders.

Discussion

The BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

Introduction

Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD).

Methods

We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium.

Results

The CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0. The CDR®-SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®-SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders.

Discussion

The BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer's disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist. How overlapping pathologic findings affect the diagnosis and treatment of clinical AD and other dementia phenotypes was the topic taken up by the Alzheimer's Association's Research Roundtable in October 2014. This review will cover the neuropathologic basis of dementia, provide clinical perspectives on multiple pathologies, and discuss therapeutics and biomarkers targeting overlapping pathologies and how these issues impact clinical trials.High prevalence of multiple pathologic findings among individuals with clinical diagnosis of AD suggests that new treatment strategies may be needed to effectively treat AD and other dementing illnesses.