Erin L. Abner

Primary age-related tauopathy (PART): a common pathology associated with human aging

We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study

Proteins pathogenic in Alzheimers disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD.

Alzheimer's disease is not "brain aging": neuropathological, genetic, and epidemiological human studies.

Human studies are reviewed concerning whether “aging”-related mechanisms contribute to Alzheimer’s disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human “accelerated aging” diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical “dementia” and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an “aging-linked” disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.

Modeling the Association between 43 Different Clinical and Pathological Variables and the Severity of Cognitive Impairment in a Large Autopsy Cohort of Elderly Persons

We evaluated the association between mini‐mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression‐based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimers disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high‐functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP‐43‐related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.

Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease

Chronic inflammation in periodontal disease has been suggested as a potential risk factor in Alzheimers disease (AD). The purpose of this study was to examine serum antibody levels to bacteria of periodontal disease in participants who eventually converted to AD compared with the antibody levels in control subjects.

Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

Objective: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. Methods: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. Results: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p ≤ 0.0003). Conclusions: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.

Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease

Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimers disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)‐serine‐type 1 insulin receptor substrate (IRS‐1) and less P‐tyrosine‐IRS‐1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P‐serine 312‐IRS‐1 and P‐pan‐tyrosine‐IRS‐1 by ELISA and the ratio of P‐serine 312‐IRS‐1 to P‐pan‐tyrosine‐IRS‐1 (insulin resistance factor, R) for AD and DM2 and P‐serine 312‐IRS‐1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significandy higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P‐serine 312‐IRS‐1, P‐pan‐tyrosine‐IRS‐1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.—Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., Frassetto, L., Petersen, R. C., Miller, B. L., Goetzl, E. J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural‐derived blood exosomes of preclinical Alzheimers disease. FASEB J. 29, 589‐596 (2015). www.fasebj.org

A computer-based approach to preventing pregnancy, STD, and HIV in rural adolescents.

A computer- and Internet-based intervention was designed to influence several variables related to the prevention of pregnancy, sexually transmitted diseases (STDs), and human immunodeficiency virus (HIV) in rural adolescents. The intervention was guided by the extended parallel process model and was evaluated using a pretest–post-test control group design with random assignment at the school level. Three hundred and twenty-six tenth-grade males and females enrolled in two rural Appalachian public high schools completed the survey at both points in time. Results indicate the vast majority (88.5%) of students in the experimental school completed at least one activity (M = 3.46 for those doing at least one activity). Further, both the overall program and all but one of the activities were rated positively by participants. Regarding the effects of the intervention, results indicate that students in the experimental school were less likely to initiate sexual activity and had greater general knowledge, greater condom negotiation self-efficacy, more favorable attitudes toward waiting to have sex, and greater situational self-efficacy than in the control school. In tandem, the results suggest that the computer-based programs may be a cost-effective and easily replicable means of providing teens with basic information and skills necessary to prevent pregnancy, STDs, and HIV.

University of Kentucky Sanders-Brown Healthy Brain Aging Volunteers: Donor Characteristics, Procedures and Neuropathology

Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.

Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease

The mild cognitive impairment (MCI) stage of dementia with Lewy bodies (MCI-DLB) has not yet been defined, but is likely to differ in the MCI stage of Alzheimers disease (MCI-AD). To determine whether clinical features distinguish MCI-DLB and MCI-AD, 9 cases of neuropathologically confirmed MCI-DLB and 12 cases of MCI-AD were compared. No significant differences were found between MCI-DLB and MCI-AD cases in age at death, gender, ApoE status, education, time followed while clinically normal, or duration of MCI. MCI-DLB and MCI-AD cases differed clinically in the expression of Parkinsonism (P=0.012), provoked hallucinations or delirium (P=0.042), or the presence of any of these noncognitive symptoms of DLB (P<0.0001). Letter fluency (P=0.007) was significantly lower and Wechsler Logical Memory I (P=0.019) was significantly higher in MCI-DLB compared to MCI-AD cases. These data demonstrate the feasibility of differentiating underlying pathologic processes responsible for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow more accurate early detection of prodromal DLB and AD.