Brains With Medial Temporal Lobe Neurofibrillary Tangles But No Neuritic Amyloid Plaques Are a Diagnostic Dilemma But May Have Pathogenetic Aspects Distinct From Alzheimer Disease

Abstract

Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak Stages III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the "amyloid cascade hypothesis" of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP− cases, we analyzed 26 NFT +/NP− patient brains identified from the University of Kentucky AD Center autopsy cohort (n = 502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had neurofibrillary tangles in the medulla oblongata. Aberrant TAR-DNA binding protein-43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer's Coordinating Center Registry (n = 5,108) and found 219 NFT+/NP− cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918-1919 pandemic. This observation may link the pathogenesis in NFT+/NP− cases to encephalitis during childhood. We conclude that NFT+/NP-cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.

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

“…Published data indicate that severe PART can be associated with memory loss in aging [66, 107]. However, the high prevalence of comorbid brain diseases in elderly individuals make clinicopathological correlations challenging in this population [76, 80, 108, 109, 117, 125], and the entire clinical-pathological spectrum of PART has yet to be systematically characterized.…”

“…Another motivation, as with the recent National Institute on Aging-Alzheimer's Association diagnostic criteria for Alzheimer's disease (AD) [64, 102], is to “disentangle” pathologic classification from clinical diagnosis for a given patient. In the case of PART, the separation of clinical information from the pathological diagnosis is especially necessary, as the term “dementia”, as in “tangle-only dementia”, implies a multi-domain cognitive impairment with a profound decrease in the ability to perform activities of daily living, both of which are absent in the majority of persons with PART [65, 66, 107, 125, 142]. Practicing neuropathologists will benefit from the revised terminology because many are reluctant to apply the clinical term “dementia” to a pathologic diagnosis when dementia was not documented clinically or when knowledge of the clinical history is limited.…”

“…NFT are practically universal in older persons' brains [22, 30, 108, 132], and are also observed in a more limited distribution in many younger individuals [30, 32, 42]. Cases at the more severe end of the pathologic spectrum (Braak stages III-IV) lacking Aβ plaques were observed in 2-10% of brains in large autopsy series that included community-based sampling [89, 94, 107, 125]. These pathologic changes were more prevalent in a few autopsy series drawing from memory disorder clinics [128, 129].…”

“…These pathologic changes were more prevalent in a few autopsy series drawing from memory disorder clinics [128, 129]. The theoretical and practical implications of these findings remain controversial [9, 15, 29, 107]. Differences in nomenclature, study design, including cohort recruitment methods, variable sensitivity in detecting pathologic changes, and conceptual interpretations have fueled uncertainty.…”

Association among Amyloid Plaque, Lipid, and Creatine in Hippocampus of TgCRND8 Mouse Model for Alzheimer Disease

“…The pathological hallmarks include extracellular deposits of amyloid peptides (A␤) derived from the amyloid precursor protein (APP), and neurofibrillary tangles formed within the neurons due to hyperphosphorylated tau protein (2). Spatial, temporal, and biochemical connections between A␤ deposits and hyperphosphorylated tau tangles are still debated (3,4). A dynamic equilibrium between the aggregated A␤ and the possibly more toxic protofibrils, mediated by neuronal membrane lipids, has been demonstrated in vitro (5).…”