Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease

Abstract

IMPORTANCE Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD.OBJECTIVE To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes. DESIGN, SETTING, AND PARTICIPANTSIn this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings.MAIN OUTCOMES AND MEASURES Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation. RESULTSIn total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm 2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n = 148), higher in typical AD (25 [19-30]; n = 727), and highest in limbic predominant AD (26 [19-32]; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, −1.5; 95% CI, −2.9 to −0.15; P = .03) and typical AD (β, −3.2; 95% CI, −3.9 to −2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, −1.8; 95% CI, −3.2 to −0.31; P = .02). Demographic and clinical progression variables were not associated ...

Concomitant LATE‐NC in Alzheimer's disease is not associated with increased tau or amyloid‐β pathological burden

“…It is well established that cortical tau burden is associated with cognitive impairment in AD as indicated by human neuropathological [26] and in vivo tau PET binding [50] studies. This study also revealed that higher burden of quantified cortical tau burden is associated with earlier age at disease onset which is in agreement with a previous quantification neuropathological study [51] as well as a tau PET binding study in autosomal dominant AD [52] that indicated that increased tau PET uptake was linked to the onset of cognitive dysfunction. Although the presence of LATE-NC has been implicated as a clinical modifier of AD, we could not find a relationship between severity of LATE-NC with age at onset or rate of cognitive decline between AD/LATE-NC and AD cases, further supporting the notion that TDP-43 pathology does not impact disease onset or progression of AD.…”

Aluminum and Neurofibrillary Tangle Co-Localization in Familial Alzheimer’s Disease and Related Neurological Disorders

“…Herein, we have made use of thioflavin S as a fluorophore for the detection of NFTs of hyperphosphorylated tau protein. ThS is frequently used for the identification of NFTs in human brain tissue [7,14,17,24,25]. When stained with ThS, NFTs most notably produce characteristic flame-like morphologies in intraneuronal occlusions, distinctive from larger extracellular senile plaques that typically span tens of microns in diameter [26].…”

Neuropathological Correlates of Cumulative Benzodiazepine and Anticholinergic Drug Use

“…The nucleus basalis is rich in acetylcholine and stimulates the cholinergic system of the neocortex [44]. Neuronal loss in this region is thought to occur in the early stages of Alzheimer's disease [45][46][47]. It is reasonable to believe anticholinergic drugs could contribute towards neuronal loss in the nucleus basalis, as studies have identified that these neurons are susceptible to other toxic agents such as cadmium, aluminium, nitric oxide and ethanol [48][49][50].…”