"New Old Pathologies": AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS)

Abstract

The pathology-based classification of Alzheimer's disease (AD) and other neurodegenerative diseases is a work in progress that is important for both clinicians and basic scientists. Analyses of large autopsy series, biomarker studies, and genomics analyses have provided important insights about AD and shed light on previously unrecognized conditions, enabling a deeper understanding of neurodegenerative diseases in general. After demonstrating the importance of correct disease classification for AD and primary age-related tauopathy, we emphasize the public health impact of an underappreciated AD "mimic," which has been termed "hippocampal sclerosis of aging" or "hippocampal sclerosis dementia." This pathology affects >20% of individuals older than 85 years and is strongly associated with cognitive impairment. In this review, we provide an overview of current hypotheses about how genetic risk factors (GRN, TMEM106B, ABCC9, and KCNMB2), and other pathogenetic influences contribute to TDP-43 pathology and hippocampal sclerosis. Because hippocampal sclerosis of aging affects the "oldest-old" with arteriolosclerosis and TDP-43 pathologies that extend well beyond the hippocampus, more appropriate terminology for this disease is required. We recommend "cerebral age-related TDP-43 and sclerosis" (CARTS). A detailed case report is presented, which includes neuroimaging and longitudinal neurocognitive data. Finally, we suggest a neuropathology-based diagnostic rubric for CARTS.

Keywords: Arteriosclerosis; Cerebrovascular disease; Frontotemporal lobar degeneration; Genome-wide association study; Neurofibrillary tangles; Plaques; VCID..

FIGURE 1

Dementia is associated with risk factors and pathologies that vary across the human aging spectrum. (A, B) Among the “oldest-old” with the clinical diagnosis of “Probable AD,” APOE ϵ4 alleles are decreasingly common after age 75 years (A) , whereas HS-Aging pathology is more prevalent with increasing age (p < 0.001 for both) in the NACC Data Set ( n  = 993 of subjects who died between 2005 and 2013) ( 57 ) (B) . Methodology for data analyses was as described previously ( 58 ). These data demonstrate the contribution to dementia of non- APOE genetic risk factors, and common non-AD pathologies in advanced old age.

FIGURE 2

Depiction of prevalence and morbidity of specific pathologies that contribute to dementia. These charts represent the subjective synthesis of the results of multiple published studies ( 19 , 29 , 33 , 52 , 59 , 60 , 61 , 62 , 63 , 58 , 64 , 65–86 ). (A) The prevalence of multiple different specific CNS disease pathologies is depicted (50% prevalence is shown for reference). Note that in large autopsy series the prevalence of advanced AD pathology levels off or decreases in advanced old age whereas other pathologies (HS-Aging, cerebrovascular diseases) increase in that group. Panel (B) shows the same conditions ranked according to the morbidity (neurologic impact and rate of disease progression). Prevalence, morbidity, and age range vary significantly. For example, FTLD is a rare but devastating illness whereas PART is relatively common but lower morbidity, and each mostly afflicts people at separate parts of the human aging spectrum.

FIGURE 3

Both Alzheimer disease (AD) and primary age-related tauopathy (PART) are diagnosed based on a grid that incorporates pathologic staging information related to amyloid plaques and neurofibrillary tangles (NFTs). Shown is the grid for determining the level of AD neuropathologic changes at autopsy (2), based on Thal Aβ stages ( 89 ), CERAD neuritic amyloid plaque stages ( 90 ), and Braak NFT stages ( 91 ). Superimposed on the AD classification scheme are criteria for “Definite PART” (red) and “Possible PART” (yellow) ( 59 ) based on the same information.

FIGURE 4

Case study illustrates clinical and neuropathologic features of common comorbid diseases. The female subject was followed from 77 years until death at age 102 years. Detailed neurocognitive tests were performed until age 98 years; MCI was diagnosed clinically at age 93, “Probable Alzheimer Disease” at age 95. APOE genotype was ϵ3/ϵ3. (A) Panel shows results of MMSE (global cognition) and animal naming (verbal fluency) results; note that the verbal fluency was relatively stable even after global cognitive status was impaired. A brain MRI (horizontal plane) 10 years before death (B) showed hippocampal atrophy (arrows). Immunohistochemistry demonstrated extremely sparse Aβ amyloid pathology in temporal neocortex (C) and no neuritic plaques. Aβ amyloid in AD brain (D) is shown for comparison. In the hippocampal formation there was Braak NFT stage II tauopathy (E) and PART and HS-Aging were both diagnosed. Note that the hippocampal sclerosis is diagnosed according to consensus-based criteria (2): “cell loss and gliosis out of proportion to plaques and tangles,” rather than complete destruction of the structure. TDP-43 pathology was present in the hippocampus; (F) shows dentate gyrus with inclusions (arrows) and (G) shows subiculum with neuronal inclusion (arrow) and slender nontapering TDP-43 neurites (arrowheads). Widespread brain arteriolosclerosis pathology was also observed (Fig. 5). Panel (H) is a low-power photomicrograph showing the hippocampal formation including CA1, dentate granule (dg), and subiculum (Sub) regions. Adjacent sections were stained for phospho-Tau (P-Tau) and P-TDP-43 and the pathology was depicted schematically (inset I) using an Aperio ScanScope as described previously ( 56 ): red dots for NFTs, green dots for P-TDP-43 inclusions, and cyan region shows area with P-TDP-43 neurites. As noted previously ( 56 ), the tauopathic distribution in TDP[+]HS[+] cases is slightly different from “classic” early Braak NFT stages. Scale bars: C , 100 μm; D , 80 μm; E , 40 μm; F , 30 μm; G , 70 μm; H , 2 mm.

FIGURE 5

Brain arteriolosclerosis (B-ASC) pathology is a complex phenotype. These panels show B-ASC vascular profiles in brains from different aged individuals to provide a small sampling of the heterogeneity of B-ASC. (A-C) Panels show hematoxylin and eosin staining. Panel (A) is a low-power photomicrograph depicting a vessel in the amygdala of a person with advanced AD and cerebrovascular disease. Note the large expanse of hyalinized material (*) that extends from the vessel wall, along with a patch of lymphocytic inflammation (arrow). By contrast, in the hippocampus of the case study ( Fig. 4 ) there is a smaller blood vessel (boxed in B , magnified in C ) that shows a vascular profile with apparent fibrinoid necrosis and/or microcalcifications in the paucicellular vessel wall. Another pattern we have seen in many cases is multiple vascular profiles in the same vessel bed, as shown in panel (D) (arterioles are here visualized using α-SMA immunohistochemistry). Collagen can be visualized using a trichrome stain (panels E, F are separate HS-Aging cases); a B-ASC profile is shown in E with the collagen labeled green. Cases with hippocampal TDP-43 in our experience often show neocortical B-ASC as visualized by the green-staining arterioles (arrows) in this low-power photomicrograph near the pia (*) of frontal neocortex, Brodmann Area 9. Scale bars: A , 200 μm; B , 90 μm; C , 10 μm; D , 25 μm; E , 70 μm; F , 100 μm.

FIGURE 6

The disease we have referred to as hippocampal sclerosis of aging (HS-Aging) is a complex phenotype that includes hippocampal sclerosis (A-C) , TDP-43 pathology (D-F) , and brain arteriolosclerosis (G-I) . Features of pathologically unaffected compartments are shown ( A, hippocampus; D, neurons; and G, arterioles) in contrast to the compartments (B, E, H) and brain areas (C, F, I) affected in this disease. Because the extant classification is suboptimal, we propose a new terminology to classify this disease: cerebral age-related TDP-43 and sclerosis, CARTS.

FIGURE 7

Pathogenesis helps guide classification of neurodegenerative diseases. This schematic depicts hypotheses about the multiple genetic and environmental factors that promote tau and TDP-43 pathologies. These may include comorbid pathologies such as amyloid plaques (associated with APOE ϵ4 allele) or brain arteriolosclerosis (B-ASC, associated with ABCC9 gene variant). There also are “downstream” genetic risk modifiers, such as GRN (rs5848), TMEM106B (rs1990662), and MAPT H1 haplotype, which appear to influence many different disease phenotypes each. Ultimately, protein misfolding contributes to symptomatic manifestations. While there are large number of rarer conditions, the common tau and TDP-43 diseases linked to cognitive impairment in advanced old age are AD, PART, and HS-Aging/CARTS.