Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy

Beach, Thomas G.; Sue, Lucia I.; Scott, Sarah; Intorcia, Anthony; Walker, Jessica E; Arce, Richard; Glass, Michael J.; Borja, Claryssa I; Cline, Madison P; Hemmingsen, Spencer J; Qiji, Sanaria H; Stewart, Analisa; Martinez, Kayleigh N; Krupp, Addison; McHattie, Rylee; Mariner, Monica; Lorenzini, Ileana; Kuramoto, Angela; Long, Kathy E.; Tremblay, Cécilia; Caselli, Richard J.; Woodruff, Bryan K.; Rapscak, Steven Z.; Belden, Christine M.; Goldfarb, Danielle; Choudhury, Parichita; Driver‐Dunckley, Erika; Mehta, Shyamal H.; Sabbagh, Marwan N.; Shill, Holly A.; Atri, Alireza; Adler, Charles H.; Serrano, Geidy E.

doi:10.1093/jnen/nlad026

Cited by 7 publications

(6 citation statements)

References 88 publications

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“…and APP mutations and Down's syndrome [55][56][57][58]. The greater WMR in the US PSEN1 group studied here, relative to the EOSADD group, may be in part due to the higher proportion of significant arteriolosclerosis, 37% vs 18%, in the PSEN1 group as compared to the EOSADD group but could also be due to the more severe AD histopathological scores as WMR probably has a dual vascular and AD-related pathogenesis [59][60][61]. Like LBD, WMR is highly prevalent in autosomal dominant ADD and thus this adds to other evidence that it is at least partially dependent on ADNC.…”

Section: Discussionmentioning

confidence: 95%

Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer’s Disease Dementia: Evidence for Dependency on Alzheimer’s Disease Neuropathological Changes

Sepulveda-Falla,

Villegas Lanau,

White

et al. 2023

Preprint

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Autopsy studies have demonstrated that comorbid neurodegenerative and cerebrovascular disease occur in the great majority of subjects with Alzheimer disease dementia (ADD), and are likely to additively alter the rate of decline or severity of cognitive impairment. The most important of these are Lewy body disease (LBD), TDP-43 proteinopathy and cerebrovascular disease, including white matter rarefaction (WMR) and cerebral infarcts. Comorbidities may interfere with ADD therapeutic trials evaluation of ADD clinical trials as they may not respond to AD-specific molecular therapeutics. It is possible, however, that at least some comorbidities may be, to some degree, secondary consequences of AD pathology, and if this were true then effective AD-specific therapeutics might also reduce the extent or severity of comorbid pathology. Comorbidities in ADD caused by autosomal dominant mutations such as those in the presenilin-1 (PSEN1) gene may provide an advantageous perspective on their pathogenesis, and deserve attention because these subjects are increasingly being entered into clinical trials. As ADD associated with PSEN1 mutations has a presumed single-cause etiology, and the average age at death is under 60, any comorbidities in this setting may be considered as at least partially secondary to the causative AD mechanisms rather than aging, and thus indicate whether effective ADD therapeutics may also be effective for comorbidities. In this study, we sought to compare the rates and types of ADD comorbidities between subjects with early-onset sporadic ADD (EOSADD; subjects dying under age 60) versus ADD associated with different types of PSEN1 mutations, the most common cause of early-onset autosomal dominant ADD. In particular, we were able to ascertain, for the first time, the prevalences of a fairly complete set of ADD comorbidities in United States (US) PSEN1 cases as well as the Colombian E280A PSEN1 kindred. Data for EOSADD and US PSEN1 subjects (with multiple different mutation types) was obtained from the National Alzheimer Coordinating Center (NACC). Colombian cases all had the E280A mutation and had a set of neuropathological observations classified, like the US cases according to the NACC NP10 definitions. Confirmatory of earlier reports, NACC-defined Alzheimer Disease Neuropathological Changes (ADNC) were consistently very severe in early-onset cases, whether sporadic or in PSEN1 cases, but were slightly less severe in EOSADD. Amyloid angiopathy was the only AD-associated pathology type with widely-differing severity scores between the 3 groups, with median scores of 3, 2 and 1 in the PSEN1 Colombia, PSEN1 US and EOSADD cases, respectively. Apoliprotein E genotype did not show significant proportional group differences for the possession of an E-4 or E-2 allele. Of ADD comorbidities, LBD was most common, being present in more than half of all cases in all 3 groups. For TDP-43 co-pathology, the Colombian PSEN1 group was the most affected, at about 27%, vs 16% and 11% for the US PSEN1 and sporadic US cases, respectively. Notably, hippocampal sclerosis and non-AD tau pathological conditions were not present in any of the US or Colombian PSEN1 cases, and was seen in only 3% of the EOSADD cases. Significant large-vessel atherosclerosis was present in a much larger percentage of Colombian PSEN1 cases, at almost 20% as compared to 0% and 3% of the US PSEN1 and EOSADD cases, respectively. Small-vessel disease, or arteriolosclerosis, was much more common than large vessel disease, being present in all groups between 18% and 37%. Gross and microscopic infarcts, however, as well as gross or microscopic hemorrhages, were generally absent or present at very low percentages in all groups. White matter rarefaction (WMR) was remarkably common, at almost 60%, in the US PSEN1 group, as compared to about 18% in the EOSADD cases, a significant difference. White matter rarefaction was not assessed in the Colombian PSEN1 cases. The results presented here, as well as other evidence, indicates that LBD, TDP-43 pathology and WMR, as common comorbidities with autosomal dominant and early-onset sporadic ADD, should be considered when planning clinical trials with such subjects as they may increase variability in response rates. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.

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Section: Discussionmentioning

confidence: 95%

Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer’s Disease Dementia: Evidence for Dependency on Alzheimer’s Disease Neuropathological Changes

Sepulveda-Falla,

Villegas Lanau,

White

et al. 2023

Preprint

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“… 158 , 159 Other postmortem signs of vascular disease include white matter atrophy and calcification of arteries. 43 , 160 , 161 …”

Section: Results Of the Reviewed Studiesmentioning

confidence: 99%

Alcohol Use Disorder and Dementia: A Review

Zahr

2024

ARCR

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PURPOSE By 2040, 21.6% of Americans will be over age 65, and the population of those older than age 85 is estimated to reach 14.4 million. Although not causative, older age is a risk factor for dementia: every 5 years beyond age 65, the risk doubles; approximately one-third of those older than age 85 are diagnosed with dementia. As current alcohol consumption among older adults is significantly higher compared to previous generations, a pressing question is whether drinking alcohol increases the risk for Alzheimer’s disease or other forms of dementia. SEARCH METHODS Databases explored included PubMed, Web of Science, and ScienceDirect. To accomplish this narrative review on the effects of alcohol consumption on dementia risk, the literature covered included clinical diagnoses, epidemiology, neuropsychology, postmortem pathology, neuroimaging and other biomarkers, and translational studies. Searches conducted between January 12 and August 1, 2023, included the following terms and combinations: “aging,” “alcoholism,” “alcohol use disorder (AUD),” “brain,” “CNS,” “dementia,” “Wernicke,” “Korsakoff,” “Alzheimer,” “vascular,” “frontotemporal,” “Lewy body,” “clinical,” “diagnosis,” “epidemiology,” “pathology,” “autopsy,” “postmortem,” “histology,” “cognitive,” “motor,” “neuropsychological,” “magnetic resonance,” “imaging,” “PET,” “ligand,” “degeneration,” “atrophy,” “translational,” “rodent,” “rat,” “mouse,” “model,” “amyloid,” “neurofibrillary tangles,” “α-synuclein,” or “presenilin.” When relevant, “species” (i.e., “humans” or “other animals”) was selected as an additional filter. Review articles were avoided when possible. SEARCH RESULTS The two terms “alcoholism” and “aging” retrieved about 1,350 papers; adding phrases—for example, “postmortem” or “magnetic resonance”—limited the number to fewer than 100 papers. Using the traditional term, “alcoholism” with “dementia” resulted in 876 citations, but using the currently accepted term “alcohol use disorder (AUD)” with “dementia” produced only 87 papers. Similarly, whereas the terms “Alzheimer’s” and “alcoholism” yielded 318 results, “Alzheimer’s” and “alcohol use disorder (AUD)” returned only 40 citations. As pertinent postmortem pathology papers were published in the 1950s and recent animal models of Alzheimer’s disease were created in the early 2000s, articles referenced span the years 1957 to 2024. In total, more than 5,000 articles were considered; about 400 are herein referenced. DISCUSSION AND CONCLUSIONS Chronic alcohol misuse accelerates brain aging and contributes to cognitive impairments, including those in the mnemonic domain. The consensus among studies from multiple disciplines, however, is that alcohol misuse can increase the risk for dementia, but not necessarily Alzheimer’s disease. Key issues to consider include the reversibility of brain damage following abstinence from chronic alcohol misuse compared to the degenerative and progressive course of ...

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“…Indeed, IHC (i.e. MBP, MAG, PLP antigens) are widely used in neuropathology (Adiele & Adiele, 2019; Beach et al, 2023; Kuhlmann et al, 2017; Stüber et al, 2014; Vakrakou et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Comparison of histological procedures and antigenicity of human post-mortem brains fixed with solutions used in gross anatomy laboratories

Frigon,

Gérin-Lajoie,

Dadar

et al. 2024

Preprint

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Background: Brain banks provide small tissue samples to researchers, while gross anatomy laboratories could provide larger samples, including complete brains to neuroscientists. However, they are preserved with solutions appropriate for gross-dissection, different from the classic neutral-buffered formalin (NBF) used in brain banks. Our previous work in mice showed that two gross-anatomy laboratory solutions, a saturated-salt-solution (SSS) and an alcohol-formaldehyde-solution (AFS), preserve antigenicity of the main cellular markers. Our goal is now to compare the quality of histology and antigenicity preservation of human brains fixed with NBF by immersion (practice of brain banks) vs. those fixed with a SSS and an AFS by whole body perfusion, practice of gross-anatomy laboratories. Methods: We used a convenience sample of 42 brains (31 males, 11 females; 25-90 years old) fixed with NBF (N=12), SSS (N=13), and AFS (N=17). One cm3 tissue blocks were cut, cryoprotected, frozen and sliced into 40 um sections. The four cell populations were labeled using immunohistochemistry (neuronal-nuclei (NeuN), glial-fibrillary-acidic-protein (GFAP), ionized-calcium-binding-adaptor-molecule1 (Iba1) and myelin-proteolipid-protein (PLP)). We qualitatively assessed antigenicity and cell distribution, and compared the ease of manipulation of the sections, the microscopic tissue quality, and the quality of common histochemical stains (e.g., Cresyl violet, Luxol fast blue, etc.) across solutions. Results: Sections of SSS-fixed brains were more difficult to manipulate and showed poorer tissue quality than those from brains fixed with the other solutions. The four antigens were preserved, and cell labeling was more often homogenous in AFS-fixed specimens. NeuN and GFAP were not always present in the NBF and SSS samples. Some antigens were heterogeneously distributed in some specimens, independently of the fixative, but an antigen retrieval protocol successfully recovered them. Finally, the histochemical stains were of sufficient quality regardless of the fixative, although neurons were more often paler in SSS-fixed specimens. Conclusion: Antigenicity was preserved in human brains fixed with solutions used in human gross-anatomy (albeit the poorer quality of SSS-fixed specimens). For some specific variables, histology quality was superior in AFS-fixed brains. Furthermore, we show the feasibility of frequently used histochemical stains. These results are promising for neuroscientists interested in using brain specimens from anatomy laboratories.

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Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy

Cited by 7 publications

References 88 publications

Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer’s Disease Dementia: Evidence for Dependency on Alzheimer’s Disease Neuropathological Changes

Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer’s Disease Dementia: Evidence for Dependency on Alzheimer’s Disease Neuropathological Changes

Alcohol Use Disorder and Dementia: A Review

Comparison of histological procedures and antigenicity of human post-mortem brains fixed with solutions used in gross anatomy laboratories

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