Browsing by Author "Kofler, Julia K."

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    11C-PiB PET can underestimate brain amyloid-β burden when cotton wool plaques are numerous
    (Oxford University Press, 2022) Abrahamson, Eric E.; Kofler, Julia K.; Becker, Carl R.; Price, Julie C.; Newell, Kathy L.; Ghetti, Bernardino; Murrell, Jill R.; McLean, Catriona A.; Lopez, Oscar L.; Mathis, Chester A.; Klunk, William E.; Villemagne, Victor L.; Ikonomovic, Milos D.; Pathology and Laboratory Medicine, School of Medicine
    Individuals with familial Alzheimer's disease due to PSEN1 mutations develop high cortical fibrillar amyloid-β load but often have lower cortical 11C-Pittsburgh compound B (PiB) retention than Individuals with sporadic Alzheimer's disease. We hypothesized this is influenced by limited interactions of Pittsburgh compound B with cotton wool plaques, an amyloid-β plaque type common in familial Alzheimer's disease but rare in sporadic Alzheimer's disease. Histological sections of frontal and temporal cortex, caudate nucleus and cerebellum were obtained from 14 cases with sporadic Alzheimer's disease, 12 cases with familial Alzheimer's disease due to PSEN1 mutations, two relatives of a PSEN1 mutation carrier but without genotype information and three non-Alzheimer's disease cases. Sections were processed immunohistochemically using amyloid-β-targeting antibodies and the fluorescent amyloid stains cyano-PiB and X-34. Plaque load was quantified by percentage area analysis. Frozen homogenates from the same brain regions from five sporadic Alzheimer's disease and three familial Alzheimer's disease cases were analysed for 3H-PiB in vitro binding and concentrations of amyloid-β1-40 and amyloid-β1-42. Nine sporadic Alzheimer's disease, three familial Alzheimer's disease and three non-Alzheimer's disease participants had 11C-PiB PET with standardized uptake value ratios calculated using the cerebellum as the reference region. Cotton wool plaques were present in the neocortex of all familial Alzheimer's disease cases and one sporadic Alzheimer's disease case, in the caudate nucleus from four familial Alzheimer's disease cases, but not in the cerebellum. Cotton wool plaques immunolabelled robustly with 4G8 and amyloid-β42 antibodies but weakly with amyloid-β40 and amyloid-βN3pE antibodies and had only background cyano-PiB fluorescence despite labelling with X-34. Relative to amyloid-β plaque load, cyano-Pittsburgh compound B plaque load was similar in sporadic Alzheimer's disease while in familial Alzheimer's disease it was lower in the neocortex and the caudate nucleus. In both regions, insoluble amyloid-β1-42 and amyloid-β1-40 concentrations were similar in familial Alzheimer's disease and sporadic Alzheimer's disease groups, while 3H-PiB binding was lower in the familial Alzheimer's disease than the sporadic Alzheimer's disease group. Higher amyloid-β1-42 concentration associated with higher 3H-PiB binding in sporadic Alzheimer's disease but not familial Alzheimer's disease. 11C-PiB retention correlated with region-matched post-mortem amyloid-β plaque load; however, familial Alzheimer's disease cases with abundant cotton wool plaques had lower 11C-PiB retention than sporadic Alzheimer's disease cases with similar amyloid-β plaque loads. PiB has limited ability to detect amyloid-β aggregates in cotton wool plaques and may underestimate total amyloid-β plaque burden in brain regions with abundant cotton wool plaques.
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    Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer’s Disease Dementia: Evidence for Dependency on Alzheimer’s Disease Neuropathological Changes
    (medRxiv, 2023-08-16) Sepulveda-Falla, Diego; Lanau, Carlos Andrés Villegas; White, Charles, III; Serrano, Geidy E.; Acosta-Uribe, Juliana; Mejía-Cupajita, Barbara; Villalba-Moreno, Nelson David; Lu, Pinzhang; Glatzel, Markus; Kofler, Julia K.; Ghetti, Bernardino; Frosch, Matthew P.; Restrepo, Francisco Lopera; Kosik, Kenneth S.; Beach, Thomas G.; Pathology and Laboratory Medicine, School of Medicine
    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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    Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study
    (Nature Research, 2020-02-03) Reiman, Eric M.; Arboleda-Velasquez, Joseph F.; Quiroz, Yakeel T.; Huentelman, Matthew J.; Beach, Thomas G.; Caselli, Richard J.; Chen, Yinghua; Su, Yi; Myers, Amanda J.; Hardy, John; Vonsattel, Jean Paul; Younkin, Steven G.; Bennett, David A.; De Jager, Philip L.; Larson, Eric B.; Crane, Paul K.; Keene, C. Dirk; Kamboh, M. Ilyas; Kofler, Julia K.; Duque, Linda; Gilbert, John R.; Gwirtsman, Harry E.; Buxbaum, Joseph D.; Dickson, Dennis W.; Frosch, Matthew P.; Ghetti, Bernardino F.; Lunetta, Kathryn L.; Wang, Li-San; Hyman, Bradley T.; Kukull, Walter A.; Foroud, Tatiana; Haines, Jonathan L.; Mayeux, Richard P.; Pericak-Vance, Margaret A.; Schneider, Julie A.; Trojanowski, John Q.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Beecham, Gary W.; Montine, Thomas J.; Jun, Gyungah R.; Alzheimer’s Disease Genetics Consortium; Pathology and Laboratory Medicine, School of Medicine
    Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.