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Progressive white matter injury in autosomal dominant Alzheimer’s disease is strongly associated with cerebral microbleeds and neurodegeneration

dc.contributor.authorShirzadi, Zahra
dc.contributor.authorSchultz, Stephanie A.
dc.contributor.authorYau, Wai-Ying Wendy
dc.contributor.authorJoseph-Mathurin, Nelly
dc.contributor.authorKantarci, Kejal
dc.contributor.authorPreboske, Gregory M.
dc.contributor.authorJack, Clifford R.
dc.contributor.authorFarlow, Martin R.
dc.contributor.authorFagan, Anne M.
dc.contributor.authorHassenstab, Jason J.
dc.contributor.authorJucker, Mathias
dc.contributor.authorMorris, John C.
dc.contributor.authorXiong, Chengjie
dc.contributor.authorKarch, Celeste M.
dc.contributor.authorFitzpatrick, Colleen D
dc.contributor.authorLevey, Allan I.
dc.contributor.authorGordon, Brian A.
dc.contributor.authorSchofield, Peter W.
dc.contributor.authorSalloway, Stephen P.
dc.contributor.authorPerrin, Richard J.
dc.contributor.authorMcDade, Eric
dc.contributor.authorLevin, Johannes
dc.contributor.authorCruchaga, Carlos
dc.contributor.authorAllegri, Ricardo Francisco
dc.contributor.authorFox, Nick C
dc.contributor.authorGoate, Alison
dc.contributor.authorGraff-Radford, Neill R.
dc.contributor.authorKoeppe, Robert
dc.contributor.authorNoble, James M
dc.contributor.authorChui, Helena C
dc.contributor.authorBerman, Sarah
dc.contributor.authorMori, Hiroshi
dc.contributor.authorSanchez-Valle, Raquel
dc.contributor.authorLee, Jae-Hong
dc.contributor.authorRosa-Neto, Pedro
dc.contributor.authorBenzinger, Tammie L.S.
dc.contributor.authorSohrabi, Hamid R
dc.contributor.authorMartins, Ralph N
dc.contributor.authorSchultz, Aaron P.
dc.contributor.authorBateman, Randall J.
dc.contributor.authorJohnson, Keith A.
dc.contributor.authorSperling, Reisa A.
dc.contributor.authorGreenberg, Steven M
dc.contributor.authorChhatwal, Jasmeer P.
dc.date.accessioned2023-01-11T16:28:11Z
dc.date.available2024-01-11 11:28:10en
dc.date.available2023-01-11T16:28:11Z
dc.date.issued2022-12
dc.identifier.citationShirzadi, Zahra; Schultz, Stephanie A.; Yau, Wai-Ying Wendy ; Joseph-Mathurin, Nelly ; Kantarci, Kejal; Preboske, Gregory M.; Jack, Clifford R.; Farlow, Martin R.; Fagan, Anne M.; Hassenstab, Jason J.; Jucker, Mathias; Morris, John C.; Xiong, Chengjie; Karch, Celeste M.; Fitzpatrick, Colleen D; Levey, Allan I.; Gordon, Brian A.; Schofield, Peter W.; Salloway, Stephen P.; Perrin, Richard J.; McDade, Eric; Levin, Johannes; Cruchaga, Carlos; Allegri, Ricardo Francisco; Fox, Nick C; Goate, Alison; Graff-Radford, Neill R. ; Koeppe, Robert; Noble, James M; Chui, Helena C; Berman, Sarah; Mori, Hiroshi; Sanchez-Valle, Raquel ; Lee, Jae-Hong ; Rosa-Neto, Pedro ; Benzinger, Tammie L.S.; Sohrabi, Hamid R; Martins, Ralph N; Schultz, Aaron P.; Bateman, Randall J.; Johnson, Keith A.; Sperling, Reisa A.; Greenberg, Steven M; Chhatwal, Jasmeer P. (2022). "Progressive white matter injury in autosomal dominant Alzheimer- s disease is strongly associated with cerebral microbleeds and neurodegeneration." Alzheimer’s & Dementia 18: n/a-n/a.
dc.identifier.issn1552-5260
dc.identifier.issn1552-5279
dc.identifier.urihttps://hdl.handle.net/2027.42/175531
dc.description.abstractBackgroundWhite matter (WM) injury visible on MRI is a common finding in Alzheimer’s disease (AD) and is often attributed to small vessel ischemic changes secondary to increased systemic vascular risk. Increased WM injury has been associated with the progression of Autosomal Dominant AD (ADAD), though ADAD pathogenic variant carriers are relatively young and may not have elevated vascular risk factors. We hypothesized that WM injury in ADAD may reflect worsening of cerebral amyloid angiopathy (CAA) and neurodegeneration. Here we examine this hypothesis using cross-sectional and longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN).MethodMRI data from ADAD pathogenic variant carriers (n=223) and non-carriers (n=136) were used in the present study (Table 1). We extracted FreeSurfer-based WM lesion (WML) volume from T1-weighted images (hypointensities). Cortical microbleed (CMB) burden was assessed visually on susceptibility weighted/T2*-weighted gradient echo images by experienced radiologists (blineded to the mutation status) at the Mayo Clinic in Rochester. Linear regression models compared WML volume at baseline in people with and without CMB. Linear mixed effect models assessed the relationships between longitudinal WML and both CMBs and FreeSurfer-based total gray matter (GM) volume. Models were corrected for age and estimated years to symptom onset (EYO).ResultGreater baseline WML volume was seen in ADAD carriers vs. non-carriers, particularly close to the age of estimated symptom onset. Baseline WML volume was greater in carriers with CMBs compared to those without (t=2.9, p=0.003, Figure 1). Longitudinal increase in WML amongst ADAD pathogenic variant carriers with CMBs was estimated to be 214 mm3/year greater than that amongst carriers without CMBs (t=4.1, p<0.001, Figure 2). Independent of this CMB effect, decreasing GM volume was strongly associated with increasing longitudinal WML volume (t=-6.2, p<0.001, Figure 3). Similar analyses in the non-carrier group yielded no significant findings.ConclusionConsistent with prior reports, WML volume was increased in ADAD pathogenic variant carriers. However, the results here suggest WML in ADAD may not solely be due to small vessel ischemic changes, but rather may be a result of worsening CAA and more rapid neurodegeneration.
dc.publisherWiley Periodicals, Inc.
dc.titleProgressive white matter injury in autosomal dominant Alzheimer’s disease is strongly associated with cerebral microbleeds and neurodegeneration
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelNeurology and Neurosciences
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/175531/1/alz066715.pdf
dc.identifier.doi10.1002/alz.066715
dc.identifier.sourceAlzheimer’s & Dementia
dc.working.doiNOen
dc.owningcollnameInterdisciplinary and Peer-Reviewed


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