Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome

Article type: Research Article

Authors: Lao, Patrick J.^{a; b; *} | Handen, Ben L.^{c; d; e; f} | Betthauser, Tobey J.^{a; b} | Mihaila, Iulia^{b; h} | Hartley, Sigan L.^{b; h} | Cohen, Annie D.^c | Tudorascu, Dana L.^{c; i; j} | Bulova, Peter D.ⁱ | Lopresti, Brian J.^k | Tumuluru, Rameshwari V.^c | Murali, Dhanabalan^{a; b} | Mathis, Chester A.^k | Barnhart, Todd E.^a | Stone, Charles K.^l | Price, Julie C.^{k; m} | Devenny, Darlynne A.ⁿ | Johnson, Sterling C.^o | Klunk, William E.^{c; g} | Christian, Bradley T.^{a; b; p}

Affiliations: [a] Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA | [b] University of Wisconsin-Madison, Waisman Center, Madison, WI, USA | [c] Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA | [d] Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA | [e] Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA | [f] Department of Instruction and Learning, University of Pittsburgh, Pittsburgh, PA, USA | [g] Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA | [h] Department of Human Development and Family Studies, University of Wisconsin-Madison, Madison, WI, USA | [i] Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA | [j] Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA | [k] Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA | [l] Department of Cardiovascular Medicine, University of Wisconsin-Madison, Madison, WI, USA | [m] Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA | [n] New York State Institute for Research in Developmental Disabilities, Staten Island, NY, USA | [o] Department of Medicine-Geriatrics, University of Wisconsin-Madison, Madison, WI, USA | [p] Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA

Correspondence: [*] Correspondence to: Patrick Lao, PhD, 1500 Highland Ave., Madison, WI 53705, USA. Tel.: +1 608 890 2959; E-mail: [email protected].

Abstract: Background:The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer’s disease (AD). Objective:The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. Methods:Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. Results:Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. Conclusions:In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Keywords: Alzheimer’s disease, amyloid-β, Down syndrome, fluorodeoxyglucose, glucose metabolism, gray matter, magnetic resonance imaging, Pittsburgh compound B

DOI: 10.3233/JAD-170720

Journal: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 631-644, 2018