Mintz, Akiva

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Background: Fibroblast activation protein (FAP) is a membrane-bound protease that is highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers. With limited expression observed in normal tissues, FAP is a promising therapeutic and imaging target for delivery of radionuclides to cancer tissues. FAP-2286, a low-molecular-weight cyclic peptide that potently and selectively binds to FAP, is attached to a linker and tetraazacyclododecane tetraacetic acid (DOTA) cage that can be used to conjugate radionuclides such as lutetium-177 (177Lu) or gallium-68 (68Ga) for therapeutic or imaging applications, respectively. 177Lu-FAP-2286 has demonstrated antitumor activity in preclinical studies. The LuMIERE study (NCT04939610) is the first phase 1/2 clinical trial of an FAP-targeted radionuclide therapy evaluating 177Lu-FAP-2286 in patients with FAP-expressing solid tumors that are identified with the imaging agent 68Ga-FAP-2286. Methods: Eligible adult patients with advanced or metastatic solid tumors and measurable disease (per RECIST v1.1) will be selected for treatment with 177Lu-FAP-2286 on the basis of FAP expression using 68Ga-FAP-2286. In phase 1, tumors must be refractory to or have progressed following prior treatment, with no satisfactory alternative treatment options. Phase 1 includes dose escalation of 177Lu-FAP-2286, starting at 3.7 GBq to a maximum of 9.25 GBq. Patients may receive up to 6 cycles of 177Lu-FAP-2286 administered on day 1 of each 6-week cycle. Three to 12 patients will be treated at each dose level in the dose-escalation portion. Tolerability will be assessed across multiple doses for determination of a recommended phase 2 dose (RP2D), which may be further evaluated in a phase 1 dose-expansion portion. FDG-PET/CT scans will be collected prior to treatment, and patients will be imaged by planar and SPECT/CT scans at multiple time points to calculate organ and tumor dosimetry to determine absorbed radiation dose. Disease status will be assessed per RECIST v1.1 every 6 weeks. The primary objective of phase 1 is to evaluate the safety of 177Lu-FAP-2286 and determine the RP2D. Secondary objectives include the assessment of radiation dosimetry, pharmacokinetics, and preliminary efficacy of 177Lu-FAP-2286 and the evaluation of safety and tumor uptake of 68Ga-FAP-2286. Phase 2 will evaluate the efficacy, safety, and dosimetry of 177Lu-FAP-2286 in patients with select FAP-expressing solid tumors. Citation Format: Jonathan McConathy, Mallika Dhawan, Ajit H. Goenka, Emerson A. Lim, Yusuf Menda, Beth Chasen, Moh'd Khushman, Akiva Mintz, Yousef Zakharia, John J. Sunderland, Owen Bowles, Jim Xiao, Andrew D. Simmons, Kenton Wride, Aaron Enke, Thomas A. Hope. LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT251.