Background and Objectives Early-onset Alzheimer disease (EOAD) is associated with substantial variability in clinical progression, and reliable biomarkers to predict the transition from mild cognitive impairment (MCI) to dementia remain limited. Structural MRI measures have demonstrated prognostic value in late-onset Alzheimer disease, but their utility for predicting progression in EOAD is less well understood. The goal was to examine whether baseline cortical atrophy predicts progression to dementia in patients with MCI because of EOAD. Methods This study included a well-characterized cohort of patients with EOAD enrolled in the large multisite natural history Longitudinal Early-Onset Alzheimer's Disease Study. Participants underwent standardized clinical assessments and structural MRI at baseline. Participants were aged between 40 and 64 years with biomarker-supported sporadic EOAD at the MCI stage. Cortical atrophy was measured within the EOAD-signature, a set of predominantly parieto-temporal regions showing greater atrophy in EOAD than in controls. Clinical severity was measured with the global Clinical Dementia Rating. Cox proportional hazards models estimated the association between baseline EOAD-signature atrophy burden and the hazard of progression to dementia over time. We evaluated whether EOAD-signature atrophy improved prognostic performance beyond baseline clinical severity using likelihood ratio tests, Akaike Information Criterion (AIC), and Harrell concordance index. Results A total of 130 patients with MCI due to EOAD (mean age 59.6 ± 4.1 years; 49% female) and 97 cognitively normal controls (mean age 56.9 ± 6.0 years; 64% female) were included. Greater baseline atrophy within the EOAD-signature predicted faster progression to dementia (hazard ratio [HR] = 1.24 per 1-SD increase in atrophy; 95% CI 1.13–1.37; p < 0.002). Adding EOAD-signature atrophy burden to a model including baseline clinical severity significantly improved model fit (ΔAIC = −4.5; likelihood ratio test p = 0.011). Discussion Baseline cortical atrophy within the EOAD-signature predicts progression from MCI to dementia in EOAD and provides prognostic information beyond baseline clinical severity. These findings support the potential value of EOAD-signature atrophy as an MRI-based biomarker for individualized prognostication and clinical trial stratification.
T. Paranhos, Yuta Katsumi, M. Brickhouse et al.· Neurology· 0 citations
Importance: The long-term efficacy of amyloid targeting therapies hinge on their ability to slow downstream neuropathologic change, but little is known about the influence of amyloid clearance on tau pathology and neurodegeneration. Objective: To determine the post-mortem and in vivo association between post-treatment amyloid levels and downstream neuropathology in a patient with patchy areas showing minimal residual amyloid following aducanumab therapy. Design, Setting, and Participants: Clinicopathologic case report from a single academic memory center. A p.R47H TREM2 (a variant associated with higher Alzheimer disease risk) male carrier in his 50s with mild cognitive impairment who received aducanumab in the EMERGE/EMBARK trials and 14 age- or TREM2-matched untreated controls from the Penn Center for Neurodegenerative Disease Research. Exposures: 30 doses of aducanumab (cumulative dose 280mg/kg) over 4.5 years. Main Outcomes and Measures: Neuropathologic evaluation of amyloid, tau, and neuroinflammation; Amyloid PET and Tau PET standardized uptake value ratio, longitudinal change in cortical thickness. Results: Four years after receiving his final dose of aducanumab, the patient died and autopsy demonstrated variable levels of amyloid pathology, including regions with very low amyloid juxtaposed with regions showing typical high amyloid burden in deep cortical layers with only low amyloid burden in superficial layers. Regions showing low post-treatment amyloid were preferentially found in gyral crests and were associated with less tau pathology than untreated controls on autopsy and slower longitudinal atrophy on in vivo MRI (β = −0.50, [−0.62, −0.37], t = −7.96, p < .001). In contrast, regions with high amyloid burden were preferentially found in sulcal depths and had similar levels of tau pathology as seen in untreated controls on autopsy. Conclusion and Relevance: In this case report, areas of extensive amyloid clearance following amyloid targeting therapy were associated with less downstream neuropathological change and appear to preferentially occur in gyral crests. Future studies should evaluate the differential mechanisms involved in amyloid clearance from superficial and deep cortical layers and in gyri and sulci, as extensive amyloid clearance may be necessary to achieve downstream neuropathologic benefit following amyloid removal.
C. A. Brown, J. Robinson, Sandhitsu R. Das et al.· Journal of the American Medi...· 0 citations
BACKGROUND AND OBJECTIVES
Histopathologic staging of Alzheimer disease has led to validation of imaging techniques that guide diagnosis and treatment. We previously constructed preliminary phases of the sequential progression of TDP-43 and tau to guide similar efforts in behavioral-variant frontotemporal dementia (bvFTD). In this article, we expand this work using digital pathology and longitudinal clinical data to more comprehensively model the relationship between clinical progression and the distribution and severity of postmortem frontotemporal lobar degeneration (FTLD) pathology.
METHODS
In this retrospective cohort study, 101 patients (42% female, median age at symptom onset = 63 years) were selected from the Penn Integrated Neurodegenerative Disease Database and had both longitudinal assessments and primary neuropathologic diagnosis of FTLD-Tau or FTLD-TDP. We used validated methods to quantify the burden of primary pathology from up to 6 cortical regions across hemispheres. FTLD-TDP pathologic phase was constructed from diagnostic pathology data based on published criteria. We tested the association between pathologic metrics and (1) disease duration or (2) the rate of clinic progression measured by 2 independent global measures (Clinical Dementia Rating Scale-Sum of Boxes [CDR-SB] and Mini-Mental State Examination [MMSE]). Linear regression and linear mixed-effects models were adjusted for hemisphere sampled, sex, age at onset, pathogenic variant status, and pathologic subtype.
RESULTS
Disease duration did not associate with pathologic burden in multiple regression (FTLD-TDP β = 0.01 [-0.06, 0.09]; p = 0.7; FTLD-Tau β = 0.1 [-0.4, 0.7]; p = 0.7). By contrast, mean TDP-43 burden, but not FTLD-Tau burden, was associated with both worse relative CDR-SB (β = 0.1 [0.06, 0.2]; p = 0.0001) and MMSE (β = -0.1 [-0.2, -0.03]; p = 0.009) among all FTLD-TDP patients. TDP-43 phase also associated with worse CDR-SB (β = 0.07 [0.02, 0.1]; p = 0.005) and MMSE (β = -0.2 [-0.3, -0.1]; p = 0.000005). TDP-43 burden (CDR-SB (β = 0.1 [0.03, 0.2]; p = 0.005 and MMSE (β = -0.2 [-0.4, -0.05]; p = 0.009)), but not phase (CDR-SB (β = 0.02 [-0.03, 0.08]; p = 0.4 and MMSE (β = -0.04 [-1, 0.07]; p = 0.5)), associated with relative decline in sensitivity analyses limited to bvFTD.
DISCUSSION
Greater TDP-43 burden was most closely associated with antemortem clinical decline rather than cumulative aggregation through the disease course. These human data suggest that the temporal dynamics of protein aggregation may differ among FTLD proteinopathies, with implications for the interpretation of FTLD-Tau and FTLD-TDP‑specific biomarkers as these are developed.
R. Magee, Sharon X. Xie, DT Ohm et al.· Neurology· 1 citation
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