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Lower MRI‐indexed locus coeruleus integrity in autosomal‐dominant Alzheimer's disease
Author(s) -
Dahl Martin J,
Mather Mara,
WerkleBergner Markus,
Kennedy Brianna L,
Qiao Yuchuan,
Shi Yonggang,
Ringman John M
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047676
Subject(s) - locus coeruleus , neuromelanin , brainstem , neuroscience , pathology , locus (genetics) , magnetic resonance imaging , psychology , medicine , disease , biology , central nervous system , parkinson's disease , radiology , genetics , substantia nigra , gene
Background Tau pathology, a hallmark of Alzheimer’s disease, accumulates early in life in the locus coeruleus, the primary source of cortical norepinephrine. Dysfunctions in the noradrenergic system are hypothesized to contribute to Alzheimer’s progression; however, in‐vivo evidence has been impeded by methodological challenges in non‐invasive assessments. Advances in high‐resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s‐related neuropathological markers in vivo. Method Eighteen participants (34.7±10.1 years; 9♀) with or known to be at‐risk for mutations in genes associated with autosomal‐dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants ( PSEN1 , n = 6; APP , n = 1), of which four were symptomatic. Participants underwent 3T‐MRI, flortaucipir positron emission tomography (PET), and cognitive testing. Locus coeruleus MRI intensity, a non‐invasive proxy for neuronal density, was semi‐automatically extracted from high‐resolution brainstem scans. Locus coeruleus ratios—that is, a ratio of peak locus coeruleus intensity standardized to a pontine reference—were computed across the rostrocaudal extent of the nucleus. Standard uptake value ratios (SUVR) were calculated from partial volume corrected flortaucipir PET data using cerebellar gray matter as reference. SUVR images were mapped to the cortical surface which was parcellated into 36 regions of interest. Associations between locus coeruleus ratios, clinical variables, cognitive status, and tau burden were evaluated using non‐parametric Mann‐Whitney U‐tests and bootstrapped Spearman’s correlations. Result Relative to healthy controls, symptomatic participants showed lower locus coeruleus ratios (Z = 2.177; p = 0.03). This effect was pronounced in rostral segments of the nucleus (Z = 3.077; p = 0.002) that project to the hippocampus. Among carriers of ADAD‐causing mutations, closer proximity to the mutation‐specific median age of dementia diagnosis was associated with lower locus coeruleus ratios ( rho = ‐0.727; p = 0.048). Higher locus coeruleus ratios were observed in participants with unimpaired cognitive performance ( rho = 0.527; p = 0.022). Tau burden, especially in occipito‐temporo‐parietal regions, was related to lower locus coeruleus ratios ( rho = 0.54, p = 0.036). Conclusion Our finding of diminished locus coeruleus integrity in autosomal‐dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.