Locus coeruleus signal intensity in progressive amnesia due to suspected non‐Alzheimer pathophysiology (SNAP)

Abstract

AbstractBackgroundSuspected non‐Alzheimer pathophysiology (SNAP) is underlain by different pathophysiological processes, among which the recently described Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), which refers to patients with cognitive/memory impairment and limbic‐predominant TDP‐43 proteinopathy, associated or not with hippocampal sclerosis (HS) characterized by severe neuronal loss and gliosis in the CA‐1 and subiculum of the hippocampal formation (Besser and al. J Neuropathol Exp Neurol. 2019), or primary age‐related tauopathy (PART). The locus coeruleus (LC) is the major noradrenergic nucleus in the brain. In AD, the early LC neuronal loss could contribute to cognitive deficits, especially mental flexibility and memory retrieval impairments (Grudzien and al. Neurobiol. Aging, 2007). The involvement of LC alteration in amnestic SNAP patients has not been studied.MethodWe included 10 SNAP subjects defined by episodic memory deficit of the hippocampal type, normal CSF biomarkers profile and negative amyloid‐PET, 26 typical AD patients defined by clinical‐biological criteria (episodic memory deficit of the hippocampal type associated with CSF biomarkers AD profile and positive amyloid PET), and 14 controls with negative amyloid‐PET. All patients had a Clinical Dementia Rating scale ≤ 1. We used the LC signal intensity (LC‐I) on 3T MRI (Neuromelanin‐sensitive T1‐weighted images) as a marker of LC atrophy (Shibata and al. Magn Reson Med Sci. 2006).ResultsSNAP patients were older than AD patients (77.9 years and 70.8 years respectively, p=0.002), with a lower proportion of APOE4 carriers. We found no difference between SNAP and AD groups in neuropsychological scores, especially for MMSE, and verbal or visual episodic memory scores, as well as for hippocampal or entorhinal cortex volumes. We found a significant decrease of the LC‐I in SNAP patients compared with controls (p<0.003) or with AD patients (p<0.009). The episodic memory score was positively correlated with the LC‐I (r=0.33, p=0.034) in SNAP patients.ConclusionOur results suggest a significant LC alteration in patients with amnesia not due to AD. LC involvement could not be specific of AD pathology, and could also be part of the pathophysiological process of non‐AD diseases. Amnestic SNAP patients could thus benefit from innovative therapeutic approaches targeting the noradrenergic system.