Substantia Nigra MRI markers are lower in Alzheimer's disease and are linked to novelty and memory

Individuals with Alzheimers disease dementia (ADD) show Alzheimers disease (AD) pathology in and heterogeneous degeneration of the Substantia Nigra (SN) postmortem. However, it is unclear how the SN degeneration is related to cognitive dysfunction across the ADD continuum. In this study, using data from a prospective dementia study (DELCODE), we investigated if in-vivo SN MRI measures are lower in cases with clinically defined ADD than in healthy control subjects (HC) and associated with functional activity during the processing of novel visual stimuli and subsequent recognition memory. 161 DELCODE participants (69 years {+/-}6 years, 88 men), including 79 Healthy Controls, 71 individuals with subjective cognitive impairment (SCD), 17 individuals with mild cognitive impairment (MCI), and 10 individuals with ADD, completed a scene novelty and encoding task and a 3T neuromelanin (NM)-sensitive MRI scan, from which in-vivo measures of SN MRI contrast and SN volume were calculated. For 71 individuals, CSF levels of phospoTau, total tau, and amyloid beta 42/40 ratio (A{beta}42/40) were available. All individuals completed a neuropsychological task battery from which a global cognitive score was calculated. SN volume but not SN MRI contrast was lower in individuals with clinical ADD (One- way ANOVA: F(3,156)=4,13, N=160, p=0.0056, Tukey posthoc test: p=0.003) and SN MRI contrast and and volume were not associated with A{beta}42/40, ptau, and ttau CSF levels (all p<0.1). SN MRI contrast was positively associated with anterior hippocampal functional activity during the presentation of novel stimuli in individuals with A{beta}42/40 ratio levels below a pathological threshold of 0.08 (A{beta}42/40 positive, (p(FWE)=0.002, 157 voxels, n=28) but not in A{beta}42/40 negative individuals. Moreover, SN volume was positively associated with recognition memory (N=160, p=0.017, r2=0.11) and global cognition (p<0.0001, N=160, r2=0.221) across the ADD continuum. Our study emphasizes the potential of using in-vivo SN MRI markers to understand the impact of AD pathology-independent SN degeneration on recognition memory and novelty processing dysfunction in ADD. Our results motivate future longitudinal studies exploring how SN volume and SN contrast change over time, how these differentially associate with cognitive decline and how the SN volume and SN contrast might be associated with other dopamine-dependent cognitive functions.