Substantia nigra integrity is associated with poorer recognition memory for novel stimuli in early Alzheimer’s disease

Abstract

AbstractBackgroundThe substantia nigra/ventral tegmental area (SN/VTA), the brain’s most prominent dopamine source, is involved in novelty exploration and episodic memory. Using a novelty detection task combined with neuromelanin‐sensitive MRI, this work aimed to investigate the relationship between SN integrity, neural novelty response and subsequent recognition memory performance in individuals with early Alzheimer’s disease.Method79 healthy subjects, 54 participants with subjective cognitive decline (SCD), 18 with mild cognitive impairment (MCI), and 10 individuals with ADD from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study performed a previously published scene novelty and encoding task (“FADE”) using 3T fMRI. Additional 3D T1‐weighted FLASH images were collected to visualize and quantify the volume and MRI contrast in the SN.Linear regression models were generated to assess for associations between either SN volume and median MRI contrast, considered as proxy integrity measures, with functional activity during novelty and subsequent recognition memory performance (dprime). We used site, gender, age and years of education as covariates. We assessed AD pathology in a subsample of individuals with CSF biomarkers (n = 71).ResultWe observed a significant decline in SN volume (p = 0.003) but not MRI contrast in ADD compared to healthy controls. The SN volume in the whole sample correlated positively with recognition memory for novel stimuli (r = 0.35; p = 0.02,). This association held in the CSF subsample (r = 0.31; p = 0.034) and also after correcting for levels of both tau (phosphotau, r = 0.57; p = 0.0284,) and amyloid (Abeta 42/40 ratio, r = 0.46; p = 0.03,). Additionally, SN median MRI contrast significantly correlated with novelty responses in the hippocampus in the CSF subsample and also in amyloid positive but not negative (Abeta 42/40 ratio<0.08, n = 26) individuals. Finally, recognition memory (p<0.001) was significantly decreased in Abeta positive compared to negative individuals.ConclusionWe show that significant degeneration to the SN in AD dementia and pathological Abeta 42/40 levels are associated with poorer recognition memory for novel stimuli. Moreover, associations between SN median MRI contrast and novelty responses differed between amyloid positive and negative individuals. These results indicate that degeneration to the SN may contribute to memory dysfunction in AD dementia which may be linked to pathological amyloid levels.