Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease

Abstract

Objective Parkinson's disease (PD) episodic memory impairments are common; however, it is not known whether these impairments are due to hippocampal pathology. Hippocampal Lewy-bodies emerge by Braak stage 4, but are not uniformly distributed. For instance, hippocampal CA1 Lewy-body pathology has been specifically associated with pre-mortem episodic memory performance in demented patients. By contrast, the dentate gyrus (DG) is relatively free of Lewy-body pathology. In this study, we used ultra-high field 7-Tesla to measure hippocampal subfields in vivo and determine if these measures predict episodic memory impairment in PD during life. Methods We studied 29 participants with PD (age 65.5 ± 7.8 years; disease duration 4.5 ± 3.0 years) and 8 matched-healthy controls (age 67.9 ± 6.8 years), who completed comprehensive neuropsychological testing and MRI. With 7-Tesla MRI, we used validated segmentation techniques to estimate CA1 stratum pyramidale (CA1-SP) and stratum radiatum lacunosum moleculare (CA1-SRLM) thickness, dentate gyrus/CA3 (DG/CA3) area, and whole hippocampus area. We used linear regression, which included imaging and clinical measures (age, duration, education, gender, and CSF), to determine the best predictors of episodic memory impairment in PD. Results In our cohort, 62.1% of participants with PD had normal cognition, 27.6% had mild cognitive impairment, and 10.3% had dementia. Using 7-Tesla MRI, we found that smaller CA1-SP thickness was significantly associated with poorer immediate memory, delayed memory, and delayed cued memory; by contrast, whole hippocampus area, DG/CA3 area, and CA1-SRLM thickness did not significantly predict memory. Age-adjusted linear regression models revealed that CA1-SP predicted immediate memory (beta[standard error]10.895[4.215], p < .05), delayed memory (12.740[5.014], p < .05), and delayed cued memory (12.801[3.991], p < .05). In the fully-adjusted models, which included all five clinical measures as covariates, only CA1-SP remained a significant predictor of delayed cued memory (13.436[4.651], p < .05). Conclusions In PD, we found hippocampal CA1-SP subfield thickness estimated on 7-Tesla MRI scans was the best predictor of episodic memory impairment, even when controlling for confounding clinical measures. Our results imply that ultra-high field imaging could be a sensitive measure to identify changes in hippocampal subfields and thus probe the neuroanatomical underpinnings of episodic memory impairments in patients with PD.

Multiparametric imaging hippocampal neurodegeneration and functional connectivity with simultaneous PET/MRI in Alzheimer’s disease

“…In patients with AD, the CA1 region was severely affected by neuron number and neurofibrillary tangle, which were significantly related to CDR scores [43]. A recent autopsy study also found that the degree of Lewy body pathology in CA1, but not CA2, predicted pre-mortem episodic memory impairment in patients with Lewy body dementia and Parkinson's disease [5,44]. Their findings suggested that CA1 might be more functionally relevant than CA2 and subiculum regions in memory impairment.…”

“…The hippocampus, as a structure playing a key role in cognitive processes, is known to remain central to the understanding of the Alzheimer's disease (AD) pathophysiology with sensitivity to the neurofibrillary tangle development and a strong association with progression to AD [1][2][3]. It is widely recognized that the hippocampus is heterogeneous and can be divided into subregions with different functions and vulnerabilities to neurodegenerative diseases [4][5][6]. While the hippocampal subregions are thought to exhibit distinct functions, the neural substrate for aberrant functionalities remains elusive.…”

“…Using in vivo MRI, the hippocampus can be divided into three subregions: cornu ammonis (CA1), CA2/3/dentate gyrus (CA2/3/DG), and subiculum [9]. Resting-state fMRI studies showed that the disrupted total hippocampal connectivity [10], right CA1 and left CA2 subregions connectivity [11], and subiculum network (functional connectivity with frontal and posterior cingulate cortex [PCC] regions) [12] in mild cognitive impairment (MCI) and AD patients were strongly associated with memory impairment [5,13,14]. In addition to fMRI, the fluorine 18 ( 18 F) fluorodeoxyglucose ( 18 F-FDG) PET showed that the glucose metabolism of the left hippocampal body CA2/3 and CA4/DG subregions was significantly lower in the early AD group than in the control group [15].…”

Cannabis Use is Associated with Lower Hippocampus and Amygdala Volume: High-Resolution Segmentation of Structural Subfields in a Large Non-clinical Sample

“…CA1 receives inputs from the DG and CA3 along the perforant path. CA1 has been specifically linked to episodic memory 14 , as well as memory retrieval and consolidation [15][16][17][18][19] , suggesting that those processes may be uniquely impacted by cannabis use. Additionally, the subfields that make up the subicular complex (subiculum, parasubiculum, presubiculum) were also associated with cannabis use.…”

“…Throughout these three divisions, the hippocampus consists of several histologically differing subfields that are interconnected through a number of pathways that pass information in and out of the hippocampus through the entorhinal cortex, and among the subfields of the hippocampus 11,12 . The hippocampal subfields have been shown to fulfill different roles in the memory processes conducted in the hippocampus; for example, the dentate gyrus and third section of the cornu ammonis (CA3) having been found to be involved in memory encoding 13 and early retrieval, while the first section of the cornu ammonis (CA1) has been linked with episodic memory 14 , memory consolidation, late retrieval, and recognition [15][16][17][18][19] . In the first study to examine the association of cannabis with hippocampal subfields, Chye et al 20 used Freesurfer's automated segmentation software (https://surfer.nmr.mgh.harvard.edu) to find many subfields of the hippocampus differentiated 39 cannabis dependent individuals from 35 non-users: CA1, CA2, CA3, CA4 and the dentate gyrus (DG).…”