A comparative study of posterior cingulate metabolism in patients with mild cognitive impairment due to Parkinson’s disease or Alzheimer’s disease – Scientific Reports

Mild cognitive impairment (MCI) precedes both Alzheimer’s disease (AD)- and Parkinson’s disease (PD)-associated dementia^2,3,4,13. This is the first comparative study to examine metabolic patterns in the PCC (via single voxel ¹H-MRS) between these two commonly neurodegenerative diseases. In the current study, the main findings were as follows. (1) Among the groups investigated, only the PCC in ADMCI cases showed significantly altered glial metabolism (Ins levels). (2) The levels of tCr were significantly reduced in the progression of cognitive impairment in PD, while in ADMCI, tCr remained unchanged. (3) Unlike ADMCI patients, individuals with PDMCI showed significantly reduced NAA, tCr, GSH, Cho and Glx levels in the PCC, but no changes were found in the PDN group. These findings suggest that ¹H-MRS of the PCC demonstrate distinct metabolic brain abnormalities in potential PDMCI and ADMCI patients. There was no metabolic alteration in the PDN group, perhaps ¹H-MRS of the PCC may be helpful for predicting cognitive impairment in PD progression. These findings may also suggest that different treatment strategies should be adopted for cognitive impairment between these two neurodegenerative disorders.

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   Different metabolic patterns in the PCC between PDMCI and ADMCI patients.

In the ADMCI group, the metabolic pattern of the PCC is well documented¹², consisting of elevated Ins concentration or Ins/Cr ratio^13,14. It has been suggested that Ins/Cr elevation in ADMCI possibly represents gliosis or indicates inflammation^1,29. Many ¹H-MRS studies in AD have detected reduced NAA and increased Ins, with less consistent findings for other metabolites³⁰, and reduced NAA/Ins ratio is a potential biomarker for predicting progression to AD as proposed by Mitolo et al.¹³. We also found elevated Ins amounts and reduced NAA/Ins ratio in PCC in ADMCI cases. However, there was a significant reduction in NAA with no changes of Ins in PDMCI, consistent with the notion that NAA is a marker of functional integrity of neurons and emphasizes that PCC pathology is likely involved in PDMCI progression²⁶. Specifically, NAA reduction in PDMCI is associated with neuronal loss, axonal injury and compromised neuronal energy metabolism, which was confirmed by other neuroimaging methods documenting gray matter atrophy²⁰, abnormal white matter integrity³¹ and lower CBF perfusion³² in the PCC of PD patients with cognitive impairment.

In addition to NAA reduction, tCr was also significantly decreased in the PDMCI group, and these changes were found in neither ADMCI nor PDN. Cr is considered a biomarker of energy metabolism, which is typically used as an internal control metabolite in ¹H-MRS^10,30. Early in 2002, Neill et al.³³ found a 24% loss of Cr in the substantia nigra (SN), and suggested loss of neurons and/or glia in the SN in PD. Therefore, putative changes in Cr in PD argue against Cr use as an internal reference in the quantitation of ¹H-MRS-derived metabolite peaks; additionally, Cr may differ between gray and white matters, Cr varies regionally across the brain, and Cr changes with normal aging^34,35. Our results also suggested that Cr amounts varied during PD progression and is not suitable as an internal control metabolite. So, there were less consistent findings for assessing metabolites by ¹H-MRS in tracking cognitive decline in PD, may be due to using Cr as an internal control metabolite. Otherwise, in ADMCI, Cr levels remained stable during AD progression. Unlike AD, single voxel ¹H-MRS of the PCC failed to show a significant association with cognitive status at baseline or over time. In the current study, we also adopted tCr ratio for investigating metabolic changes in the PCC among groups, but less useful information was found (Fig. 2B).

Due to improved signal-to-noise ratio and the utilization of the LCmodel software, besides NAA, Cr and Ins, other metabolites such as GSH, Cho, Glu and Glx can also be detected in this study. Compared with HCs, PDMCI patients had reduced GSH, Cho and Glx in the PCC, and these changes were not found in ADMCI or PDN. GSH is an endogenous antioxidant that affects many cellular functions^36,37. Iskusnykh³⁶ revealed that impaired GSH function in the brain is linked to neuronal loss during the aging process or as a result of neurological diseases, including Huntington’s disease, Parkinson’s disease, stroke, and Alzheimer’s disease. Sian et al.³⁸ also reported altered GSH levels in PD. Cho is a marker of both membrane catabolism and anabolism. Cao et al.³⁹ demonstrated that Cho/Cr in the substantia nigra is associated with PD severity, without mentioning cognitive impairment. Nie et al.²⁶ reported that elevated Cho/Cr ratio in the PCC is associated with PDMCI, and suggested that Cho/Cr ratio may be used as a marker of PDMCI. The role played by Glu in idiopathic PD remains somewhat elusive^40,41, and previous studies applying ¹H-MRS in PD have not observed metabolic abnormalities in Glu, which may be because the studies were conducted with 1.5 T MRI scanners or adopted Glu/Cr ratio for reflecting Glu alteration (while Cr varies during PD progression as mentioned above). So, ¹H-MRS at 3 T or higher magnetic field strengths should be applied in future investigation to track the course of metabolic brain changes in association with disease progression in PD cases. In this study, we also found Glx reduction in the PCC of PDMCI patients, corroborating Griffith et al., who reported Glu level reduction in the cerebral cortex of PD patients.

PDMCI and PDN patients showed distinct PCC metabolic ¹H-MRS profiles. Compared with controls, tCr, NAA, Ins, GSH and tCho levels were significantly decreased in the PCC in the PDMCI group, while no significantly changes were found in the PDN group, with a slightly downward trend observed. Previous studies have reported no metabolite differences between PD patients and control subjects in either metabolite ratios or absolute concentrations of NAA, Cho, and Cr in various brain regions^{9,27,42,43,44}. Significant alterations in neurochemical levels may provide evidence to elucidate the pathophysiological mechanisms underlying of PD¹¹. This suggests there are no serious neuronal degenerations in the early onset of PD in cases with normal cognition. These results corroborated other studies reporting changes of NAA and Cho levels in the early cognitive impairment phase of PD⁴⁵, and lower NAA/Cr ratio in the occipital lobe in PD patients with mild cognitive impairment²⁶. The aforementioned metabolic abnormalities in the PCC in PDMCI may be due to lower regional cerebral blood flow in this region compared with PD with normal cognition, as revealed by Hosokai et al.²¹. Therefore, this study suggests that a comparison of PCC ¹H-MRS profiles across mild cognitive impairment provides useful information for tracking cognitive decline in PD patients and can provide a window for potential therapeutic intervention in PDMCI.

Besides, ROC curve analysis revealed the absolute tCr concentration could differentiate between PDMCI and PDN with an AUC of 0.71, a sensitivity of 44.4%, and a specificity of 90.0%, with a cutoff of < 15.45 mM. Meanwhile, NAA/Ins ratio could differentiate subjects with MCI from controls with normal cognitive function with an AUC of 0.74, a sensitivity of 72.2%, and a specificity of 76.0%, with a cutoff of < 0.84. These findings were in line with Waragai et al.¹⁴, who found an AUC of 0.78, a sensitivity of 67.9%, and a specificity of 67.9% between the remaining normal versus progressor MCI groups. Future studies should take into consideration other neuroimaging indicators (hippocampus volume, diffusion tensor parameters and cortical thickness) to improve the sensitivity and specificity in discriminating between PDMCI and PDN, as well as ADMCI and healthy controls with normal cognitive function. This work proposes a promising biomarker that may possibly predict early PD cognitive impairment.

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   Metabolic patterns in PDMCI and ADMCI

In ADMCI, the metabolic pattern of the PCC is well documented^12,13,14, consisting of increased Ins and reduced NAA/Ins ratio; increased Ins in ADMCI possibly represents gliosis or neuroinflammation, although the underlying mechanism remains undefined. A prior comparison of AD with other dementia forms found Ins elevation only in patients with AD, while reduced NAA was not specific to AD⁴⁶. This finding was consistent with prior reports demonstrating that Ins is not increased in PDMCI (and PDN), possibly suggesting that the degree of gliosis or inflammation is different in PDMCI (and PDN) compared with ADMCI.

Unlike ADMCI cases, PDMCI patients showed significantly reduced NAA and tCr. These findings were consistent with the notion of NAA as a marker of functional integrity in neurons, and Cr is usually considered a marker of energy metabolism, also emphasizing that posterior cortical pathology is likely implicated in PDMCI. According to Braak’s hypothesis⁴⁷, PCC regions showed atrophy during PD progression, possibly indicating neuronal dysfunction and energy metabolism abnormalities in the progression of cognitive decline in PD. In ADMCI patients, different degrees of neuronal dysfunction and energy metabolism abnormalities are present.

Few studies have reported brain metabolism differs between Alzheimer disease and Parkinson disease dementia (PDD)⁴⁶. Additionally, brain oscillatory patterns differed between ADMCI and PDMCI patients in a EEG study⁴⁸. However, there is no comparative study examining metabolism between these two MCI forms. Therefore, in this study, comparing the ¹H-MRS profiles of the PCC to examine cognitive impairment between PDMCI and ADMCI may provide useful information for better defining the disease process and elucidating possible treatment.

However, the current study had several limitations. First, single voxel ¹H-MRS of the PCC was applied in this study, and other key brain regions related to cognitive impairment in PD were not taken into consideration; future studies should adopt multi-voxel ¹H-MRS methods to detect additional neurobiomarkers. Secondly, the sample size was relatively small, and PD patients with dementia were not included; future studies should track PD’s cognitive status from normal cognitive to dementia. Thirdly, this was a single-center study, with heterogeneity in patient characteristics, including disease duration, disease severity, cognitive status and other non-motor clinical features, not clearly classified; therefore, further multi-center studies are required to investigate the different stages of PD progression. Fourthly, morphological changes of brain structure in PD have close relationships with cognitive deterioration, and thus may determine the progression of the disease. In future longitudinal studies, metabolites with other morphological parameters should be combined to track cognitive decline during PD progression.