The relationship between the neurodegenerative process and cognitive decline in PD remains unclear. Regarding neuropathologic features, PDD is associated with diffuse Lewy body disease manifestations, including in the transentorhinal and entorhinal cortices, hippocampus, other limbic cortex regions, and neocortex.28,29
In addition, more than half of PD patients have AD-related neuropathologic changes on autopsy,30,31
including in the hippocampus.29,32
Thus, the neurodegeneration that contributes to cognitive decline in PD, particularly in regions predisposed to AD pathologic changes (eg, the hippocampus), is likely due to a complex interaction of different diseases.33
Patients with PDD are reported to have decreased hippocampal, temporal, and parietal lobes and decreased prefrontal cortex volumes compared with HCs and nondemented PD patients.7-9,34-37
Nondemented PD patients are reported to have varying degrees of atrophy compared with HCs,8,36,38,39
with mixed evidence of a correlation between atrophy and neuropsychological test performance or conversion to PDD.7,40-42
However, nondemented PD patients are a heterogeneous group that includes PD-NC and PD-MCI patients, thus blurring any distinctions between the 2 groups. In addition, there are no consensus diagnostic criteria for PD-MCI; therefore, MCI populations can vary widely in terms of cognitive abilities. One study of PD patients with amnestic MCI reported GM atrophy in the precuneus and the left prefrontal and left primary motor cortices compared with HCs,43
and other studies44,45
reported mixed results for the presence of atrophy at the stage of PD-MCI.
After separating nondemented PD patients into PD-NC and PD-MCI groups purely on the basis of cognitive performance, we found that PD-NC patients had regional brain volumes similar to those of HCs. This suggests that significant regional brain atrophy does not occur in PD in the absence of comorbid cognitive impairment.
Patients with only MCI demonstrated hippocampal atrophy using ROI and VBM analyses and basal ganglia (putamen and globus pallidus), amygdala, and insula atrophy using VBM analyses. The putamen and globus pallidus are associated with learning, executive abilities, and attention in PD patients,46,47
and the amygdala has been shown to subserve memory and attention.48
At the stage of PDD, we found additional medial temporal lobe atrophy (ie, in the entorhinal cortex, perirhinal cortex, and posterior parahippocampal gyrus). This suggests that hippocampal neurodegeneration is associated with the initial stages of cognitive decline in PD, with more severe cognitive impairment associated with additional atrophy in medial temporal lobe structures.
The positive correlation between memory performance specifically (ie, memory subscales of the DRS-2 and the HVLT-R) and hippocampal volume in nondemented PD patients extends the aforementioned results. On the HVLT-R, the correlation was with recognition discrimination ability, which requires memory encoding and storage abilities subserved by medial temporal lobe structures and has been shown to be impaired in a subset of nondemented PD patients.49,50
There was no correlation between hippocampal volume and free recall performance, which in part reflects retrieval abilities that depend on frontostriatal circuitry.
Our preliminary results using a pattern classification approach to identify patterns of atrophy associated with dementia in PD suggest that it is possible to differentiate PDD and PD-NC patients with high sensitivity and NPV (ie, good for screening), although the specificity and PPV were suboptimal (ie, not adequate for diagnos-ing). However, the relatively low specificity (ie, high false-positive rate) may indicate patients who are at increased risk of future cognitive decline. We anticipate that, with a larger sample of PDD patients and additional clinical characterization (ie, application of formal diagnostic criteria to support neuropsychological test results), the psychometric properties of the pattern classifier will improve.
The PD-MCI patients demonstrated a pattern of atrophy different than that of the PD-NC patients and similar to although less severe than that of the PDD patients. This suggests that a diffuse pattern of GM and WM brain atrophy can be detected at an early stage of cognitive decline in PD if sensitive imaging analyses are used. Because the use of traditional imaging methods in PD patients has produced mixed results regarding the correlation between atrophy and current and future cognitive performance,40,41
additional research is needed to determine whether the pattern classifier for PDD is able to predict cognitive decline in nondemented PD patients, as has been reported for individuals with MCI in the general population.27
Our study has a number of limitations. First, the classification of patients into cognitive groups was based solely on neuropsychological test results because formal MCI and PDD diagnostic criteria were not applied. However, there currently are no commonly accepted diagnostic criteria for PD-MCI, and the validity of self-reporting of nonmotor symptoms in PD has been called into question.51
Second, the DRS-2 was the primary neuropsychological test; consequently, sensitivity may have been suboptimal. In addition, the recommended standardized DRS-2 cutoff scores for MCI and PDD have not been validated in PD, and the mean standardized DRS-2 scores for all 3 cognitive groups were lower than those reported in previous research using formal diagnostic criteria for PD-MCI and PDD.52
Third, the PD sample was predominantly male, and there was a sex imbalance between HCs and PD-NC patients. Finally, the sample sizes of PDD and PD-MCI patients were relatively small, which may affect the reproducibility of our findings.
With growing recognition of PD-MCI as common and clinically significant, it will be important to develop consensus diagnostic criteria, validate assessment instruments for use in clinical care and research, and test treatments for their symptomatic and disease-modifying effects. Validating biomarkers of neurodegeneration associated with MCI and distinguishing PD-MCI from the early stages of dementia with Lewy bodies will inform our understanding of the development, course, profile, and neuropathophysiologic features of the initial stage of cognitive decline in PD. Emerging evidence implicates hippocampal involvement early in the course of cognitive—and specifically memory—decline in PD.