Mild Cognitive Impairment in Parkinson's Disease
Mild Cognitive Impairment in Parkinson's Disease
The exact underlying pathophysiology of PD-MCI remains the subject of debate, largely due to the scarcity of neuropathological data. Structural and functional imaging, neurophysiological techniques and cerebrospinal fluid (CSF) analysis provides some in vivo evidence of the mechanisms underlying MCI. Only one neuropathological study in well-characterised PD-MCI in which participants were followed prospectively has been reported. Eight cases were examined, of whom four were classified as amnestic and four as non-amnestic MCI. The neuropathology was heterogeneous, with five cases exhibiting limbic or neocortical LB pathology and the remainder predominantly consisting of brainstem LB pathology. Diffuse amyloid plaques were seen in the majority of cases, with two of the amnestic MCI subgroup meeting neuropathological criteria for AD. Cerebrovascular pathology was frequently seen. In correspondence relating to this study, Kurt Jellinger reported on a further eight cases of MCI, where four cases were defined as aMCI-sd, three were naMCI-sd and one MCI multiple domains. Again the neuropathology was heterogeneous, with most patients having limbic or neocortical LB deposition, and some displaying Alzheimer-type pathology. These studies provide evidence that the neuropathology underlying PD-MCI may be similar to, but less advanced than, that found in PDD.
Changes seen in structural and functional imaging provide further evidence of the possible underlying pathogenesis of PD-MCI. Extensive grey matter loss on structural magnetic resonance imaging is a consistent finding in PDD; in MCI, a more selective loss has been observed. Atrophy was noted in frontal, prefrontal, temporal, hippocampal, amygdala, parietal and occipital regions, and may be attributable to neuronal and synaptic loss from LB and/or AD-type pathology. However, a study in de novo incident PD cases did not demonstrate significant grey matter loss, perhaps due to the shorter disease duration, arguing for functional neurotransmitter loss rather than structural grey matter loss as a pathological basis for MCI.
Functional imaging using 18F-fluorodeoxyglucose positron emission tomography (PET) has demonstrated metabolic abnormalities associated with PD-MCI, with metabolic reductions demonstrated in frontal and parietal association areas plus relative increases in the cerebellar vermis and dentate nuclei. This pattern predicted performance in memory and visuospatial domains, with a more recent PET study by the same authors revealing a difference in parietal and prefrontal metabolism in those with multiple-domain MCI compared with PD-CN participants. Other studies have demonstrated cerebral hypometabolism in posterior cortical regions in participants with PD-MCI compared with those with PD and normal cognition. Taken together, neurotransmitter deficits in PD-MCI may explain the PET findings, with dopaminergic dysfunction accounting for frontal hypometabolism and subcortical cholinergic loss leading to posterior changes. Although these imaging findings suggest a causal link, they may be secondary contributors, with other markers (such as those measuring neurotransmitter changes or neuropathology) more sensitive to the upstream process.
Other potential mechanisms that may underpin the pathophysiology of MCI in PD include cholinergic dysfunction and abnormal processing of the amyloid precursor protein. Cholinergic loss is an established feature of PDD and may contribute to PD-MCI: evidence from a PET study demonstrating a reduction in nicotinic acetylcholine (ACh) receptors in the midbrain, pons and cerebellum in PD subjects with MCI support this hypothesis. In addition, short latency afferent inhibition (SAI) is abnormal in PD-MCI and is an independent predictor of slower gait speed. SAI is a non-invasive neurophysiological technique that relies on cholinergic excitability in the cerebral cortex, and hence can be used as a proxy measure of cholinergic activity. This theory of a cholinergic basis to MCI has biological plausibility in terms of the Braak hypothesis; at Braak Stage 3, where the motor disease may become apparent, there is already destruction of the basal forebrain cholinergic nuclei and consequent ACh loss. Lastly, abnormal amyloid-β deposition and fibrillization due to altered amyloid precursor processing may contribute to PD-MCI. Reduced CSF levels of Aβ42, a marker of amyloid deposition and aggregation, were found in those with PD and who were cognitively impaired but not demented. Reduced CSF Aβ42, 40 and 38 levels also correlated with memory function in early de novo PD participants. However, detection of amyloid-β deposition using PET imaging with Pittsburgh Compound B (PiB) in PD-MCI has been less convincing. In a small cross-sectional study, PiB retention did not differ between groups with PD and normal cognition, PD-MCI or PDD, although in more recent longitudinal work, amyloid burden at baseline predicted cognitive decline during the follow-up.
In summary, the pathogenesis of PD-MCI is heterogeneous and may differ between individuals and between subtypes. LB deposition, amyloid deposition and neurotransmitter deficits are all likely to contribute, although to a lesser degree than those changes seen in PDD. Further in vivo and post-mortem studies will facilitate future work.
Pathogenesis
The exact underlying pathophysiology of PD-MCI remains the subject of debate, largely due to the scarcity of neuropathological data. Structural and functional imaging, neurophysiological techniques and cerebrospinal fluid (CSF) analysis provides some in vivo evidence of the mechanisms underlying MCI. Only one neuropathological study in well-characterised PD-MCI in which participants were followed prospectively has been reported. Eight cases were examined, of whom four were classified as amnestic and four as non-amnestic MCI. The neuropathology was heterogeneous, with five cases exhibiting limbic or neocortical LB pathology and the remainder predominantly consisting of brainstem LB pathology. Diffuse amyloid plaques were seen in the majority of cases, with two of the amnestic MCI subgroup meeting neuropathological criteria for AD. Cerebrovascular pathology was frequently seen. In correspondence relating to this study, Kurt Jellinger reported on a further eight cases of MCI, where four cases were defined as aMCI-sd, three were naMCI-sd and one MCI multiple domains. Again the neuropathology was heterogeneous, with most patients having limbic or neocortical LB deposition, and some displaying Alzheimer-type pathology. These studies provide evidence that the neuropathology underlying PD-MCI may be similar to, but less advanced than, that found in PDD.
Changes seen in structural and functional imaging provide further evidence of the possible underlying pathogenesis of PD-MCI. Extensive grey matter loss on structural magnetic resonance imaging is a consistent finding in PDD; in MCI, a more selective loss has been observed. Atrophy was noted in frontal, prefrontal, temporal, hippocampal, amygdala, parietal and occipital regions, and may be attributable to neuronal and synaptic loss from LB and/or AD-type pathology. However, a study in de novo incident PD cases did not demonstrate significant grey matter loss, perhaps due to the shorter disease duration, arguing for functional neurotransmitter loss rather than structural grey matter loss as a pathological basis for MCI.
Functional imaging using 18F-fluorodeoxyglucose positron emission tomography (PET) has demonstrated metabolic abnormalities associated with PD-MCI, with metabolic reductions demonstrated in frontal and parietal association areas plus relative increases in the cerebellar vermis and dentate nuclei. This pattern predicted performance in memory and visuospatial domains, with a more recent PET study by the same authors revealing a difference in parietal and prefrontal metabolism in those with multiple-domain MCI compared with PD-CN participants. Other studies have demonstrated cerebral hypometabolism in posterior cortical regions in participants with PD-MCI compared with those with PD and normal cognition. Taken together, neurotransmitter deficits in PD-MCI may explain the PET findings, with dopaminergic dysfunction accounting for frontal hypometabolism and subcortical cholinergic loss leading to posterior changes. Although these imaging findings suggest a causal link, they may be secondary contributors, with other markers (such as those measuring neurotransmitter changes or neuropathology) more sensitive to the upstream process.
Other potential mechanisms that may underpin the pathophysiology of MCI in PD include cholinergic dysfunction and abnormal processing of the amyloid precursor protein. Cholinergic loss is an established feature of PDD and may contribute to PD-MCI: evidence from a PET study demonstrating a reduction in nicotinic acetylcholine (ACh) receptors in the midbrain, pons and cerebellum in PD subjects with MCI support this hypothesis. In addition, short latency afferent inhibition (SAI) is abnormal in PD-MCI and is an independent predictor of slower gait speed. SAI is a non-invasive neurophysiological technique that relies on cholinergic excitability in the cerebral cortex, and hence can be used as a proxy measure of cholinergic activity. This theory of a cholinergic basis to MCI has biological plausibility in terms of the Braak hypothesis; at Braak Stage 3, where the motor disease may become apparent, there is already destruction of the basal forebrain cholinergic nuclei and consequent ACh loss. Lastly, abnormal amyloid-β deposition and fibrillization due to altered amyloid precursor processing may contribute to PD-MCI. Reduced CSF levels of Aβ42, a marker of amyloid deposition and aggregation, were found in those with PD and who were cognitively impaired but not demented. Reduced CSF Aβ42, 40 and 38 levels also correlated with memory function in early de novo PD participants. However, detection of amyloid-β deposition using PET imaging with Pittsburgh Compound B (PiB) in PD-MCI has been less convincing. In a small cross-sectional study, PiB retention did not differ between groups with PD and normal cognition, PD-MCI or PDD, although in more recent longitudinal work, amyloid burden at baseline predicted cognitive decline during the follow-up.
In summary, the pathogenesis of PD-MCI is heterogeneous and may differ between individuals and between subtypes. LB deposition, amyloid deposition and neurotransmitter deficits are all likely to contribute, although to a lesser degree than those changes seen in PDD. Further in vivo and post-mortem studies will facilitate future work.
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