Mild Cognitive Impairment in Newly Diagnosed Parkinson's Disease
Mild Cognitive Impairment in Newly Diagnosed Parkinson's Disease
This study investigated cognitive performances and motor dysfunction in a sample of 121 de novo PD patients. With regard to the first goal of this study, that is, the definition of MCI prevalence in newly diagnosed drug-naive PD patients, we identified a higher prevalence of MCI relative to age-matched HCs (14.8% vs 7%): this finding suggests that, at the time of clinical diagnosis, PD patients present a higher risk of MCI. Thus, the adoption of more conservative diagnostic criteria led to the identification of a lower prevalence of MCI in comparison with previous studies (range 18–36%).
PD patients were more depressed than HCs, confirming previous findings of a high prevalence of depressive disorders in this clinical population, which may sometimes coincide with the clinical motor onset or precede it. After adequately controlling for depression, HCs outperformed PD patients in several cognitive domains: verbal and visual episodic memory, language, attention and executive functions, visuospatial functions and constructional praxis.
Also, on comparing HCs only with non-MCI PD patients, it emerged that patients had more difficulties in verbal episodic memory tasks and in an executive screening task. This suggests that even in cognitively preserved, newly diagnosed drug-naive PD patients there is probably a frequent subthreshold cognitive impairment involving episodic memory and executive functions, as also suggested by the different prevalences of subjects with at least one impaired cognitive performance (41.3% in PD vs 9% in HCs).
The second goal of this study was the investigation of the relation between cognitive performances, MCI and motor dysfunction in newly diagnosed drug-naive PD patients. This goal is important for two reasons. First, the time of diagnosis is a crucial point both for the patient and for the physicians, as the possibility of reaching an inference about the risk of cognitive impairment early in the disease course could help the choice of the best therapeutic option. Second, specific relationships between motor dysfunction and cognitive performances could shed light on the neuropathology of different clinical motor and non-motor signs of PD patients. Most previous studies have been performed in moderate and advanced disease stages, reporting that axial impairment, postural instability and absence of tremor should be considered motor signs of an increased risk of dementia. A recent study with newly diagnosed drug-naive PD patients reported significant correlations between bradykinesia and set-shifting and between axial signs and memory and visuospatial functions. In our study, older age and higher severity of bradykinesia are associated with the presence of MCI. The older age of MCI-PD patients suggests that PD onset at older ages represents a risk factor for an earlier development of MCI relative to patients with PD onset at a younger age. Moreover, considering that bradykinesia represents the best clinical measure of the nigrostriatal lesion in PD, the higher severity of bradykinesia in MCI-PD suggests that the presence of MCI in the early clinical motor stages of PD is probably related to the severity of the nigrostriatal lesion. Although MCI-PD patients reported a more severe bradykinesia score relative to cognitively preserved PD patients, suggesting a possible role for the nigrostriatal lesion in cognitive features of PD, our results revealed a more complex relationship between cognitive and motor functions. The bradykinesia score predicted performances on the executive tasks (FAB, MCST, TMT). The strong association between bradykinesia and performances on the executive tasks confirms that these different features depend on a common dopaminergic dysfunctional system, related to the nigrostriatal lesion, as also suggested by the enhancement effect of dopaminergic drugs both on bradykinesia and executive tasks of mental flexibility (such as MCST and TMT). Correlation analyses revealed that axial signs were associated not only with executive deficits but also with more diffuse cognitive impairment (involving memory and visuospatial functions), probably reflecting an involvement of cholinergic and cortical systems, as also suggested by the poorer effect of dopaminergic drugs on these motor and non-motor signs. Interestingly, visuospatial dysfunction correlated with all non-tremor motor scores: although the executive impairment may play a role in the poor visuospatial performance; this suggests that non-executive cognitive difficulties of newly diagnosed drug-naive PD patients may probably be related to an early cortical involvement, especially of parieto-occipital cortices. Moreover, although the correlations between cognitive and motor symptoms suggest a common subcortical pathogenesis, the widespread cognitive impairment in MCI-PD patients could be considered a marker of early cortical involvement, as suggested by functional neuroimaging.
With regard to the classification of motor dysfunction of PD patients, we adopted two different criteria. The first criterion proposed by Jankovic distinguishes PIGD-D, TR-D and ND patients. The second criterion, which distinguishes TR-Y and TR-N patients, was adopted to highlight the role of tremor and to the limit of subjective evaluation of the motor dysfunction with the UPDRS. MCI was more severe and had a higher frequency in PIGD-D and TR-N patients, confirming that axial symptoms represent a risk factor for the development of dementia in PD patients. Therefore, even if we could speculate on a protective role of tremor in PD, it seems more likely that the risk of MCI in the TR-N group is related to the higher severity of axial symptoms in this group, because all PD patients have a greater chance to develop MCI in comparison with the healthy population.
In conclusion, our findings suggest that PD represents a risk factor for the development of MCI relative to age-matched subjects without PD, in the early untreated stages of disease. Bradykinesia, axial impairment and absence of tremor should be considered motor signs of an increased risk of MCI; bradykinesia, associated with deficits of executive functions, probably reflects the severity of the nigrostriatal lesion; axial symptoms, also associated with an involvement of memory and visuospatial functions, probably reflects the involvement of non-dopaminergic systems or cortical structures, in line with neuropathological evidence of a more diffuse cortical involvement of Lewy-Body pathology in non-tremor dominant PD. Although previous longitudinal studies have shown that PIGD-D patients have a worse cognitive decline in comparison with TR-D patients, significant cognitive differences between these motor subtypes were not evident at the time of the clinical motor onset. This lack of significant difference could be due to the small numbers of MCI patients in each PD subgroup, limiting the power of statistical comparison between them; more probably cognitive differences may be only subthreshold at this stage and become clinically evident with the progression of PD. Otherwise, this could suggest that the classification of Jankovic is not adequate in the early phase of PD, considering that its hallmarks, such as falls and postural instability, are more frequent in moderate and advanced stages of PD. Therefore, a distinction of the different motor symptoms or a classification of PD patients that highlights the presence/absence of tremor, as proposed in this study, would be more suitable for the early stages of PD.
The major strengths of the present study are the nature of the study (drug-naive population study), the large neuropsychological evaluation that covered many cognitive domains, the comparison with a large sample of age-matched HCs and the accurate motor characterisation of PD patients. There are also some limitations in this study; first, although clinical follow-up, positive response to dopaminergic treatment and evidence of nigrostriatal degeneration on FP-CIT SPECT should have provided confidence about the clinical diagnosis of PD, we do not have any pathological confirmation of the diagnosis. Second, we chose not to consider the subjective report of cognitive dysfunction, owing to the difficultly in splitting the change due to the recent motor impairment to the cognitive change. Moreover, although the lack of an objective measure of the premorbid cognitive status could have produced an over- or underestimation of the occurrence of MCI, the same education level in patients with and without MCI should indicate a similar level of cognitive reserve in these subgroups. Third, despite the large number of patients recruited, the number of patients in the MCI subgroup was limited, as in the PIGD-D and TR-D groups, which may have limited the effect of the negative results. Finally, neuropsychological follow-up is needed to investigate the possible different clinical evolution of different MCI subtypes and different motor subtypes and their risk of developing dementia.
Discussion
This study investigated cognitive performances and motor dysfunction in a sample of 121 de novo PD patients. With regard to the first goal of this study, that is, the definition of MCI prevalence in newly diagnosed drug-naive PD patients, we identified a higher prevalence of MCI relative to age-matched HCs (14.8% vs 7%): this finding suggests that, at the time of clinical diagnosis, PD patients present a higher risk of MCI. Thus, the adoption of more conservative diagnostic criteria led to the identification of a lower prevalence of MCI in comparison with previous studies (range 18–36%).
PD patients were more depressed than HCs, confirming previous findings of a high prevalence of depressive disorders in this clinical population, which may sometimes coincide with the clinical motor onset or precede it. After adequately controlling for depression, HCs outperformed PD patients in several cognitive domains: verbal and visual episodic memory, language, attention and executive functions, visuospatial functions and constructional praxis.
Also, on comparing HCs only with non-MCI PD patients, it emerged that patients had more difficulties in verbal episodic memory tasks and in an executive screening task. This suggests that even in cognitively preserved, newly diagnosed drug-naive PD patients there is probably a frequent subthreshold cognitive impairment involving episodic memory and executive functions, as also suggested by the different prevalences of subjects with at least one impaired cognitive performance (41.3% in PD vs 9% in HCs).
The second goal of this study was the investigation of the relation between cognitive performances, MCI and motor dysfunction in newly diagnosed drug-naive PD patients. This goal is important for two reasons. First, the time of diagnosis is a crucial point both for the patient and for the physicians, as the possibility of reaching an inference about the risk of cognitive impairment early in the disease course could help the choice of the best therapeutic option. Second, specific relationships between motor dysfunction and cognitive performances could shed light on the neuropathology of different clinical motor and non-motor signs of PD patients. Most previous studies have been performed in moderate and advanced disease stages, reporting that axial impairment, postural instability and absence of tremor should be considered motor signs of an increased risk of dementia. A recent study with newly diagnosed drug-naive PD patients reported significant correlations between bradykinesia and set-shifting and between axial signs and memory and visuospatial functions. In our study, older age and higher severity of bradykinesia are associated with the presence of MCI. The older age of MCI-PD patients suggests that PD onset at older ages represents a risk factor for an earlier development of MCI relative to patients with PD onset at a younger age. Moreover, considering that bradykinesia represents the best clinical measure of the nigrostriatal lesion in PD, the higher severity of bradykinesia in MCI-PD suggests that the presence of MCI in the early clinical motor stages of PD is probably related to the severity of the nigrostriatal lesion. Although MCI-PD patients reported a more severe bradykinesia score relative to cognitively preserved PD patients, suggesting a possible role for the nigrostriatal lesion in cognitive features of PD, our results revealed a more complex relationship between cognitive and motor functions. The bradykinesia score predicted performances on the executive tasks (FAB, MCST, TMT). The strong association between bradykinesia and performances on the executive tasks confirms that these different features depend on a common dopaminergic dysfunctional system, related to the nigrostriatal lesion, as also suggested by the enhancement effect of dopaminergic drugs both on bradykinesia and executive tasks of mental flexibility (such as MCST and TMT). Correlation analyses revealed that axial signs were associated not only with executive deficits but also with more diffuse cognitive impairment (involving memory and visuospatial functions), probably reflecting an involvement of cholinergic and cortical systems, as also suggested by the poorer effect of dopaminergic drugs on these motor and non-motor signs. Interestingly, visuospatial dysfunction correlated with all non-tremor motor scores: although the executive impairment may play a role in the poor visuospatial performance; this suggests that non-executive cognitive difficulties of newly diagnosed drug-naive PD patients may probably be related to an early cortical involvement, especially of parieto-occipital cortices. Moreover, although the correlations between cognitive and motor symptoms suggest a common subcortical pathogenesis, the widespread cognitive impairment in MCI-PD patients could be considered a marker of early cortical involvement, as suggested by functional neuroimaging.
With regard to the classification of motor dysfunction of PD patients, we adopted two different criteria. The first criterion proposed by Jankovic distinguishes PIGD-D, TR-D and ND patients. The second criterion, which distinguishes TR-Y and TR-N patients, was adopted to highlight the role of tremor and to the limit of subjective evaluation of the motor dysfunction with the UPDRS. MCI was more severe and had a higher frequency in PIGD-D and TR-N patients, confirming that axial symptoms represent a risk factor for the development of dementia in PD patients. Therefore, even if we could speculate on a protective role of tremor in PD, it seems more likely that the risk of MCI in the TR-N group is related to the higher severity of axial symptoms in this group, because all PD patients have a greater chance to develop MCI in comparison with the healthy population.
In conclusion, our findings suggest that PD represents a risk factor for the development of MCI relative to age-matched subjects without PD, in the early untreated stages of disease. Bradykinesia, axial impairment and absence of tremor should be considered motor signs of an increased risk of MCI; bradykinesia, associated with deficits of executive functions, probably reflects the severity of the nigrostriatal lesion; axial symptoms, also associated with an involvement of memory and visuospatial functions, probably reflects the involvement of non-dopaminergic systems or cortical structures, in line with neuropathological evidence of a more diffuse cortical involvement of Lewy-Body pathology in non-tremor dominant PD. Although previous longitudinal studies have shown that PIGD-D patients have a worse cognitive decline in comparison with TR-D patients, significant cognitive differences between these motor subtypes were not evident at the time of the clinical motor onset. This lack of significant difference could be due to the small numbers of MCI patients in each PD subgroup, limiting the power of statistical comparison between them; more probably cognitive differences may be only subthreshold at this stage and become clinically evident with the progression of PD. Otherwise, this could suggest that the classification of Jankovic is not adequate in the early phase of PD, considering that its hallmarks, such as falls and postural instability, are more frequent in moderate and advanced stages of PD. Therefore, a distinction of the different motor symptoms or a classification of PD patients that highlights the presence/absence of tremor, as proposed in this study, would be more suitable for the early stages of PD.
The major strengths of the present study are the nature of the study (drug-naive population study), the large neuropsychological evaluation that covered many cognitive domains, the comparison with a large sample of age-matched HCs and the accurate motor characterisation of PD patients. There are also some limitations in this study; first, although clinical follow-up, positive response to dopaminergic treatment and evidence of nigrostriatal degeneration on FP-CIT SPECT should have provided confidence about the clinical diagnosis of PD, we do not have any pathological confirmation of the diagnosis. Second, we chose not to consider the subjective report of cognitive dysfunction, owing to the difficultly in splitting the change due to the recent motor impairment to the cognitive change. Moreover, although the lack of an objective measure of the premorbid cognitive status could have produced an over- or underestimation of the occurrence of MCI, the same education level in patients with and without MCI should indicate a similar level of cognitive reserve in these subgroups. Third, despite the large number of patients recruited, the number of patients in the MCI subgroup was limited, as in the PIGD-D and TR-D groups, which may have limited the effect of the negative results. Finally, neuropsychological follow-up is needed to investigate the possible different clinical evolution of different MCI subtypes and different motor subtypes and their risk of developing dementia.
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