Article Text

Research paper
Mild cognitive impairment and cognitive-motor relationships in newly diagnosed drug-naive patients with Parkinson's disease
  1. Michele Poletti1,2,
  2. Daniela Frosini1,
  3. Cristina Pagni1,
  4. Filippo Baldacci1,2,
  5. Valentina Nicoletti1,
  6. Gloria Tognoni1,
  7. Claudio Lucetti2,
  8. Paolo Del Dotto2,
  9. Roberto Ceravolo1,
  10. Ubaldo Bonuccelli1,2
  1. 1Department of Neuroscience, University of Pisa, Pisa, Italy
  2. 2Neurology Unit, USL of Viareggio, Viareggio, Italy
  1. Correspondence to Dr Professor Ubaldo Bonuccelli, Department of Neuroscience, University of Pisa, Pisa I56125, Italy; u.bonuccelli{at}med.unipi.it

Abstract

Background and aims (1) To establish the prevalence of mild cognitive impairment (MCI) in newly diagnosed drug-naive patients with Parkinson's disease adopting recently proposed and more conservative preliminary research criteria. (2) To investigate the relation between cognitive performances, MCI and motor dysfunction.

Methods 132 consecutive newly diagnosed drug-naive PD patients and 100 healthy controls (HCs) underwent a neuropsychological evaluation covering different cognitive domains. Moreover, on the basis of the Unified Parkinson's Disease Rating Scale II/III, different motor scores were calculated and patients were classified in motor subtypes. 11 patients were excluded from the analysis during clinical follow-up which was continued at least 3 years from the diagnosis; therefore, the final sample included 121 patients.

Results MCI prevalence was higher in PD (14.8%) patients than in HCs (7.0%). PD patients reported lower cognitive performances than HCs in several cognitive domains; HCs also outperformed cognitively preserved PD patients in tasks of episodic verbal memory and in a screening task of executive functions. MCI-PD patients presented a more severe bradykinesia score than non-MCI PD patients and patients mainly characterised by tremor had better performances in some cognitive domains, and specific cognitive-motor relationships emerged.

Conclusions Although the adoption of more conservative diagnostic criteria identified a lower MCI prevalence, we found evidence that newly diagnosed drug-naive PD patients present a higher risk of MCI in comparison with HCs. Axial symptoms and bradykinesia represent risk factors for MCI in PD patients and a classification of PD patients that highlights the presence/absence of tremor, as proposed in this study, is probably better tailored for the early stages of PD than classifications proposed for more advanced PD stages.

  • Drug-naive Parkinson's disease
  • Mild Cognitive Impairment
  • motor-phenotype
  • tremor
  • bradykinesia
  • neuropsychology
  • Parkinson's disease
  • frontal lobe
  • Alzheimer's disease
  • nuclear medicine
  • cerebral metabolism
  • neuropsychiatry
  • functional imaging
  • movement disorders
  • PET
  • neuropharmacology
  • movement disorders

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Introduction

The term mild cognitive impairment (MCI) defines the presence of cognitive deficits not severe enough to warrant the diagnosis of dementia; diagnostic criteria include the presence of cognitive concern, cognitive impairment in one or more domains as assessed by neuropsychological examination, normal functional activities and the absence of dementia.1 Although specific diagnostic criteria are not actually available,2 3 MCI has also been reported in patients with Parkinson's disease (PD), with a prevalence of 25.8% in a recent multicenter pooled study4 carried out on 1346 patients, and is associated with an increased risk of developing dementia.5–7

Most studies on MCI in PD patients have been based on patients receiving dopaminergic medications that may either enhance or impair cognition.8 9 Few recent studies have assessed cognition in newly diagnosed drug-naive PD patients,10–15 with incidence of cognitive deficits varying from 18% to 36% on the basis of different adopted diagnostic criteria; these studies have globally shown that from the early untreated stages of PD there is an increased risk of developing MCI relative to age-matched healthy controls (HCs), although its anatomical substrate is not yet fully understood.16 The first aim of this study is to establish the prevalence of MCI in a sample of 132 consecutive newly diagnosed drug-naive PD patients without dementia, by adopting recently proposed preliminary research criteria of MCI in PD,17 and to compare cognitive performances of these patients with those of 100 age-matched HCs.

Moreover, MCI has been differently related to motor subtypes of PD. Jankovic and colleagues18 adopted the Unified Parkinson's Disease Rating Scale (UPDRS)19 in order to classify PD patients on the basis of the predominant motor symptoms. The subgroup characterised by postural instability and gait difficulty was cognitively more impaired than the subgroup characterised by tremor. Subsequent studies confirmed that PD patients whose motor dysfunction is not principally characterised by tremor present increased rates of cognitive impairment and dementia.20–23 These studies have been performed on PD patients under dopaminergic treatment and presented two main confounding factors: the unknown effect of therapy on cognition and the different effect of dopaminergic treatment on different motor symptoms. A recent study24 investigated the relationship between cognitive performances and motor dysfunction in newly diagnosed drug-naive PD patients, reporting correlations between bradykinesia and set-shifting and between axial signs and memory and visuospatial functions. Thus, the second aim of this study is to investigate the relation between cognitive performances, MCI and motor dysfunction in newly diagnosed drug-naive PD patients.

Methods

Subjects

A sample of 132 consecutive, de novo PD outpatients was recruited from two movement disorder tertiary clinics (Neuroscience Department, University of Pisa; Versilia Hospital of Viareggio, USL12 Toscana). All patients fulfilled the research diagnostic criteria for idiopathic PD25; atypical parkinsonian disorders, such as multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, and other neurological or major medical conditions were considered as exclusion criteria. All patients underwent a 1.5T MRI to evaluate radiological signs of atypical parkinsonisms, neoplastic lesions, hydrocephalus or extensive vascular damage and a 123IFP-CIT SPECT (iodine-123 fluoropropyl-carbomethoxy-(iodophenyl)tropane single photon emission computed tomography) to confirm nigrostriatal degeneration. L-Dopa challenge was performed in all patients to evaluate acute dopaminergic treatment efficacy, and only patients with a consistent (>30%) improvement in the tapping test were considered eligible. A total of 100 age-matched subjects enrolled from patients' family members served as healthy controls (HCs). These subjects were free from parkinsonism, dementia, major depression and psychosis. Informed consent was obtained in compliance with research standards for human research for all participating institutions and in accordance with the Helsinki Declaration.

Assessment

In all PD patients we recorded gender, age, years of education, disease duration, side and type of symptoms onset and concomitant medications. Clinical evaluation was completed using the UPDRS II/III score,19 the Geriatric Depression Scale Short Form (GDS-15)26 and an extensive neuropsychological battery, administered by trained clinical neuropsychologists (MP, CP). Diagnosis of depression was made according to DSM IV-TR criteria.27 Global cognitive status was assessed using the Mini-Mental State Examination (MMSE).28 A variety of standardised neuropsychological tests were used (see table 1). These tests were allocated to the following cognitive domains: (1) verbal and visual memory, (2) language, (3) executive functions, (4) constructional praxis and (5) visuospatial abilities.

Table 1

Neuropsychological tests administered to Parkinson's disease patients and healthy controls

Follow-up and patient exclusion

At the end of the neuropsychological assessment, an appropriate treatment was started and clinical follow-up was continued at least 3 years from the diagnosis to evaluate response to dopaminergic treatment and the appearance of signs of atypical parkinsonism, especially dementia, hallucinations, frequent falls and ocular abnormalities. Eleven patients were excluded from the final analysis: two patients developed dementia according to DSM-IV-TR criteria,27 one patient developed hallucinations resistant to dopamine-agonist withdrawal, five were lost to follow-up and four did not show a sustained response to dopaminergic treatment.

Definition of MCI

Considering the lack of consensus in the definition of MCI in PD,2 3 we adopted the recently proposed preliminary research criteria of MCI in PD17: at least two scores below 1.5SDs within any single domain (single domain-MCI) or one score below 1.5SDs in at least two domains (multi domain-MCI). There is some evidence that subjective reporting of memory or cognitive complaints by patients or family members may not be reliable, resulting in either under- or over-reporting. Due to this lack of agreement, we chose not to consider the subjective cognitive complaints and only refer to objective cognitive testing. We adopted Petersen's1 criteria to define the presence of MCI in HCs.

Definition of motor phenotype

By evaluating UPDRS II/III subitems, we calculated four scores: a Rigidity score (rigidity (22)/5); an Axial score: (falling (13) + freezing (14) + walking (15) + arising (27) + posture (28) + gait (29) + stability (30))/7 (the number of single subitems included); a Bradykinesia score (finger tapping (23) + hand movements (24) + hand pronate supinate (25) + toe tapping (26) + body bradykinesia (31))/9 and a Tremor score (tremor at rest (20) + action tremor (21))/7.

According to the criteria proposed by Jankovic,18 we derived two scores from the UPDRS II/III: the Tremor-Dominant score (tremor at rest (20) + action tremor (21))/7 and the Postural Instability Gait Disorder-Dominant score (speech (18) + facial expressions (19) + rigidity (22) + arising from chair (27) + posture (28) + gait (29) + postural stability (30) and body bradykinesia (31))/12. The Tremor-Dominant group (TR-D) was defined as patients with a ratio of mean Tremor-Dominant score/mean Postural Instability Gait Disorder score ≥1.5; the Postural Instability Gait Disorder Dominant group (PIGD-D) included all patients with a ratio of ≤1.0. Other cases were classified as ‘not determined’ (ND). Moreover, we divided patients into two groups according to the presence (TR-Y) (any score ≥1) or absence of tremor (TR-N) in items 20 and 21 of the UPDRS III.

Statistical analysis

Differences in demographical and clinical characteristics between PD patients and HCs were analysed using independent two-tailed t tests. Mann–Whitney test was used to analyse ordinal data, whereas the χ2 test was used to analyse nominal variables. To assess the pattern of cognitive disturbances, two sets of analyses were conducted. First, to examine relative differences between PD patients and HCs and between PD subgroups, multivariate analyses of covariance with age and depression as covariates were conducted within each cognitive domain using raw test scores. When multivariate comparisons revealed significant results, Bonferroni-corrected univariate analyses of covariance with age and depression as covariates were conducted to examine single neuropsychological measures. The relation between quantitative variables was evaluated using a linear correlation. Multiple regression analyses were performed to assess the ability of motor scores to predict cognitive performances in PD patients.

Results

MCI prevalence

One hundred and twenty-one PD patients and 100 controls were enrolled in the study. No statistically significant differences emerged between PD patients and HCs as regards demographic characteristics (table 2). Twenty-six PD patients (21.5%; 10 patients with major depression: 8.2%; 16 patients with minor depression: 13.3%) and eight HCs (8%; all minor depression) presented with depressive symptoms on the GDS-15 and in the following neuropsychiatric interview. PD patients were more depressed on the GDS-15 than HCs (p<0.001). Fifty PD patients (41.3%) and nine HCs (9%) showed an impaired performance in at least one cognitive task (x2=21.39, p<0.001). MCI criteria identified 18 PD patients with MCI (14.8%), of whom 7 (38.9% of the MCI group; 5.7% of the PD sample) were single domain-MCI (5 non-amnestic; 2 amnestic) and 11 (61.1% of the MCI group; 9.1% of the PD sample) were multi domain-MCI (6 non-amnestic; 5 amnestic), and 7 HCs (x2=14, p<0.001) were all single domain-MCI (5 amnestic; 2 non-amnestic).

Table 2

Demographics, baseline characteristics and neuropsychological test scores for healthy controls and newly diagnosed drug-naive PD patients as a whole and divided into non-MCI and MCI subgroups

Comparison between PD patients and HCs

Multivariate analyses of covariance, with depression as covariate, revealed that HCs outperformed PD patients, with a statistically significant difference, in the following cognitive tasks (table 2): RAVLT Immediate Recall (p<0.001); RAVLT Delayed Recall (p<0.001); Rey Copy Immediate Recall (p<0.01); Rey Copy Delayed Recall (p<0.01); Boston Naming Test (p<0.05); Frontal Assessment Battery (FAB; p<0.01); phonemic verbal fluency (p<0.05); Visual Search (p<0.05); CPM-47 (p<0.01); Rey Figure Copy Test (p<0.01). HCs outperformed MCI-PD patients in all cognitive domains (p<0.001) except semantic verbal fluency. HCs outperformed non-MCI PD patients in: RAVLT Immediate Recall (p<0.001), RAVLT Delayed Recall (p<0.001) and FAB (p<0.05).

Comparison between PD subgroups

MCI-PD patients were older (p<0.001) and presented a higher Bradykinesia score (p<0.001) than cognitively preserved PD patients (0.82±0.49 vs 0.36±0.41). Also, on comparing PD patients with or without at least one or more cognitive tests impaired, cognitively impaired patients were older (p<0.05) and had a higher Bradykinesia score (p<0.01). As expected, cognitively preserved PD patients outperformed MCI-PD patients in all tests (p<0.05 for TMT B–A, MCST perseverative errors, Stroop errors; p<0.001 for all other tests), except semantic verbal fluency, confirming the appropriateness of our classification based on Troster's MCI criteria.17

Motor phenotype and cognition

With regard to the motor phenotype, according to Jankovic's criteria, 48 (39.7%) patients were classified as TR-D, 56 (46.3%) patients as PIGD-D and 17 (14.0%) patients as ND (the last subgroup was not further analysed); PIGD-D patients presented a higher frequency of MCI (13 MCI out of 56 patients: 23.2%) relative to TR-D patients (3 MCI out of 48 patients: 6.3%) (x2 5.7, p<0.05). The comparison between cognitive performances of TR-D patients and PIGD-D patients showed that the former outperformed the latter only in the Boston Naming Test Short Form (p≤0.01). For detailed description see online supplementary table 4.

Moreover, 88 (72.7%) patients were classified as TR-Y and 33 (27.3%) patients as TR-N. TR-N presented a higher frequency of MCI (10 MCI out of 33: 30.3%) relative to TR-Y patients (8 MCI out of 88 patients: 9.1%) (x2 8.5, p<0.01). The comparison between cognitive performances of TR-Y patients and TR-N PD showed that the former outperformed the latter in the RAVLT Immediate (p<0.05) and Delayed Recall (p<0.05) and in the digit span test (p<0.05). For detailed description see online supplementary table 4. Non-parametric correlations connected three motor scores (bradykinesia, axial symptoms and rigidity) to a range of cognitive measures: the Rigidity score significantly correlated with CPM-47 (r=−0.251, p<0.01), Rey Figure Copy (r=−0.215, p<0.01) and Rey Figure delayed Recall (r=−0.348, p<0.01); the Axial score significantly correlated with FAB (r=−0.248, p<0.05), MMSE (r=−0.308, p<0.01), RAVLT Immediate Recall (r=0.232, p<0.05), Rey Figure Copy (r=−0.286, p<0.01) and the number of achieved categories in the MCST (r−0.355, p<0.01); the Bradykinesia score correlated with MMSE (r=−0.542, p<0.01), Rey Figure Copy (r=−0.280, p<0.01), TMT-A (r0.358, p<0.01), TMT-B (r=0.365, p<0.01), TMT B–A (r=0.367, p<0.01) and the number of achieved categories in the MCST (r=−0.589, p<0.01); the Tremor score did not correlate with any cognitive measure. In the multiple linear regressions (table 3), with age, sex, education and the other motor signs controlled for, the following motor signs contributed to the model. Bradykinesia was significantly associated with MMSE (β=−0.478, p<0.01), FAB (β=−0.283, p<0.01), MCST category completed (β=−0.359, p<0.01) and TMT B–A (β=0.359, p<0.01). Rigidity was significantly associated with the Rey Figure Delayed Recall (β=−0.548, p≤0.05). Any significant association emerged between cognitive measures and Tremor and Axial scores.

Table 3

Multiple regression analyses to assess the ability of motor signs to predict cognitive performance in Parkinson's disease patients with age, sex, education and other motor signs controlled for

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%).10–15

PD patients were more depressed than HCs, confirming previous findings of a high prevalence of depressive disorders in this clinical population,29 which may sometimes coincide with the clinical motor onset or precede it.30 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.20–23 A recent study24 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,31 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 bradykinesia31 and executive tasks of mental flexibility32 (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,33 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.34–37 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.37

With regard to the classification of motor dysfunction of PD patients, we adopted two different criteria. The first criterion proposed by Jankovic18 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 lesion38; 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.39 40 Although previous longitudinal studies have shown that PIGD-D patients have a worse cognitive decline in comparison with TR-D patients,20–23 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 Jankovic18 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 reserve2 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.

References

Supplementary materials

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Footnotes

  • Funding This work was supported by a Tuscany Region grant.

  • Competing interests None.

  • Patient consent A local consent form has been signed by the patients according to our local ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All authors state that no additional unpublished data are available and/or shared.

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