Comparing postural instability and gait disorder and akinetic-rigid subtyping of Parkinson disease and their stability over time.

BACKGROUND AND PURPOSE: Parkinson disease (PD) patients are classically classified according to two alternative motor subtyping methods: (i) tremor-dominant versus postural instability and gait disorder; (ii) tremor-dominant versus akinetic-rigid. The degree of overlap between the two classification systems at diagnosis of PD and their temporal stability, as well as the correspondence between the two systems, were examined over a follow-up period of 4 years. METHODS: Newly diagnosed, untreated PD patients were classified as tremor-dominant versus postural instability and gait disorder and tremor-dominant versus akinetic-rigid at baseline and after 2 and 4 years. RESULTS: There was a poor overlap between the two classification systems at any time point and baseline subtype status could not predict 4-year subtype membership. In fact, about half of our cohort shifted category during the first 2 years, regardless of the classification scheme adopted. A lower rate of shift was observed from 2- to 4-year follow-up. CONCLUSIONS: The two classical motor subtyping methods of PD poorly overlap, which implies that a patient can be categorized as tremor-dominant in one classification system but not in the other. Moreover, their temporal instability undermines their prognostic value in the early stage of PD.

The non-motor side of the honeymoon period of Parkinson's disease and its relationship with quality of life: a 4-year longitudinal study.

BACKGROUND AND PURPOSE: Very little is known about the progression of non-motor symptoms (NMSs) in Parkinson's disease (PD) and there are no longitudinal studies exploring this topic from the earliest stage, when patients receive the diagnosis. We here report on the progression of NMSs over 4 years from diagnosis in a cohort of de-novo, previously untreated, patients with PD. METHODS: Consecutive de-novo (disease duration < 2 years), untreated patients with PD were enrolled in this observational study. Evaluations were then scheduled every 2 years and included assessment of motor and non-motor features as well as of quality of life measures. RESULTS: Sixty-one patients were prospectively followed-up for 4 years from diagnosis. The majority of NMSs increased over time and significantly affected quality of life, whereas motor disability did not. There was no significant association between NMSs and dopaminergic therapy in terms of both drug class and total levodopa-equivalent daily dosage. Excessive daytime sleepiness was the only NMS correlating with therapy with dopamine agonists. Female patients were more likely to have worse quality of life. CONCLUSIONS: Non-motor symptoms significantly increase over time, with a different progression rate for each one. NMSs significantly affect quality of life in PD and we here demonstrated that this was especially the case when patients were in their (motor) honeymoon period. Future trials should target non-dopaminergic networks and consider NMSs in their outcomes.

Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson's disease.

BACKGROUND AND PURPOSE: Uric acid (UA) has been studied extensively as a valuable biomarker of Parkinson's disease (PD), but its relationship with non-motor symptoms (NMS) in de novo PD has been poorly investigated. Our aim was to evaluate the usefulness of baseline serum UA as a marker of NMS progression in newly diagnosed PD. METHODS: Sixty-nine newly diagnosed PD patients were enrolled. At baseline, all patients completed the NMS questionnaire (NMSQuest), and serum UA levels were measured. After 2 years, the NMSQuest was completed again and patients were categorized into four groups: NMS improvement (domain involvement at baseline but not at 2-year follow-up visit), NMS absence (domain not involved at baseline or 2-year follow-up visits), NMS presence (domain involvement both at baseline and 2-year follow-up visits) and NMS worsening (domain not involved at baseline but involved at 2-year follow-up). RESULTS: ANOVA with post hoc Bonferroni correction showed that patients with NMS absence presented significantly higher UA values than patients with NMS presence with regard to the attention/memory (P = 0.023), depression/anxiety (P = 0.028) and cardiovascular domains (P = 0.002), whilst no differences were found with regard to both the NMS improvement and worsening groups. In addition, multinomial regression analysis showed that the lowest tertile of NMS progression presented higher UA levels (P = 0.023; odds ratio 0.488) compared with patients with greater NMS progression. CONCLUSIONS: This is the first report of a relationship between serum UA and presence/progression of multiple NMS in de novo PD, providing additional evidence of the reliability of UA as a biomarker of PD and opening new insights on PD neuroprotection.

Relationship between apathy and cognitive dysfunctions in de novo untreated Parkinson's disease: a prospective longitudinal study.

BACKGROUND AND PURPOSE: Apathy may be either a symptom of major depression or a behavioral disturbance occurring in concomitance with depression or alone in Parkinson's disease (PD). The aim of the present study was to determine the progression of cognitive impairment in drug-naïve untreated PD patients with or without clinically significant apathy. METHODS: Sixty-two PD patients with a disease duration <2 years and without history of present or past therapy with pro-dopaminergic agents were included and underwent the Apathy Evaluation Scale (S-AES), a clinical interview based on diagnostic criteria for apathy and a comprehensive neuropsychological battery to assess memory, frontal functions and visuospatial functions. Two years after the first assessment, all patients were re-evaluated on the S-AES, a clinical interview and neuropsychological tests. RESULTS: According to the cut-off value of the S-AES and diagnostic criteria for apathy, eight patients experienced apathy at both baseline and follow-up (A+A+), nine patients had apathy only at follow-up (A-A+), 37 patients never experienced apathy (A-A-) and eight patients showed apathy at the baseline only (A+A-). Cognitive performance significantly declined in all four groups. At both baseline and follow-up A+A+ performed worse than A-A- on visuospatial and frontal tests; A-A+ had lower scores than A-A- on the interference task of the Stroop test (IT-ST). Regression analysis showed that poor performance on the IT-ST at baseline was the only independent predictor of onset of apathy at follow-up. CONCLUSIONS: The results indicated a relationship between apathy and dysexecutive syndrome in early PD. Reduced scores on the IT-ST may predict development of apathy in PD patients.

Increased bilirubin levels in de novo Parkinson's disease.

BACKGROUND AND PURPOSE: Oxidative stress is a central pathogenic mechanism of Parkinson's disease (PD), and the heme oxygenase (HO) bilirubin pathway is one of the main mammalian antioxidative defences. Indeed, there is growing evidence of HO-bilirubin upregulation from early phases of PD. Our aim was to investigate bilirubin as a possible biomarker of PD diagnosis and progression. METHODS: A cross-sectional case-control study was performed to evaluate differences in bilirubin levels between newly diagnosed, drug-naïve PD subjects and controls. Afterwards, PD subjects were included in a 2-year longitudinal study to evaluate disease progression in relation to baseline bilirubin levels. RESULTS: Seventy-five de novo PD subjects were selected and matched with 75 controls by propensity score. Analysis of variance showed higher bilirubin levels in PD patients compared with controls (P < 0.001). Linear regression analysis failed to show a relationship between bilirubin and Unified Parkinson's Disease Rating Scale (UPDRS) part III (P = 0.283) at baseline evaluation. At 2-year follow-up, indirect relationships between bilirubin levels and UPDRS part III (P = 0.028) and between bilirubin levels and levodopa-equivalent daily dosage (P = 0.012) were found. CONCLUSIONS: Parkinson's disease subjects showed higher levels of bilirubin compared with controls. Bilirubin increase might be due to HO overexpression as a compensatory response to oxidative stress occurring from early stages of PD.

Uric acid relates to dopamine transporter availability in Parkinson's disease.

BACKGROUND: Diagnosing Parkinson's disease (PD) and tracking its progression may require the combination of reliable biomarkers. Among them, both serum uric acid (UA) and dopamine transporter (DaT) binding deserve more investigations. AIMS OF THE STUDY: We aimed to investigate the relationship between serum UA levels and DaT availability in newly diagnosed, drug-naïve PD patients, by means of semiquantitative [(123) I]FP-CIT-SPECT. METHODS: We recruited 52 newly diagnosed, drug-naïve PD patients, and performed serum UA dosage and [(123) I]FP-CIT-SPECT. RESULTS: Pearson's correlation analysis showed that UA levels were significantly higher in patients with higher averaged, ipsilateral and contralateral DaT binding in caudate, putamen, and striatum. CONCLUSIONS: We showed, for the first time, by regional semiquantitative analysis of DaT binding in PD patients that UA levels significantly correlates with the severity of dopaminergic impairment in caudate, putamen, and striatum. This study broadens our knowledge on the importance of UA as a biomarker of PD.

Cognitive performances and DAT imaging in early Parkinson's disease with mild cognitive impairment: a preliminary study.

OBJECTIVES: Mild cognitive impairment (MCI) is a common feature in Parkinson's disease (PD). We performed an exploratory study to investigate dopaminergic nigrostriatal innervation and its cognitive correlates in early untreated PD patients with MCI as compared to cognitively intact patients. PATIENTS AND METHODS: A consecutive series of 34-de-novo, drug-naïve patients with PD were enrolled. They underwent [123-I] FP-CIT SPECT and comprehensive neuropsychological battery. MCI was identified in 15 of 34 patients with PD. RESULTS: The two groups did not show any statistically significant difference in age, sex, disease duration, education, lateralization, and H&Y and Hospital Anxiety and Depression Scale scores. Logistic regression analysis showed that UPDRS-III was weakly associated with MCI (P = 0.034). Partial correlation analysis controlling for UPDRS-III and age suggested that in PD patients with MCI reduced V3″ values in the more affected caudate were correlated with reduced performances in frontal assessment battery, Trail Making Test: part B minus Part A and copy task of the Rey-Osterrieth complex figure test. Reduced V3″ values in the more and less affected putamen were significantly related with reduced performance in frontal assessment battery and in copy task of Rey-Osterrieth complex figure test, respectively. No correlation was found between neuropsychological scores and DAT availability in PD patients without MCI. CONCLUSIONS: Although preliminary, our results suggest that striatal dopamine depletion may contribute to some cognitive deficit in early never treated PD patients with MCI.

Insulin-like growth factor-1 predicts cognitive functions at 2-year follow-up in early, drug-naïve Parkinson's disease.

BACKGROUND AND PURPOSE: Cognitive impairment is common in Parkinson's disease (PD), even in the early stages. We aimed to assess the relationship between insulin-like growth factor-1 (IGF-1) and cognitive functions in early, drug-naïve patients with PD. METHODS: Serum IGF-1 was measured in 65 early, drug-naïve patients with PD that underwent a complete neuropsychological battery at baseline and after 2 years. Linear regression analysis was used to evaluate the relationships between neuropsychological scores and IGF-1. Repeated-measures anova was applied to assess changes in neuropsychological variables over time. RESULTS: At baseline, IGF-1 levels were related to phonological fluency. At follow-up, IGF-1 levels were associated with the Rey auditory verbal learning test (RAVLT) - immediate and delayed recall, Frontal Assessment Battery, verbal span and Benton judgement of the line orientation test. Patients with low IGF-1 levels at baseline showed a significantly faster decline of performances than patients with high IGF-1 levels on immediate and delayed recall of the RAVLT and interference task of the Stroop test. CONCLUSIONS: Low serum IGF-1 levels are related to poor performance on executive tasks in early, drug-naïve patients with PD, and may predict poor performance on attention/executive and verbal memory tasks after a 2-year follow-up.

Gender differences in microRNA expression in levodopa-naive PD patients.

Gender is an important factor influencing epidemiological and clinical features of Parkinson's disease (PD). We aimed to evaluate gender differences in the expression of a panel of miRNAs (miR-34a-5p, miR-146a, miR-155, miR-29a, miR-106a) possibly involved in the pathophysiology or progression of disease. Serum samples were obtained from 104 PD patients (58 men and 46 women) never treated with levodopa. We measured levels of miRNAs using quantitative PCR. Correlations between miRNA expression and clinical data were assessed using the Spearman's correlation test. We used STRING to evaluate co-expression relationship among target genes. MiR-34a-5p was significantly upregulated in PD male patients compared to PD female patients (fc: 1.62; p < 0.0001). No correlation was found with age, BMI, and disease severity, assessed by UPDRS III scale, in male and female patients. MiR-146a-5p was significantly upregulated in female as compared to male patients (fc: 3.44; p < 0.0001) and a significant correlation was also observed between disease duration and mir-146a-5p. No differences were found in the expression of miR-29a, miR-106a-5p and miR-155 between genders. Predicted target genes for miR-34a-5p and miR-146-5p and protein interactions in biological processes were reported. Our study supports the hypothesis that there are gender-specific differences in serum miRNAs expression in PD patients. Follow-up of this cohort is needed to understand if these differences may affect disease progression and response to treatment.

Apathy in Parkinson's disease: differences between caregiver's report and self-evaluation.

Apathy is a state of diminished goal-directed speech, motor activity and emotions. The prevalence of apathy in Parkinson's disease (PD) ranges from 16 to 62%. Several studies have investigated the relationships between apathy and other dimensions of PD, but little is known about possible discrepancies between self-evaluation (SE) and caregiver reporting (CR) of this symptom. The aim of this study is twofold: 1) to investigate the differences in apathy evaluations according to the point of view from which apathy is reported (SE vs CR); 2) to identify the possible relationships between each of the two evaluations (SE and CR) and cognitive and affective dimensions of PD. Forty-eight patients with PD were assessed using the Apathy Evaluation Scale (AES) in its SE and CR versions (AES-SE and AES-CR); cognitive, affective and behavioral symptoms were also assessed. AES-SE scores were significantly higher than AESCR ones. Neither AES version correlated with depression, whereas both correlated with motor impairment, disease stage and behavioral symptoms. Mini-Mental State Examination and Frontal Assessment Battery scores showed significant negative correlations only with AES-SE scores. Our findings suggest that the point of view from which apathy is seen can lead to significant discrepancies, even when using the same tool. This should be taken into account in order to obtain correct assessment of this disabling and distressing symptom.

Prevalence and associated features of self-reported freezing of gait in Parkinson disease: The DEEP FOG study.

Freezing of Gait (FOG) is a common and disabling symptom in patients with Parkinson disease (PD). The relationship between FOG and dopaminergic medication is complex. The aim of the present study was to estimate the prevalence of self-reported FOG, its associated clinical features, and its relationship with wearing-off in a wide PD population. This is an observational multicenter study of 634 consecutive non-demented PD patients. Patients were identified either as freezers or non-freezers based on item-3 of the Freezing of Gait-Questionnaire. FOG was then classified as on, off and onoff freezing based on its relationship with wearing-off. Patients were assessed with Unified Parkinson's Disease Rating Scale, Hoehn and Yahr scale, 8-item Parkinson's disease Questionnaire, Mini-Mental State Examination. Data from 593 patients were analyzed, 325 (54.3%) were freezers of whom 200 (61.6%) experienced FOG only during off state (off-freezers), 6 (1.8%) only during on state and 119 (36.6%) either in on and off states or independently of dopaminergic response-related symptoms (onoff-freezers). Overall, freezers vs non-freezers had longer disease duration, more advanced disease and greater disability. Moreover, freezers more frequently reported wearing-off and experienced worse quality of life. Onoff-freezers vs off-freezers were older, more severely disabled, less likely to experience wearing-off, treated with lower levodopa equivalent daily dose and with poorer cognitive performance. Self-reported FOG is mainly recognizable in advanced PD and is associated with more disability and worse quality of life. Onoff-FOG may represent the result of under-treatment or rather interpretable as a distinct clinical entity.

Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study.

Among 101 patients homozygous for GAA expansion within the X25 gene, 11 from 8 families had Friedreich's ataxia with retained reflexes in the lower limbs (FARR). These patients had a lower occurrence of decreased vibration sense, pes cavus, and echocardiographic signs of left ventricular hypertrophy than the 90 FA patients with areflexia. The mean age at onset was significantly later (26.6+/-11.4 vs. 14.2+/-6.9 years), and the mean size of the smaller allele was significantly less (408+/-252 vs. 719+/-184 GAA triplets) in FARR patients. The neurophysiological findings were consistent with milder peripheral neuropathy and milder impairment of the somatosensory pathways in FARR patients.

Regional gray matter atrophy in patients with Parkinson disease and freezing of gait.

BACKGROUND AND PURPOSE: FOG is a troublesome symptom of PD. Despite growing evidence suggesting that FOG in PD may be associated with cognitive dysfunction, the relationship between regional brain atrophy and FOG has been poorly investigated. MATERIALS AND METHODS: Optimized VBM was applied to 3T brain MR images of 24 patients with PD and 12 HC. Patients were classified as either FOG- or FOG+ (n = 12) based on their responses to a validated FOG Questionnaire and clinical observation. All patients with PD also underwent a detailed neuropsychological evaluation. RESULTS: The VBM analysis in patients with FOG+ showed a reduced GM volume in the left cuneus, precuneus, lingual gyrus, and posterior cingulate cortex compared with both patients with FOG- and HC. We did not detect any significant change of GM volume when comparing HC versus all patients with PD (FOG- and FOG+). FOG clinical severity was significantly correlated with GM loss in posterior cortical regions. Finally, patients with FOG+ scored lower on tests of frontal lobe function. CONCLUSIONS: Our findings provide the first evidence that the development of FOG in patients with PD is associated with posterior GM atrophy, which may play a role in the complex pathophysiology of this disabling symptom.

Mild cognitive impairment in drug-naive patients with PD is associated with cerebral hypometabolism.

OBJECTIVE: To characterize brain metabolic changes associated with mild cognitive impairment (MCI) in drug-naive patients with Parkinson disease (PD) using (18)F-fluorodeoxyglucose (FDG) and PET (FDG-PET). METHODS: This cross-sectional study included newly diagnosed patients with PD with MCI in single or multiple domain (PD-MCI; n =12) and without MCI (PD-nMCI; n =12), and healthy controls (n =12). The groups were matched for age. Moreover, the patient groups were matched for motor disability. All subjects underwent a FDG-PET study. Cerebral regional relative metabolic maps were compared in PD-MCI, PD-nMCI, and controls using regions of interest analysis (ROIs) and voxel-based analysis with statistical parametric mapping. RESULTS: ROIs and voxel-based analyses revealed significant relative hypometabolism in the prefrontal, superior/inferior parietal, and associative occipital cortices as well as in the striatum in patients with PD-MCI relative to controls (p < 0.05) and to a lesser extent in patients with PD-nMCI. In contrast, patients with PD-nMCI did not show significant metabolic changes as compared to controls. CONCLUSION: MCI in patients with PD is associated with cortical hypometabolism since the earliest stage, independent of therapy or motor disability. The early involvement of posterior cortical region, a pattern shared by advanced stages of PD-MCI and PD with dementia, could represent an early marker of dementia. The relevance of this pattern in predicting prodromal dementia has to be evaluated in longitudinal studies.

Clinical and neurological abnormalities in adult celiac disease.

We assessed the occurrence of neurological signs and symptoms in adult patients with celiac disease and evaluated the correlation between neurological features and diet. A total of 176 patients and 52 age-matched controls underwent a semistructural interview and a neurologic examination. The effect of gluten-free diet was evaluated by comparing the prevalence of signs and symptoms among patients adhering to a gluten-free diet and patients on an unrestricted diet. The occurrence of headache, dysthymia and signs of peripheral neuropathy was significantly higher in patients with celiac disease than in control subjects. Adherence to a strict gluten-free diet was associated with a significant reduction of headache, dysthymia, cramps and weakness, but did not modify the occurrence of paresthesia or hyporeflexia. Neurological signs and symptoms are associated with celiac disease and can be ameliorated by a gluten-free diet.

Imaging of dopaminergic dysfunction with [123I]FP-CIT SPECT in early-onset parkin disease.

OBJECTIVE: To investigate whether the presence of parkin gene mutations is associated with different nigrostriatal impairment than other early-onset parkinsonism. METHODS: Eighteen consecutive early-onset Parkinson disease (PD) patients (nine parkin and nine nonparkin patients) and six controls were studied with [123I]FP-CIT SPECT. RESULTS: Parkin patients had longer disease duration (15 +/- 9 vs 6 +/- 2 years, p = 0.008) and higher Unified Parkinson's Disease Rating Scale (UPDRS) motor score (35.8 +/- 13.7 vs 22.8 +/- 7.9, p = 0.025) than nonparkin patients. Caudate and putamen DAT density were reduced by 60% and 79% in parkin and by 43% and 70% in nonparkin patients. Multiple regression analysis showed that the UPDRS and the presence of parkin gene mutations, but not the disease duration, were significantly correlated with the striatal DAT density. Parkin patients showed a more symmetric DAT loss in both caudate and putamen as compared with nonparkin patients. CONCLUSIONS: Parkin-related disease may be associated with a higher degree of nigrostriatal impairment, independently of the clinical severity of the disease, and a more symmetric involvement as compared with non-parkin early-onset disease.