Nicola Tambasco

Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap

Levodopa is the most effective drug for the treatment of Parkinsons disease. However, the long-term use of this dopamine precursor is complicated by highly disabling fluctuations and dyskinesias. Although preclinical and clinical findings suggest pulsatile stimulation of striatal postsynaptic receptors as a key mechanism underlying levodopa-induced dyskinesias, their pathogenesis is still unclear. In recent years, evidence from animal models of Parkinsons disease has provided important information to understand the effect of specific receptor and post-receptor molecular mechanisms underlying the development of dyskinetic movements. Recent preclinical and clinical data from promising lines of research focus on the differential role of presynaptic versus postsynaptic mechanisms, dopamine receptor subtypes, ionotropic and metabotropic glutamate receptors, and non-dopaminergic neurotransmitter systems in the pathophysiology of levodopa-induced dyskinesias.

Cerebrospinal Fluid Biomarkers in Parkinson's Disease with Dementia and Dementia with Lewy Bodies

BACKGROUND Clinical criteria for differentiating Parkinsons disease (PD) with dementia (PDD) from dementia with Lewy bodies (DLB) are unsatisfactory. Their existence as distinct clinicopathologic entities is still debated, although the burden of Alzheimers disease (AD) pathology seems higher in DLB. Thus, analysis of cerebrospinal fluid (CSF) biomarkers (beta-amyloid(1-42) [Abeta42], total tau, and hyperphosphorylated tau [p-tau]) in living subjects might provide significant pathophysiological information on these diseases. METHODS Cerebrospinal fluid biomarkers were measured in DLB (n = 19), PDD (n = 18), and AD (n = 23) subjects matched for age, sex, and dementia severity, as well as in PD (n = 20) and normal control subjects (n = 20). RESULTS DLB showed the lowest mean CSF Abeta42 levels, with a negative association to dementia duration (rho = -.42, p = .07). In DLB patients, mean CSF total tau levels were significantly lower than in AD patients (508 +/- 387 vs. 960 +/- 619, respectively) but twofold to threefold higher than in PDD (286 +/- 184), PD (160 +/- 64), or normal control subjects (177 +/- 76), with a positive association to dementia severity (Mini-Mental State Examination: rho = -.54, p = .02; Milan Overall Dementia Assessment: rho = -.66, p = .002). PDD patients had mean CSF Abeta42 and total tau levels similar to those seen in PD patients. Hyperphosphorylated tau was significantly increased in the AD group only. CONCLUSIONS Cerebrospinal fluid Abeta42 and total tau have a different behavior in DLB and PDD, being related to duration and severity of dementia in DLB alone. Hyperphosphorylated tau is not significantly altered in these conditions.

Cerebrospinal fluid biomarkers in Parkinson disease

Clinical diagnosis of Parkinson disease (PD) is difficult in early stages of disease, with high risk of misdiagnosis. The long preclinical phase of PD provides the possibility for early therapeutic intervention once disease-modifying therapies have been developed, but lack of biomarkers for early diagnosis and monitoring of disease progression represents a major obstacle to achievement of this goal. Accordingly, research efforts aimed at identification of novel biomarkers have been increasing in the past 5 years. Cerebrospinal fluid (CSF) is an accessible source of brain-derived proteins, which mirror molecular changes that take place in the CNS. In this Review, we discuss evidence from numerous studies that have focused on identification of candidate CSF biomarkers for PD. Notably, molecular pathways related to α-synuclein, tau and β-amyloid peptides have received considerable attention. CSF levels of the protein DJ-1 are also of interest, although further investigation of this candidate marker is required. These studies support the usefulness of a combination of various CSF biomarkers of PD to increase diagnostic accuracy during early phases of the disease, and to differentiate PD from other neurodegenerative disorders.

Cerebrospinal fluid Tau/α-synuclein ratio in Parkinson's disease and degenerative dementias.

Although alpha‐synuclein is the main constituent of Lewy bodies, cerebrospinal fluid determination on its own does not seem fundamental for the diagnosis of synucleinopathies. We evaluated whether the combination of classical biomarkers, Aβ1–42, total tau, phosphorylated tau, and α‐synuclein can improve discrimination of Parkinsons disease, dementia with Lewy bodies, Alzheimers disease, and frontotemporal dementia. Aβ1–42, total tau, phosphorylated tau, and α‐synuclein were measured in a series of patients with Parkinsons disease (n = 38), dementia with Lewy bodies (n = 32), Alzheimers disease (n = 48), frontotemporal dementia (n = 31), and age‐matched control patients with other neurological diseases (n = 32). Mean α‐synuclein levels in cerebrospinal fluid were significantly lower in the pathological groups than in cognitively healthy subjects. An inverse correlation of α‐synuclein with total tau (r = −0.196, P < .01) was observed. In the group of patients with Parkinsons disease, Aβ1–42, total tau, and phosphorylated tau values were similar to controls, whereas total tau/α‐synuclein and phosphorylated tau/α‐synuclein ratios showed the lowest values. Cerebrospinal fluid α‐synuclein alone did not provide relevant information for Parkinsons disease diagnosis, showing low specificity (area under the curve, 0.662; sensitivity, 94%; specificity, 25%). Instead, a better performance was obtained with the total tau/α‐syn ratio (area under the curve, 0.765; sensitivity, 89%; specificity, 61%). Combined determination of α‐synuclein and classical biomarkers in cerebrospinal fluid shows differential patterns in neurodegenerative disorders. In particular, total tau/α‐synuclein and phosphorylated tau/α‐synuclein ratios can contribute to the discrimination of Parkinsons disease.

Cerebrospinal Fluid Lysosomal Enzymes and Alpha-Synuclein in Parkinson's Disease

To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinsons disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β‐glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α‐synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β‐glucocerebrosidase, β‐mannosidase, β‐hexosaminidase, and β‐galactosidase were measured with established enzymatic assays, while α‐synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β‐glucocerebrosidase‐encoding gene (GBA1). In the PD group, β‐glucocerebrosidase activity was reduced (P < 0.05) and patients at earlier stages showed lower enzymatic activity (P < 0.05); conversely, β‐hexosaminidase activity was significantly increased (P < 0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total α‐synuclein were significantly reduced (P < 0.05) in PD, in contrast to increased levels of α‐synuclein oligomers, with a higher oligomeric/total α‐synuclein ratio in PD patients when compared with controls (P < 0.001). A combination of β‐glucocerebrosidase activity, oligomeric/total α‐synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve = 0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD.

Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's disease

There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis and prognosis of Parkinsons disease (PD). CSF alpha synuclein (α-syn) species, namely total and oligomeric α-syn (t-α-syn and o-α-syn), have shown to be of help for PD diagnosis. Preliminary evidences show that the combination of CSF t-α-syn and classical Alzheimers disease (AD) biomarkers—β-amyloid 1–42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau)—differentiate PD patients from controls, and that reduced levels of Aβ42 represent a predictive factor for development of cognitive deterioration in PD. In this prospective study carried out in 44 PD patients and 25 neurological controls we wanted to verify whether the combination of CSF α-synuclein species—t-α-syn and o-α-syn—and classical AD biomarkers may help in differentiating PD from neurological controls, and if these biomarkers may predict cognitive decline. The median of follow-up duration was 3 years (range: 2–6 years). Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used for monitoring cognitive changes along time, being administered once a year. Oligo/total α-syn ratio (o/t-α-syn ratio) confirmed its diagnostic value, significantly contributing to the discrimination of PD from neurological controls. A greater diagnostic accuracy was reached when combining o/t-α-syn and Aβ42/tau ratios (Sens = 0.70, Spec = 0.84, AUC = 0.82; PPV = 0.89, NPV = 0.62, LR+ = 4.40, DOR = 12.52). Low CSF Aβ42 level was associated with a higher rate of MMSE and MoCA decline, confirming its role as independent predictive factor for cognitive decline in PD. None of the other biomarkers assessed (t-tau, p-tau, t-α-syn and o-α-syn) showed to have prognostic value. We conclude that combination of CSF o/t-α-syn and Aβ42/tau ratios improve the diagnostic accuracy of PD. PD patients showing low CSF Aβ42 levels at baseline are more prone to develop cognitive decline.

Risk factors for spread of primary adult onset blepharospasm: a multicentre investigation of the Italian movement disorders study group

OBJECTIVES Little is known about factors influencing the spread of blepharospasm to other body parts. An investigation was carried out to deterrmine whether demographic features (sex, age at blepharospasm onset), putative risk, or protective factors for blepharospasm (family history of dystonia or tremor, previous head or face trauma with loss of consciousness, ocular diseases, and cigarette smoking), age related diseases (diabetes, hypertension), edentulousness, and neck or trunk trauma preceding the onset of blepharospasm could distinguish patients with blepharospasm who had spread of dystonia from those who did not. METHODS 159 outpatients presenting initially with blepharospasm were selected in 16 Italian Institutions. There were 104 patients with focal blepharospasm (mean duration of disease 5.3 (SD 1.9) years) and 55 patients in whom segmental or multifocal dystonia developed (mainly in the cranial cervical area) 1.5 (1.2) years after the onset of blepharospasm. Information was obtained from a standardised questionnaire administered by medical interviewers. A Cox regression model was used to examine the relation between the investigated variables and spread. RESULTS Previous head or face trauma with loss of consciousness, age at the onset of blepharospasm, and female sex were independently associated with an increased risk of spread. A significant association was not found between spread of dystonia and previous ocular diseases, hypertension, diabetes, neck or trunk trauma, edentulousness, cigarette smoking, and family history of dystonia or tremor. An unsatisfactory study power negatively influenced the validity and accuracy of the negative findings relative to diabetes, neck or trunk trauma, and cigarette smoking. CONCLUSIONS The results of this exploratory study confirm that patients presenting initially with blepharospasm are most likely to experience some spread of dystonia within a few years of the onset of blepharospasm and suggest that head or face trauma with loss of consciousness preceding the onset, age at onset, and female sex may be relevant to spread. The suggested association between edentulousness and cranial cervical dystonia may be apparent because of the confounding effect of both age at onset and head or face trauma with loss of consciousness. The lack of influence of family history of dystonia on spread is consistent with previous findings indicating that the inheritance pattern is the same for focal and segmental blepharospasm.

Validation of the Italian version of the Movement Disorder Society--Unified Parkinson's Disease Rating Scale.

The Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an ‘Official MDS translation,’ the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Cerebrospinal fluid β-glucocerebrosidase activity is reduced in Dementia with Lewy Bodies

The autophagy-lysosomal degradation pathway plays a role in the onset and progression of neurodegenerative diseases. Clinical and genetic studies indicate that mutations of beta-glucocerebrosidase represent genetic risk factors for synucleinopathies, including Parkinsons Disease (PD) and Dementia with Lewy Bodies (DLB). We recently found a decreased activity of lysosomal hydrolases, namely beta-glucocerebrosidase, in cerebrospinal fluid of PD patients. We have thus measured the activity of these enzymes - alpha-mannosidase (EC 3.2.1.24), beta-mannosidase (EC 3.2.1.25), beta-glucocerebrosidase (EC 3.2.1.45), beta-galactosidase (EC 3.2.1.23) and beta-hexosaminidase (EC 3.2.1.52) - in cerebrospinal fluid of patients suffering from DLB, Alzheimers Disease (AD), Fronto-Temporal Dementia (FTD) and controls. Alpha-mannosidase activity showed a marked decrease across all the pathological groups as compared to controls. Conversely, beta-glucocerebrosidase activity was selectively reduced in DLB, further suggesting that this enzyme might specifically be impaired in synucleinopathies.

Magnetization transfer changes of grey and white matter in Parkinson's disease

Since the attempt to evidence structural brain damage in Parkinsons disease (PD) by conventional magnetic resonance imaging (MRI) is usually disappointing, we have investigated whether the magnetization transfer ratio (MTR) can reflect changes in grey and white matter of PD patients. MTR was quantified in 44 regions of interest (ROIs) in both grey and white matter of 11 non-demented PD patients, ranging from 2 to 4 on the Hoehn and Yahr Scale, and eight age-matched healthy subjects. MTR differences between patients and controls were found in the supratentorial white matter and in the brainstem. In particular, lower MTR values were found in the paraventricular white matter of PD patients (p<0.05) while no differences were observed in corpus callosum, frontal, parietal, occipital lobes or centrum semiovalis. Lower MTR values were found in substantia nigra (p<0.001), red nucleus (p<0.05) and pons (p<0.05) of the patient group. No differences were discovered in basal ganglia and thalamus. These findings suggest that MTR measurements in the paraventricular white matter and brainstem may help to recognize a marker for probable PD.