Aroldo Rossi

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 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.

Possible risk factors for primary adult onset dystonia: a case-control investigation by the Italian Movement Disorders Study Group

OBJECTIVES Little is known about the aetiology of idiopathic adult onset dystonia. The Italian Movement Disorders Study Group promoted a case-control study on some hypothetical risk factors including past medical events, life events, life habits, occupational hazards, and family hystory of dystonia, parkinsonism, and tremor. METHODS Cases affected by idiopathic adult onset dystonia (age at symptom onset >20 years, duration of disease >one year and <five years) were selected among consecutive outpatients attending 14 Italian centres. Control outpatients matched for age (±5 years), sex, and referral centre were identified among diagnostic categories thought to be unassociated with study exposures. Information was obtained by a standardised questionnaire administered by medical interviewers. Conditional logistic univariate and multivariate regression analyses were performed by a standard statistical package. RESULTS Multivariate analysis on 202 cases and 202 age and sex matched control outpatients indicated that head or facial trauma with loss of consciousness, family history of dystonia, and family history of postural tremor independently increased the risk of developing adult onset dystonia, whereas hypertension and cigarette smoking exerted a protective effect. The findings also suggested a positive association between local body injury—for example, previous ocular diseases and neck or trunk trauma—and dystonia of the same body part. CONCLUSIONS The results support the idea that environmental and genetic factors may both be important in the aetiology of adult onset dystonia, and suggest aetiological clues worthy of further analytical investigation.

Botulinum Toxin A for Overactive Bladder and Detrusor Muscle Overactivity in Patients With Parkinson's Disease and Multiple System Atrophy

PURPOSE Urinary disturbances are common in patients with Parkinsons disease and multiple system atrophy. We investigated the effectiveness and safety of botulinum toxin type A injected into the detrusor muscle in patients with Parkinsons disease and multiple system atrophy who had refractory overactive bladder symptoms and detrusor overactivity. MATERIALS AND METHODS All participants underwent clinical and urodynamic assessment, and completed a quality of life questionnaire before botulinum toxin type A treatment, and 1 and 3 months thereafter. Four patients with Parkinsons disease and 2 with multiple system atrophy were enrolled in the study. All patients received 200 U botulinum toxin type A injected into the detrusor muscle at 20 sites under cystoscopic guidance at a single session on an inpatient basis. Outcome measures were clinical assessment (a voiding diary including daytime and nighttime urinary frequency, and episodes of urgency and urge urinary incontinence), urodynamic assessment (including first volume and maximum pressure of uninhibited detrusor contractions, and maximum cystometric capacity) and pressure flow studies. RESULTS One and 3 months after botulinum toxin type A injection all patients reported that daytime and nighttime urinary frequency had decreased and quality of life scores improved. No patients had further episodes of urgency and urge urinary incontinence during the 5-month followup. Urodynamics showed improvement in all urinary function variables tested. No systemic side effects were recorded during or after treatment. In all patients post-void urinary residual volume increased and intermittent catheterization was required only in those with multiple system atrophy. CONCLUSIONS The new beneficial effect that we report in a small study sample encourages larger trials to confirm botulinum toxin type A injection into the detrusor muscle as an effective and safe treatment for refractory overactive bladder symptoms and detrusor overactivity related to Parkinsons disease and multiple system atrophy.

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.

Lysosomal hydrolases in cerebrospinal fluid from subjects with Parkinson's disease

Recent studies have shown a genetic association between glucocerebrosidase deficiencies and Parkinsons disease (PD). To further explore this issue the activity of β‐glucocerebrosidase and the activities of other lysosomal enzymes, α‐mannosidase, β‐mannosidase, β‐hexosaminidase, and β‐galactosidase have been evaluated in the cerebrospinal fluid (CSF) of PD patients. The activities of α‐mannosidase, β‐mannosidase, β‐glucocerebrosidase, and β‐hexosaminidase were substantially decreased in the CSF of PD patients, while levels of β‐galactosidase were essentially identical to controls. This study indicates that in PD several lysosomal hydrolases have decreased activities, further supporting a possible link between pathophysiological mechanisms underlying PD and lysosomal hydrolases.

Botulinum toxin type A in patients with Parkinson's disease and refractory overactive bladder

PURPOSE In this 6-month followup study we investigated the effect of intradetrusor injection of 100 U botulinum toxin type A in patients with Parkinsons disease and refractory detrusor overactivity. MATERIALS AND METHODS Eight patients with Parkinsons disease and detrusor overactivity refractory to anticholinergics were injected with 100 U botulinum toxin type A. Daytime and nighttime urinary frequency, and urinary incontinence episodes were recorded. Patients also completed a standardized quality of life questionnaire on incontinence and a visual analog scale on the impact of bladder problems on daily life activities, and underwent urodynamic assessment, including pressure flow studies. Clinical and urodynamic assessment was performed before, and 1, 3 and 6 months after injection. RESULTS In all patients 100 U botulinum toxin type A induced decreased daytime and nighttime urinary frequency, a decreased number of urinary incontinence episodes, increased quality of life scores and, as shown by increased maximum cystometric capacity, improved urodynamic findings. In 2 patients with Parkinsons disease post-void residual urine volume developed. CONCLUSIONS Intradetrusor injection of 100 U botulinum toxin type A induced clinical and urodynamic improvement in overactive bladder symptoms that lasted at least 6 months in patients with Parkinsons disease.

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.

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.