Silvia Ramat

Interaction of caudate dopamine depletion and brain metabolic changes with cognitive dysfunction in early Parkinson's disease

Damage to nonmotor dopamine (DA)-mediated frontostriatal circuits has been proposed as the main pathophysiological basis of cognitive dysfunction in Parkinsons disease (PD). In the present study, 18 early nondemented drug naive PD patients were investigated, by dual-tracer N-ω-fluoropropyl-2β-carbomethoxy-3β-4-[123I]iodophenyl-nortropane ([123I]FP-CIT) single-photon emission computed tomography (SPECT)/[18F] fluoro-deoxyglucose (FDG) positron emission tomography (PET) imaging, to test whether an early and not yet treatment-modulated relation exists between cognitive functions, caudate nucleus (CN) DA impairment and brain metabolism (CMRglc) in associative frontostriatal circuits. Verbal fluency performance correlated with DA impairment in CN, and with CMRglc in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Further, CMRglc in orbitofrontal cortex, DLPFC, and ACC was shown to be early modulated by the level of DA impairment in CN. The present study demonstrates in vivo the early functional disruption of nonmotor frontostriatal circuits in PD. The effect of CN DA impairment on DLPFC and ACC metabolism is proposed as a possible early pathophysiological and functional substrate for executive dysfunction in PD.

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.

Psychosis associated to Parkinson's disease in the early stages: relevance of cognitive decline and depression

Objective To evaluate the prevalence of psychosis associated with Parkinsons disease (PSY-PD) in its early stages, its incidence over a 24 month follow-up period and the association with motor and non-motor clinical features. Methods PRIAMO is a 2 year longitudinal observational study that has enrolled patients with parkinsonism in 55 Italian centres. A cohort of 495 patients with early disease stage PD (baseline Hoehn and Yahr score ≤2, diseases duration (median) 3.4 years) were followed for 2 years. PSY-PD was evaluated by means of a clinician rated questionnaire and defined as the presence of at least one of the following symptoms occurring for at least 1 month: illusions, hallucinations, jealousy ideas and persecutory ideas. Patients with and without PSY-PD were compared on several clinical variables, encompassing motor and non-motor features. Results The prevalence of PSY-PD at baseline was 3%; the incidences at 12 and 24 months were 5.2% and 7.7%, respectively. Longer disease duration and prescription of dopamine agonists at baseline were associated with the development of PSY-PD over the 24 month period. At this follow-up time, worse disease severity, decline in cognitive performances, presence of depressive symptoms and anxiety were more frequently observed in PSY-PD. Conclusions Psychotic type symptoms may occur in the early stages of PD although less frequently than in later stages. Beyond dopaminergic treatment, there are disease related factors, such as disease severity and the occurrence of cognitive and depressive symptoms, which may underlie the onset of psychotic type symptoms from the earliest stages.

The relationship between cerebral vascular disease and parkinsonism: The VADO study.

BACKGROUND The observation of gait abnormalities, parkinsonism and vascular lesions in elderly patients is often reported as vascular parkinsonism (VP). However the status of striatal dopamine transporter (DAT) and the effects of brain vascular lesions on motor features and levodopa responsiveness are poorly defined. METHODS We recorded clinical features, chronic response to levodopa and vascular risk factors in a cross-sectional cohort of consecutive elderly patients with possible Parkinsons disease (PD) or VP recruited in 20 centers in Italy. RESULTS We included a total of 158 patients. Onset of motor symptoms was asymmetric in 93 (59%) and symmetric in 65 patients (41%). Symmetric motor onset was associated with greater disease severity. Chronic levodopa response was positive in 75 (47.8%) and negative in 82 patients (52.2%). A negative response to levodopa was associated with greater frequency of symmetric onset of motor symptoms, worst disease severity, absence of dyskinesia and greater number of vascular risk factors. Frontal lobe showed largest vascular load. Striatal DAT was normal in 48 (30.4%) and abnormal in 110 (69.6%) patients. Patients with normal DAT binding showed higher vascular load at MRI. Significant predictive factors of worst disease severity and negative response to levodopa were hypertension, vascular lesions in basal ganglia/periventricular regions, and normal DAT uptake. CONCLUSIONS Multiple cerebral vascular lesions modify clinical presentation and severity in patients with parkinsonism and this is underlined by specific risk factors primarily hypertension. Striatal DAT assessment is helpful in identifying patients where therapy benefit is less likely.

Brain metabolic correlates of dopaminergic degeneration in de novo idiopathic Parkinson’s disease

PurposeThe aim of the present study was to evaluate the reciprocal relationships between motor impairment, dopaminergic dysfunction, and cerebral metabolism (rCMRglc) in de novo Parkinson’s disease (PD) patients.MethodsTwenty-six de novo untreated PD patients were scanned with 123I-FP-CIT SPECT and 18F-FDG PET. The dopaminergic impairment was measured with putaminal 123I-FP-CIT binding potential (BP), estimated with two different techniques: an iterative reconstruction algorithm (BPOSEM) and the least-squares (LS) method (BPLS). Statistical parametric mapping (SPM) multiple regression analyses were performed to determine the specific brain regions in which UPDRS III scores and putaminal BP values correlated with rCMRglc.ResultsThe SPM results showed a negative correlation between UPDRS III and rCMRglc in premotor cortex, and a positive correlation between BPOSEM and rCMRglc in premotor and dorsolateral prefrontal cortex, not surviving at multiple comparison correction. Instead, there was a positive significant correlation between putaminal BPLS and rCMRglc in premotor, dorsolateral prefrontal, anterior prefrontal, and orbitofrontal cortex (p < 0.05, corrected for multiple comparison).ConclusionsPutaminal BPLS is an efficient parameter for exploring the correlations between PD severity and rCMRglc cortical changes. The correlation between dopaminergic degeneration and rCMRglc in several prefrontal regions likely represents the cortical functional correlate of the dysfunction in the motor basal ganglia-cortical circuit in PD. This finding suggests focusing on the metabolic course of these areas to follow PD progression and to analyze treatment effects.

Deficit of short-term memory in newly diagnosed untreated parkinsonian patients: reversal after L-dopa therapy

Abstract.We assessed the effect of pathology and L-dopa therapy on attention, working memory, and executive functions, in newly diagnosed Parkinson’s disease patients. Twenty-one consecutive outpatients who met the criteria for de novo Parkinson’s disease, and were naive for L-dopa therapy, were observed for the first time. All patients underwent clinical and neuropsychological evaluations (cognitive decline, memory, executive control). Each patient was reevaluated on standard L-dopa therapy. Serial Position Curves showed an increased primacy effect (5.18±2.07) and a decreased recency effect (13.35±5.51). These findings normalized after L-dopa therapy (3.50±1.72 and 16.20±3.09 respectively). The effect of L-dopa on working memory is discussed.

Parkinsonism and Anderson Fabry's disease : A case report

We describe and present a videotape of a 57‐year‐old woman admitted to our Neurological Clinic at 46 years of age due to extrapyramidal manifestations suggesting Parkinsons disease (PD) and with a brain magnetic resonance imaging scan showing multi‐infarctual leukoencephalopathy. Various investigations led to the diagnosis of Anderson Fabrys disease (AFD). We discuss the possibility of correlation between the patients parkinsonism and AFD.

The validity and reliability of the Italian Olfactory Identification Test (IOIT) in healthy subjects and in Parkinson's disease patients.

BACKGROUND Olfactory function can be rapidly evaluated by means of standardized olfactory tests. Multiple-choice smell identification tests can be conditioned by cultural background. To investigate a new tool for detecting olfactory deficit in Italian subjects we developed a multiple-choice identification test prepared with odorants belonging to the Italian culture. METHODS The Italian Olfactory Identification Test (IOIT) was developed with 33 microencapsulated odorants with intensity of odors and headspace Gas Chromatography being tested. Test-retest reliability of the IOIT was evaluated. The IOIT was administered to 511 controls and 133 Parkinsons patients. RESULTS In healthy subjects the number of IOIT errors increased with age for both females (p < 0.0001) and males (p < 0.0001), while in the Parkinsons disease group the number of IOIT errors was significantly greater where compared to healthy subjects (p < 0.0001 in all age groups). The reference limits applied to all age groups revealed an IOIT sensitivity of 93% and a specificity of 99%. The test-retest reliability was excellent. CONCLUSION The IOIT is highly reliable, disposable, easy to administer, not fragile, and has a long shelf-life. All these features make the IOIT suitable for clinical use as well as for population screening and to discriminate Parkinsons patients from healthy subjects.

A direct ROI quantification method for inherent PVE correction: accuracy assessment in striatal SPECT measurements

PurposeThe clinical potential of striatal imaging with dopamine transporter (DAT) SPECT tracers is hampered by the limited capability to recover activity concentration ratios due to partial volume effects (PVE). We evaluated the accuracy of a least squares method that allows retrieval of activity in regions of interest directly from projections (LS-ROI).MethodsAn Alderson striatal phantom was filled with striatal to background ratios of 6:1, 9:1 and 28:1; the striatal and background ROIs were drawn on a coregistered X-ray CT of the phantom. The activity ratios of these ROIs were derived both with the LS-ROI method and with conventional SPECT EM reconstruction (EM-SPECT). Moreover, the two methods were compared in seven patients with motor symptoms who were examined with N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl) (FP-CIT) SPECT, calculating the binding potential (BP).ResultsIn the phantom study, the activity ratios obtained with EM-SPECT were 3.5, 5.3 and 17.0, respectively, whereas the LS-ROI method resulted in ratios of 6.2, 9.0 and 27.3, respectively. With the LS-ROI method, the BP in the seven patients was approximately 60% higher than with EM-SPECT; a linear correlation between the LS-ROI and the EM estimates was found (r = 0.98, p = 0.03). ConclusionThe LS-ROI PVE correction capability is mainly due to the fact that the ill-conditioning of the LS-ROI approach is lower than that of the EM-SPECT one. The LS-ROI seems to be feasible and accurate in the examination of the dopaminergic system. This approach can be fruitful in monitoring of disease progression and in clinical trials of dopaminergic drugs.

Clinical correlation of the binding potential with 123I-FP-CIT in de novo idiopathic Parkinson’s disease patients

PurposeThe aim of this study was to evaluate the accuracy of different single-photon emission computed tomography (SPECT) reconstruction techniques in measuring striatal N-ω-fluoropropyl-2β-carbomethoxy-3β-4-[123I]iodophenyl-nortropane (123I-FP-CIT) binding in de novo Parkinson’s disease (PD) patients, in order to find a correlation with clinical scales of disease severity in the initial phases of disease.MethodsThirty-six de novo PD patients underwent 123I-FP-CIT SPECT and MRI scan. SPECT data were reconstructed with filtered back projection (FBP), with an iterative algorithm (ordered subset expected maximization, OSEM) and with a method previously developed in our institution, called least-squares (LS) method. The ratio of specific to non-specific striatal 123I-FP-CIT binding (binding potential, BP) was used as the outcome measure with all the reconstruction methods (BPFBP, BPOSEM, BPLS).ResultsThe range of values of striatal BPLS was significantly greater than BPFBP and BPOSEM. For all striatal regions, estimates of BPFBP correlated well with BPOSEM (r = 0.84) and with BPLS (r = 0.64); BPOSEM correlated significantly with BPLS (r = 0.76). A good correlation was found between putaminal BPLS and Hoen and Yahr, Unified PD Rating Scale (UPDRS) and lateralized UPDRS motor scores (r = −0.46, r = −0.42, r = −0.39, respectively). Neither putaminal BPFBP nor putaminal BPOSEM correlated with any of these motor scores.ConclusionsIn de novo PD patients, 123I-FP-CIT BP values derived from FBP and OSEM reconstruction techniques do not permit to differentiate PD severity. The LS method instead finds a correlation between striatal BP and disease severity scores. The results of this study support the use of 123I-FP-CIT BP values estimated with the LS method as a biomarker of PD severity.