Marina Picillo

Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism.

Autosomal recessive, early‐onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1‐like domains of other proteins. Sequencing the SYNJ1 ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early‐onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis.

Freezing of Gait and Executive Functions in Patients with Parkinson's Disease

Freezing of gait (FOG) is a frequent, disabling symptom of Parkinsons disease (PD). FOG usually lasts a few seconds. It refers to brief paroxysmal events during which a subject is unable to start or continue locomotion. Despite its frequency, FOG pathophysiology is unclear. Because a frontal lobe dysfunction or a disconnection between the frontal lobe and basal ganglia has been implicated in FOG, we explored frontal functions in PD patients using neuropsychological tests. Thirteen early‐stage PD patients [Hoehn & Yahr score (H&Y) ≤ 2.5] with freezing during “on ” state (FOG+), and 15 age‐, H&Y score‐, and disease‐duration‐matched PD patients without freezing (FOG−) were investigated. No patient was demented or depressed. Assessment included the Unified Parkinsons Disease Rating Scale (UPDRS), FOG questionnaire, Mini Mental State Examination (MMSE), frontal assessment battery (FAB), phonemic verbal fluency, Stroop test (parts II and III), and ten‐point clock test (TPCT). UPDRS and MMSE scores did not differ between the two groups. FAB, verbal fluency, and TPCT scores were significantly lower in FOG+ patients than in FOG− patients (FAB: P = 0.008; phonemic verbal fluency: P = 0.011; TPCT: P = 0.024). FOG correlated with lower scores at frontal tests in patients with early‐stage PD.

The heterogeneity of early Parkinson's disease: a cluster analysis on newly diagnosed untreated patients.

Background The variability in the clinical phenotype of Parkinson’s disease seems to suggest the existence of several subtypes of the disease. To test this hypothesis we performed a cluster analysis using data assessing both motor and non-motor symptoms in a large cohort of newly diagnosed untreated PD patients. Methods We collected data on demographic, motor, and the whole complex of non-motor symptoms from 100 consecutive newly diagnosed untreated outpatients. Statistical cluster analysis allowed the identification of different subgroups, which have been subsequently explored. Results The data driven approach identified four distinct groups of patients, we have labeled: 1) Benign Pure Motor; 2) Benign mixed Motor-Non-Motor; 3) Non-Motor Dominant; and 4) Motor Dominant. Conclusion Our results confirmed the existence of different subgroups of early PD patients. Cluster analysis revealed the presence of distinct subtypes of patients profiled according to the relevance of both motor and non-motor symptoms. Identification of such subtypes may have important implications for generating pathogenetic hypotheses and therapeutic strategies.

Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson's disease

Visual hallucinations (VHs) represent a frequent and disturbing complication of Parkinsons disease. Evidence suggests that VH can be related to central cholinergic dysfunction. Short-latency afferent inhibition (SAI) technique gives the opportunity to test an inhibitory cholinergic circuit in the human cerebral motor cortex. This inhibition of motor-evoked potentials can be observed when transcranial magnetic stimulation is delivered with a delay ranging from 2 to 8 ms, after a peripheral nerve afferent input has reached the somatosensory cortex. We applied SAI technique in 10 non-demented patients with Parkinsons disease with VHs, in 12 non-demented patients with Parkinsons disease without VHs (NVH-pts) and in 11 age-matched normal controls. All patients with Parkinsons disease underwent a battery of neuropsychological tests to assess frontal and visuospatial functions, memory and attention. SAI was significantly reduced in patients with VHs compared with controls and patients without VHs. Neuropsychological examination showed a mild cognitive impairment in 16 out of 22 patients with Parkinsons disease. In addition, we found that in our patients with VHs, performance of some tasks evaluating visuospatial functions and attentional/frontal lobe functions was significantly more impaired than in patients without VHs. SAI abnormalities, presence of VH and neuropsychological results strongly support the hypothesis of cholinergic dysfunction in some patients with Parkinsons disease, who will probably develop a dementia. A follow-up study of our patients is required to verify whether SAI abnormalities can predict a future severe cognitive decline. Moreover, SAI can also be very useful to follow-up the efficacy of anti-cholinesterase therapies.

Non-motor symptoms in early Parkinson's disease: a 2-year follow-up study on previously untreated patients

Background Non-motor symptoms are very common among patients with Parkinsons disease since the earliest stage, but little is known about their progression and their relationship with dopaminergic replacement therapy. Methods We studied non-motor symptoms before and after 2 years from dopaminergic therapy introduction in ninety-one newly diagnosed previously untreated PD patients. Results At baseline, nearly all patients (97.8%) referred at least one non-motor symptom. At follow-up, only few non-motor symptoms significantly changed. Particularly, depression and concentration became less frequent, while weight change significantly increased after introduction of dopamine agonists. Conclusions We reported for the first time a 2-year prospective study on non-motor symptoms before and after starting therapy in newly diagnosed PD patients. Even if non-motor symptoms are very frequent in early stage, they tend to remain stable during the early phase of disease, being only few non-motor symptoms affected from dopaminergic therapy and, specifically, by the use of dopamine agonists.

Neuropathy and levodopa in Parkinson's disease: Evidence from a multicenter study

The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinsons disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (≥3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P < 0.001; odds ratio [OR], 1.08; 95% confidence interval [CI], 1.037‐1.128). The risk of neuropathy was 2.38 higher in the LELD group than in the control group (P = 0.022; OR, 2.38; 95% CI, 1.130‐5.014). In a comparison between patients with and without neuropathy (Students t test), the levodopa dose was higher (P < 0.0001), serum vitamin B12 levels were lower (P = 0.0102), and homocysteine levels were higher (P < 0.001) in the patients with neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical‐neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa.

Resting-state functional connectivity associated with mild cognitive impairment in Parkinson’s disease

Cognitive impairment is common in PD, even in early stages. The construct of mild cognitive impairment has been used to identify clinically evident cognitive impairment without functional decline in PD patients (PD-MCI). The aim of the present study was to investigate brain connectivity associated with PD-MCI through RS-fMRI. RS-fMRI at 3T was collected in 42 PD patients and 20 matched healthy controls. Among PD patients, 21 were classified as having MCI (PD-MCI) and 21 as cognitively unimpaired (PD-nMCI) based on criteria for possible PD-MCI (level I category). Single-subject and group-level ICA was used to investigate the integrity of brain networks related to cognition in PD patients with and without MCI. Image data processing and statistical analysis were performed in BrainVoyager QX. In addition, we used VBM to test whether functional connectivity differences were related to structural abnormalities. PD-nMCI and PD-MCI patients compared with controls showed decreased DMN connectivity. PD-MCI patients, but not PD-nMCI, compared with controls, showed decreased functional connectivity of bilateral prefrontal cortex within the frontoparietal network. The decreased prefrontal cortex connectivity correlated with cognitive parameters but not with clinical variables. VBM analysis did not reveal any difference in local gray matter between patients and controls. Our findings suggest that an altered DMN connectivity characterizes PD patients, regardless of cognitive status, whereas a functional disconnection of the frontoparietal network could be associated with MCI in PD in the absence of detectable structural changes.

Anxiety is associated with striatal dopamine transporter availability in newly diagnosed untreated Parkinson's disease patients

BACKGROUND Anxiety is a common non-motor symptom among patients with Parkinsons disease (PD). Although the etiology of anxiety in PD is likely to be multifactorial, a dysfunction in the dopaminergic system might be implicated in its pathogenesis. The aim of our study was to investigate a possible dopaminergic mechanism involved in anxiety in newly diagnosed never-medicated PD patients using SPECT and ¹²³I-FP-CIT as the dopamine transporter ligand. METHODS Thirty-four newly diagnosed, untreated PD patients with asymmetric motor symptoms were included in the study: 17 patients with right- and 17 with left-motor onset, matched for age, disease duration and motor disability constituted the group. They were all evaluated for anxiety and depression and underwent an SPECT with ¹²³I-FP-CIT. Dopamine transporter (DAT) availability values for right and left caudate and putamen were calculated and compared between patients with and without anxiety. Regression analyses were also performed in order to correlate DAT availability with the severity of the anxiety symptoms. RESULTS Comparison between PD patients with and those without anxiety revealed significant differences of DAT availability in all the examined regions except the right putamen. In the group of patients considered as a whole, a significant correlation was found between increased anxiety severity and decreased DAT availability in right caudate. CONCLUSIONS We reported an association between nigrostriatal DAT availability deficits and anxiety symptoms in newly diagnosed, untreated PD patients. Our results suggest that hypofunction of the nigrostriatal dopaminergic system may represent one of the functional anomalies involved in anxiety in PD from the earliest stages of disease and irrespective of any therapy.

Diffusion-weighted imaging in multiple system atrophy: A comparison between clinical subtypes†

Multiple system atrophy can be classified into two main types, a Parkinsonian (MSA‐P) and a cerebellar (MSA‐C) variant based on clinical presentation. We obtained diffusion‐weighted magnetic resonance imaging (DWI) in 9 MSA‐P and 12 MSA‐C patients and 11 controls, and correlated DWI changes with disease duration and severity. We found that Trace (D) values in the entire and anterior putamen were significantly higher in MSA‐P than in MSA‐C patients and controls, whereas Trace (D) values in the cerebellum and middle cerebellar peduncle (MCP) were significantly higher in MSA‐C than in MSA‐P patients and controls. Increased disease duration was significantly correlated with increased Trace (D) values in pons of MSA‐P patients, and in cerebellum and MCP of MSA‐C patients. Both UMSARS and UPDRS motor scores positively correlated with entire and posterior putaminal Trace (D) values in MSA‐P patients. The diffusivity changes parallel phenotypical and pathologic differences between MSA‐P and MSA‐C patients, suggesting that DWI is a feasible tool for in vivo evaluation of neurodegeneration in MSA. Based on our findings, Trace (D) measurements in the putamen and pons in MSA‐P patients and in the cerebellum and MCP in MSA‐C patients could serve as quantitative markers for microstructural damage in the course of disease.

Mild Cognitive Impairment in newly diagnosed Parkinson's disease: A longitudinal prospective study

INTRODUCTION In PD, Mild Cognitive Impairment (PD-MCI) occurs since early stages of disease. The aims were to assess presence of PD-MCI in untreated, drug-naive PD patients, and to follow-up the sample over 4 years to ascertain evolution of neurocognitive profile. METHODS Seventy-six patients underwent neuropsychological testing at baseline (T0), and after 2 (T1:n = 62) and 4 years (T2:n = 55). Diagnosis of PD-MCI and PD-associated dementia (PDD) was made according to current consensus criteria. RESULTS PD-MCI occurred in 25/76 patients (32.9%) at baseline, and 4 of them reverted from PD-MCI to Normal Cognition (Reverters), 7 remained stable (Non-Reverters) and 2 developed PDD at T2; 12 patients were lost to the follow-up. Among the 51 patients with normal cognition (PD-CN) at T0, 27 had normal cognition at T2 (5 of them were Reverters with respect to diagnosis at T1), 5 had MCI at T1 and T2 (Non-Reverters), 9 had MCI at T2 only, whereas 1 developed PDD; 9 patients were lost to the follow-up. At baseline, Reverters (n = 9) had younger age at onset and better performance on constructional visuospatial task than Non-Reverters (n = 12). Compared to patients without PD-MCI at all evaluations (n = 19), Reverters had poorer performance on verbal immediate recall and attention tasks and higher level of apathy at T0. Reduced performance on the Stroop Test at baseline predicted PD-MCI at T2. CONCLUSION Executive dysfunctions predicted development of PD-MCI after few years from onset. Reversal from PD-MCI to PD-CN was related to young age at onset and high level of apathy at baseline evaluation.