Theory of Mind in multiple system atrophy: comparison with Parkinson's disease and healthy subjects.

Theory of Mind is defined as the ability to attribute mental state and emotions to other people and is relevant to social relationships. The cortical and subcortical regions involved in Theory of Mind are damaged by neurodegenerative processes of Parkinsonian syndromes, so the aim of the present study was to explore, for the first time, possible deficits of Theory of Mind and their cognitive correlates in multiple system atrophy (MSA). Twenty-six patients with MSA, 25 patients with Parkinson's disease (PD) and 25 healthy subjects were enrolled. Cognitive and affective subcomponents of Theory of Mind, executive functions, long-term memory and apathy were evaluated. The three groups did not differ on demographic variables. MSA and PD groups performed worse than healthy subjects on both cognitive (advanced test of ToM) and affective (emotion attribution task) ToM tasks, but no significant difference was found between patients' groups. However, when using another affective ToM task (Eyes Test), MSA group had poorer performance than healthy subjects and Parkinsonian patients, whereas Parkinsonian patients had similar performance to healthy subjects. Regression analysis revealed an association between poor cognitive flexibility and dysfunctional cognitive component of Theory of Mind. Deficit of cognitive and affective components of Theory of Mind occurred in MSA. Dysfunction of cognitive component was related to executive dysfunction (i.e. cognitive rigidity). These findings might suggest the usefulness of an early evaluation of social cognition in MSA to identify individuals with impaired Theory of Mind who are at risk of social withdrawal, and reduced quality of life.

Effects of gender on cognitive and behavioral manifestations in multiple system atrophy.

Gender differences have been described in several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. The effects of gender on cognitive and behavioral manifestations in multiple system atrophy and the changes of cognitive functions over time according to gender have not been investigated so far. Fifty-five patients with a diagnosis of multiple system atrophy underwent a comprehensive neuropsychological and neuropsychiatric battery at baseline and 26 of them could be re-evaluated at 1-year follow-up. At baseline women with multiple system atrophy had poorer global cognitive state and visuo-spatial abilities, and a higher prevalence of depression and apathy than males. At follow-up, female patients deteriorated more than males on attention abilities and motor functions, and had a higher prevalence of depression than men. Executive functions and visuo-spatial abilities significantly worsened over time in both groups. Mild Cognitive Impairment single domain was significantly more frequent in females than males. Cognitive and behavioral differences between genders in multiple system atrophy involve global cognition, planning, attention, visual-perceptive skills, and depression, with female patients more compromised than males. Female patients deteriorated more than men over time as for motor functions and attention. Further longitudinal studies are deserved to confirm gender differences in progression of cognitive and behavioral features of multiple system atrophy.

Serum miR-30c-5p is a potential biomarker for multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease that belongs to the α synucleinopathies. Clinically, there is an overlap between MSA and Parkinson's disease (PD), especially at the early disease stage. However, these two pathologies differ in terms of disease progression. Currently, no biomarker exists to differentiate MSA from PD. MicroRNAs are non-coding RNAs implicated in gene expression regulation. MiRNAs modulate cellular activity and they control a range of physiological and pathological functions. miRNAs are found in biofluids, such as blood, serum, plasma, saliva, and cerebrospinal fluid. Many groups, including ours, found that circulating miRNAs are differently expressed in blood, plasma, serum and cerebrospinal fluid of PD and MSA patients. In the present study, our primary aim was to determine if serum mir-30-5p and mir-148b-5p can be used as biomarkers for early diagnosis of PD and/or MSA. Our secondary goal was to determine if serum levels of those miRNAs can be correlated with the patients' clinical profile. Using quantitative PCR (qPCR), we evaluated expression levels of miR-30c-5p and miR148b-5p in serum samples from PD (n = 56), MSA (n = 49), and healthy control (n = 50) subjects. We have found that miR-30c-5p is significantly upregulated in MSA if compared with PD and healthy control subjects. Moreover, serum miR-30c-5p levels correlate with disease duration in both MSA and PD. No significant difference was found in miR-148b-5p among MSA, PD and healthy control subjects. Our results suggest a possible role of serum miR-30-5p as a biomarker for diagnosis and progression of MSA.

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 Parkinson's 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, disease's 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.

Frontal assessment battery scores and non-motor symptoms in parkinsonian disorders.

Using data from the PRIAMO study, we investigated non-motor symptoms (NMS) versus frontal lobe dysfunction in patients with idiopathic Parkinson disease (PD); 808 patients with PD and 118 with atypical parkinsonisms (AP) were consecutively enrolled at 55 Centers in Italy. Twelve categories of NMS were investigated. Cognitive impairment was defined as a Mini-Mental Status Evaluation score ≤ 23.8 and frontal lobe dysfunction as a Frontal Assessment Battery (FAB) score ≤ 3.48. Multivariable logistic regression was used to identify predictor of frontal lobe dysfunction in 524 PD patients, and a generalized linear model was used for each of the six FAB items. Not only the total FAB scores but also the single FAB items were lower in AP versus PD (p ≤ 0.005). Age (OR = 1.05), cognitive impairment (OR = 9.54), lack of cardiovascular symptoms (OR = 3.25), attention or memory problems (OR = 0.59) and treatment with L: -DOPA (OR = 5.58) were predictors of frontal lobe dysfunction. MMSE was negatively associated with all FAB items (ß ≤ -0.16) and age with all FAB items but prehension behavior (ß ≤ -0.01). Previous use of L: -DOPA was negatively associated with verbal fluency (ß = -0.32) possibly acting as surrogate marker of disease duration. Cognitive impairment is a predictor of frontal lobe dysfunction. Among NMS, lack of attention or memory problems were negatively associated with frontal impairment. Further studies are nonetheless needed to better identify the predictors of frontal impairment in PD patients.

A novel phenotype in an Italian family with a rare progranulin mutation.

INTRODUCTION: Progranulin (PGRN) is a secreted glycoprotein encoded in humans by the GRN gene, located on chromosome 17q21. Several nonsense and missense pathogenetic GRN mutations have been described. OBJECTIVE: We herein describe two sisters carrying a rare GRN mutation with extremely different clinical features and family history of dementia and behavioral disorders, with a novel presentation with stridor and dysphonia. METHODS: Patients underwent a multidimensional assessment including neurological and neuropsychological evaluation, structural and functional imaging, and genetic screening. RESULTS: The younger sister presented at the age of 64 with inspiratory stridor, dysphonia and exercise-induced dyspnea. Transnasal fiberoptic laryngoscopy showed bilateral adduction of the vocal cords at rest and paradoxical further adduction of the vocal cords during forced inspiration, suggesting the hypothesis of an adductor laryngeal dystonia. The older sister presented at the age of 63 with a rapidly progressive corticobasal syndrome. The only clinical feature common to both sisters was a dysexecutive syndrome. The c.893G > A mutation in exon 9 of GRN was found in heterozygosis in both sisters, causing a missense Arginine to Histidine substitution in position 298 of the protein (p.R298H). CONCLUSIONS: Our report supports the pathogenicity of the GRN p.R298H mutation, which is first detected in two members from the same family, showing an extremely different phenotypes. Moreover, we report the first case of an FTD-associated mutation presenting with inspiratory stridor and dysphonia linked to adductor laryngeal dystonia, thus expanding the clinical spectrum of GRN-related disorders.

Evolution of neuropsychological profile in motor subtypes of multiple system atrophy.

INTRODUCTION: Cognitive deficits and neuropsychiatric symptoms occur in parkinsonian and cerebellar subtypes of Multiple System Atrophy (MSA-P and MSA-C). These symptoms have been investigated mainly in cross-sectional studies. The present 1-year follow-up study aimed at evaluating the evolution of cognitive and neuropsychiatric profile in patients with MSA-C and MSA-P. METHODS: Twenty-nine patients with MSA-P, 21 with MSA-C and 30 healthy subjects (HCs) underwent a neuropsychological battery and questionnaires assessing depression and apathy (T0). After 1 year (T1), patients with MSA-C and MSA-P underwent the same neuropsychological and neuropsychiatric tools employed at T0. RESULTS: At T0, MSA-P and MSA-C groups were more depressed and apathetic and performed worse on tests assessing repetition abilities, executive and attentive functions than HCs. MSA-P and MSA-C groups did not differ on cognitive variables and neuropsychiatric scales. At T1, a significant worsening in spatial planning and psychomotor speed in MSA-C group and a significant worsening in memory, spatial planning, repetition abilities and functional autonomy in MSA-P group were found. The prevalence of apathy increased in both subtypes, whereas the prevalence of depression was reduced in MSA-C and relatively consistent in MSA-P. CONCLUSIONS: The finding revealed a wide-ranging worsening of cognitive functions in MSA-P and a significant decline in processing speed in MSA-C. These results underline the relevance of evaluating cognitive and psychiatric features of MSA over the course of the disease in the daily clinical practice.

Subcortical atrophy and perfusion patterns in Parkinson disease and multiple system atrophy.

BACKGROUND: The clinical differentiation between Parkinson disease (PD) and multiple system atrophy (MSA) is difficult. OBJECTIVES: Arterial spin labeling (ASL) is an advanced MRI technique that obviates the use of an exogenous contrast agent for the estimation of cerebral perfusion. We explored the value of ASL in combination with structural MRI for the differentiation between PD and MSA. METHODS: Ninety-four subjects (30 PD, 30 MSA and 34 healthy controls) performed a morphometric and ASL-MRI to measure volume and perfusion values within basal ganglia and cerebellum. A region-of-interest analysis was performed to test for structural atrophy and regional blood flow differences between groups. RESULTS: MSA patients showed higher subcortical atrophy than both PD patients and HC, while no differences were observed between the latter. MSA and PD showed lower volume-corrected perfusion values than HC in several cerebellar areas (Crus I, Crus II, right VIIb, right VIIIa, right VIIIb), right caudate and both thalami. MSA and PD patients displayed similar perfusion values in all aforementioned areas, but the right cerebellar area VIIIb (lower in MSA) and right caudate and both thalami (lower in PD). Similar results were obtained when comparing PD and MSA patients with the parkinsonian variant. CONCLUSIONS: A perfusion reduction was equally observed in both MSA and PD patients in cerebellar areas that are putatively linked to cognitive (i.e., executive) rather than motor functions. The observed hypo-perfusion could not be explained by atrophy, suggesting the involvement of the cerebellum in the pathophysiology of both MSA and PD.

The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease.

We performed a multicenter survey using a semistructured interview in 1,072 consecutive patients with Parkinson's disease (PD) enrolled during 12 months in 55 Italian centers to assess the prevalence of nonmotor symptoms (NMSs), their association with cognitive impairment, and the impact on patients' quality of life (QoL). We found that 98.6% of patients with PD reported the presence of NMSs. The most common were as follows: fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%). The mean number of NMS per patient was 7.8 (range, 0-32). NMS in the psychiatric domain were the most frequent (67%). Frequency of NMS increased along with the disease duration and severity. Patients with cognitive impairment reported more frequently apathy, attention/memory deficit, and psychiatric symptoms. Apathy was the symptom associated with worse PDQ-39 score but also presence of fatigue, attention/memory, and psychiatric symptoms had a negative impact on QoL. These findings further support a key role for NMS in the clinical frame of PD and the need to address them specifically in clinical trials using dedicated scales.

Progression of tumefactive demyelinating lesion in a child demonstrated with MRI.

Tumefactive demyelinating lesions (TDLs) are atypical presentations of various demyelinating diseases. They can mimic brain tumors in their clinical and radiological features and usually respond favorably to corticosteroid therapy. We report a case of a 17-year-old girl with a single TDL suddenly increasing in size even under steroid therapy. She underwent very strict follow-up examinations with conventional magnetic resonance and diffusion-weighted imaging, perfusion-weighted imaging, proton-magnetic resonance spectroscopy. The behavior of the lesion during the different follow-up sessions posed a diagnostic challenge as it expanded its size during the final examination, in stark contrast to what we forecast. Diagnosis of TDL was initially hypothesized, but the aggressive behavior of the lesion required biopsy.

The progression of non-motor symptoms in Parkinson's disease and their contribution to motor disability and quality of life.

Non-motor symptoms are gaining relevance in Parkinson's disease (PD) management but little is known about their progression and contribution to deterioration of quality of life. We followed prospectively 707 PD patients (62 % males) for 2 years. We assessed non-motor symptoms referred to 12 different domains, each including 1-10 specific symptoms, as well as motor state (UPDRS), general cognition, and life quality. Hoehn & Yahr (H&Y) stage was used to categorize patient status (I-II mild; III moderate; IV-V severe). We found that individual non-motor symptoms had variable evolution over the 2-year follow-up with sleep, gastrointestinal, attention/memory and skin disturbances (hyperhidrosis and seborrhea) becoming more prevalent and psychiatric, cardiovascular, and respiratory disorders becoming less prevalent. Development of symptoms in the cardiovascular, apathy, urinary, psychiatric, and fatigue domains was associated with significant life-quality worsening (p < 0.0045, alpha with Bonferroni correction). During the observation period, 123 patients (17 %) worsened clinically while 584 were rated as stable. There was a fivefold greater increase in UPDRS motor score in worse compared with stable patients over 24 months (p < 0.0001 vs. baseline both in stable and worse group). The total number of reported non-motor symptoms increased over 24 months in patients with motor worsening compared to stable ones (p < 0.001). Thirty-nine patients died (3.4 % of patients evaluable at baseline) with mean age at death of 74 years. Deceased patients were older, had significantly higher H&Y stage and motor score, and reported a greater number of non-motor symptoms at baseline. In conclusion, overall non-motor symptom progression does not follow motor deterioration, is symptom-specific, and only development of specific domains negatively impacts quality of life. These results have consequences for drug studies targeting non-motor features.

Non-motor symptoms in atypical and secondary parkinsonism: the PRIAMO study.

The PRIAMO study is a cross-sectional longitudinal observational study aimed at describing epidemiology and evolution of non-motor symptoms (NMS) in patients with different forms of parkinsonism recruited in 55 Italian centres and evaluated over 24 months. In this paper, we are reporting prevalence and clinical characteristics of NMS in patients with atypical and secondary parkinsonism. Out of 1307 consecutive patients with a diagnosis of parkinsonism, 83 patients had vascular parkinsonism (VP), 34 had multiple system atrophy (MSA), 30 had progressive supranuclear palsy (PSP), 14 had dementia with Lewy bodies (DLB) and 11 had corticobasal degeneration (CBD). MSA and DLB had the highest number of NMS domains and symptoms, respectively. Gastrointestinal symptoms, pain, urinary problems and postural instability due to orthostatic hypotension were most frequent in MSA. Sleep disturbances were also common with a prevalence of approximately 70% in all diagnostic groups but CBD (36%). Psychiatric symptoms and attention and memory impairment were frequently observed in all diagnoses but were most prevalent among DLB patients, whereas the prevalence of skin and respiratory disorders was rather low in all forms, ranging between 10 and 30%. Atypical parkinsonism patients also reported a low QoL, with no significant differences among the different forms, whereas PD and VP patients had a better QoL.

High prevalence of Dopaminergic Premonitory Symptoms in migraine patients with Restless Legs Syndrome: a pathogenetic link?

In order to assess the prevalence of Dopaminergic Premonitory Symptoms (DPS) in migraine patients with Restless Legs Syndrome (RLS), we chose migraine patients from a large Italian clinical headache population previously investigated for an association between primary headaches and RLS. We evaluated a total sample of 164 patients with migraine, in particular 114 with migraine without aura (MO), 10 with migraine with aura (MA) and 40 with MO and MA in various combinations between them or with episodic tension-type headache (ETTH), defined as a "mixed group". About 20% of all migraine patients referred at least one of the following DPS: yawning, nausea, somnolence or food craving, confirming data already indicated in the literature. Among migraine patients with RLS (25.6%), DPS were referred from about half of the patients (47.6%) compared to those without RLS (47.6% vs. 13.1%; p<0.001). Based on migraine subtype, patients with MO referred DPS (26.3%) more frequently compared to the MA group and "mixed group" (12.0%, p<0.05), particularly in the presence of RLS (63.0% vs. 20.0%, p<0.01). No statistical differences were found between clinical and demographic data of the subgroups or related to medical conditions investigated (anxiety, depression, sleep disorders, body mass index). It is interesting that the chances of having RLS in migraine patients were more than 5 times higher in the presence of DPS. These results could support a hypothetical dopaminergic imbalance in RLS and migraine, as the dopamine is involved in the pathogenesis of both disorders and it is responsible for the migraine DPS reported above.

Restless legs syndrome and primary headaches: a clinical study.

Based on recent data about the association between restless legs syndrome (RLS) and migraine, we performed an observational study on the occurrence of RLS in patients affected by primary headaches. Two hundred headache patients (149 women and 51 men) and 120 (90 women and 30 men) sex-and age-matched control subjects were included. In the headache group, migraine without aura (MO) was the most represented headache type (n=114), followed by the "mixed" group (n=40) with MO, migraine with aura (MA) and frequent episodic tension-type headache (ETTH) in various combinations, and by ETTH alone (n=22). The remaining patients suffered from MA alone (n=10 MA), episodic cluster headache (ECH n=12) and primary stabbing headache (n=2). RLS frequency was significantly higher in headache patients than in control subjects (22.4% vs. 8.3, p=0.002) independently of sex, although with a female preponderance (84%) in both groups. More than 60% (n=27) of RLS patients were affected by MO and 30% (n=13) by a combination of two headache types (p> or =0.001), with a very low frequency of RLS for the other types of headache. No RLS patient had ECH. No statistical differences were observed among clinical characteristics of different types of headache in groups with and without RLS. In both headache and control groups, higher scores for depression and anxiety were more frequent in subjects with RLS compared with those without RLS. Furthermore, headache patients with RLS reported sleep disturbances more frequently compared to those without RLS (50.0% vs. 32.7%; p<0.0001) and showed a normal or underweight body mass index. Our data seem to confirm the existence of an association between RLS and primary headaches, particularly with migraine, as already demonstrated. The absence of RLS in ECH patients is very interesting. Many pathogenetic considerations about links between RLS and primary headaches could be given, the most fitting involving dopamine and melatonin.

Parkinsonism and essential tremor in a family with pseudo-dominant inheritance of PARK2: an FP-CIT SPECT study.

We report a family with 5 affected individuals manifesting either essential tremor (ET), Parkinsonism, or both, consistent with pseudo-dominant inheritance of PARK2. Two homozygotes presented postural and kinetic tremor several years before the onset of Parkinsonism. Postural and kinetic tremor mimicking ET was the only feature in 1 homozygous and 2 heterozygous carriers of the mutation. Striatal dopamine transporter density was reduced in accordance with phenotype and number of mutated alleles. In 3 homozygotes and 1 heterozygote, a 2-year follow-up single photon emission computed tomography suggested no progression of nigrostriatal deficit.

Paradoxical response to apomorphine in a case of atypical parkinsonism.

We describe a patient with clinical signs of parkinsonism showing a paradoxical response to apomorphine injection. We discuss possible pathogenetic mechanisms with regard to the literature and suggest the diagnosis of a striatonigral degeneration at an early stage.