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White matter hyperintensities (WMH) are considered magnetic brain imaging (MRI) biomarkers of cerebral small vessel disease but their clinical role in neurodegenerative-related disorders is poorly understood. This study describes the distribution of WMH on brain MRI in Progressive Supranuclear Palsy (PSP) in comparison with Parkinson's disease (PD) and explores their possible impact on disease's features. Sixty PSP and 33 PD patients were included. Motor symptoms, cardiovascular risk factors and the age-related white matter changes (ARWMC) score was computed to rate WMH for both groups. Pearson's correlation and linear or logistic regression analysis were used to check for relationships between ARWMC and PSP clinical scores. The mean (standard deviation) ARWMC total score in the PSP cohort was 4.66 (3.25). Any degree of WMH was present in 68% of PSP (ARWMC +). Compared to ARWMC-, ARWMC + did not have greater disease severity or more cardiovascular risk factors. WMH were frequently localized in fronto-parietal lobes and were mild in severity. Linear regression analysis showed that ARWMC total score was related to the PSP-rating scale, irrespective of age, disease duration and the Charlson modified comorbidity index. Logistic regression analysis confirmed that ARWMC total score was related to the use of wheelchair, irrespective of above-mentioned covariates. Vascular risk factors as well as severity and distribution of WMH did not have an impact on the PSP phenotype. No differences were found with PD patients. Our results suggest that WMH in PSP might be markers of neurodegenerative-related pathology rather than being simple expression of atherosclerotic cerebrovascular changes., (© 2024. The Author(s).)

Introduction: Little is known about metabolic changes in progressive supranuclear palsy. Goals of the present study are to: (1) investigate whether early progressive supranuclear palsy is associated with changes in energy expenditure, body composition and dietary intake compared with Parkinson's disease and healthy controls; (2) assess the accuracy of the Harris-Benedict equation to predict measured rest energy expenditure in progressive supranuclear palsy; (3) verify differences according to sex, phenotypes, disease severity and presence of dysphagia in progressive supranuclear palsy., Methods: Twenty-one progressive supranuclear palsy, 41 Parkinson's disease and nine healthy controls were included. Rest energy expenditure was assessed with indirect calorimeter, body composition with bio-impedance analysis and physical activity and dietary intake were estimated with a validated frequency questionnaire. Parametric testing was used to analyze differences between groups., Results: Progressive supranuclear palsy showed reduced total daily energy expenditure and physical activity compared to both other cohorts (p < 0.001) and a tendency toward lower fat-free mass compared to Parkinson's disease (p > 0.05). Limited accuracy was shown for the Harris-Benedict equation (accurate prediction frequency < 60%). Greater disease severity was associated with lower rest energy expenditure (p = 0.030), fat-free mass (p = 0.026) and muscle mass (p = 0.029)., Conclusion: Greater disease severity is associated with reduction in rest energy expenditure likely due to the reduction in lean mass and muscle mass. Such data may pave the way to clinical trials evaluating the efficacy of muscle-targeted nutritional support and physical therapy in preserving muscle mass and improving motor performances in progressive supranuclear palsy at early stages., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Functional motor disorders (FMDs) are usually categorized according to the predominant phenomenology; however, it is unclear whether this phenotypic classification mirrors the underlying pathophysiologic mechanisms., Objective: To compare the characteristics of patients with different FMDs phenotypes and without co-morbid neurological disorders, aiming to answer the question of whether they represent different expressions of the same disorder or reflect distinct entities., Methods: Consecutive outpatients with a clinically definite diagnosis of FMDs were included in the Italian registry of functional motor disorders (IRFMD), a multicenter data collection platform gathering several clinical and demographic variables. To the aim of the current work, data of patients with isolated FMDs were extracted., Results: A total of 176 patients were included: 58 with weakness, 40 with tremor, 38 with dystonia, 23 with jerks/facial FMDs, and 17 with gait disorders. Patients with tremor and gait disorders were older than the others. Patients with functional weakness had more commonly an acute onset (87.9%) than patients with tremor and gait disorders, a shorter time lag from symptoms onset and FMDs diagnosis (2.9 ± 3.5 years) than patients with dystonia, and had more frequently associated functional sensory symptoms (51.7%) than patients with tremor, dystonia and gait disorders. Patients with dystonia complained more often of associated pain (47.4%) than patients with tremor. No other differences were noted between groups in terms of other variables including associated functional neurological symptoms, psychiatric comorbidities, and predisposing or precipitating factors., Conclusions: Our data support the evidence of a large overlap between FMD phenotypes., (© 2021. The Author(s).)

Objectives: To explore the impact of sex and age on relationship between prodromal constipation and disease phenotype in Parkinson's disease at early stages., Methods: A total of 385 Parkinson's disease patients from the PRIAMO study were classified according to the presence of prodromal constipation and followed for 24 months. Multivariable mixed-effect models were applied. All analyses were performed separately for sex (64.1% men) and median age (different by sex: 67 years-old in men and 68 years-old in women)., Results: As for sex, prodromal constipation was associated with greater odds of attention/memory complaints and apathy symptoms in women only. As for age, prodromal constipation was associated with lower cognitive and higher apathy scores in older patients only., Conclusions: Prodromal constipation anticipates lower cognitive performances and more severe apathy since the earliest stages in women and older patients. Sex- and age-related heterogeneity of prodromal markers of Parkinson's disease may impact disease phenotype.

Background: Parkinsonian syndromes are characterized by a wide spectrum of non-motor symptoms. A few studies explored cognitive deficits and neuropsychiatric symptoms in atypical parkinsonism compared to Parkinson's disease (PD). The study was performed to identify cognitive and neuropsychiatric differences between PD, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and to evaluate the influence of clinical features, depressive symptomatology and apathy on cognitive performances in the three groups., Methods: Fifty-five PD, 44 MSA and 42 PSP patients underwent cognitive tests assessing attention, language, memory, visuospatial and executive functions as well as scales assessing depression and apathy. Out of these patients, 20 PD, 20 MSA and 20 PSP patients were selected to be matched for age, education and global cognitive status. Within each whole patients group, correlational analysis was performed between clinical, behavioural and cognitive parameters., Results: The main difference among the groups matched was on cognitive tests exploring verbal learning, executive and linguistic functions. The PSP group was more impaired than the PD and MSA groups on cognitive tests assessing executive functions. On the other hand, MSA group obtained similar cognitive performance to the PD group. As to behavioural symptoms, in whole PSP and MSA groups, apathy and depression were more severe than in PD group, while apathy (but not depression) were more severe in the PSP group as compared to the MSA group., Conclusions: The present study underlined the pervasiveness of cognitive deficits, apathy and depressive symptoms in PSP, whereas little cognitive differences were found between PD and MSA. The findings indirectly supported a dysfunction of prefronto-subcortical circuitries (i.e., dorsolateral prefrontal and limbic circuits) in PSP and PD. Cognitive similarities between MSA and PD reinforced the pivotal role of altered basal ganglia and corresponding frontal deafferentation in the occurrence of the cognitive deficits.

Parkinson disease (PD) is a multifactorial disease, where a genetic predisposition combines with putative environmental risk factors. Mounting evidence suggests that the initial PD pathological manifestations may be located in the gut to subsequently affect brain areas. Moreover, several lines of research demonstrated that there are bidirectional connections between the central nervous system and the gut, the "gut-brain axis" that influences both brain and gastrointestinal function. This opens a potential therapeutic window suggesting that specific dietary strategies may interact with the disease process and influence the risk of PD or modify its course. Dietary components can also theoretically modulate the chronic activation of the inflammatory response that is associated with aging, the strongest risk factor for PD, that has been suggested to hasten the underlying neurodegenerative process in PD. Here, we reviewed the evidence supporting an association between certain dietary compound and either the risk or progression of PD and have provided an overview of the possible pathomechanisms linking nutrition and neurodegeneration. The results of our review would not support a clear role for any dietary components in reducing the risk or progression of PD. However, the evidence favouring a connection between gut abnormalities, inflammation, and neurodegeneration in PD have become too compelling to be ignored, so that further research, also in the field of nutritional genomics, is highly warranted.

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.

The aim of this review was to evaluate the sensitivity and specificity of postictal creatine kinase (CK) levels in the differential diagnosis of epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES). A systematic search was conducted for studies that evaluated postictal CK levels in patients with ES (all types) and PNES. Sensitivity and specificity with 95 % confidence intervals were determined for each study, taking into account: (a) the upper limits adopted; and (b) the 95.7th percentile values, which are recently proposed practical upper reference limits for CK activity. Four studies, comprising a total of 343 events (248 ES and 95 PNES), were available for analysis. Most patients (47/78, 60 %) with ES considered had primarily or secondarily generalized tonic-clonic seizures. The sensitivity of increased postictal CK levels for ES ranged from 14.6 to 87.5, whereas specificity ranged from 85.0 to 100.0. At the 95.7th percentile threshold, sensitivity ranged from 14.6 to 62.5 and specificity was 100.0. The limited number of studies available, their small sample size, and lack of individual event data prevented further stratification analysis by seizure type. Despite the clinical heterogeneity and the limitations of the included studies, increased postictal CK levels are highly specific for the diagnosis of ES, although no definite conclusion on its role in differentiating between convulsive and non-convulsive ES can be drawn. Postictal serum CK levels can provide valuable retrospective information at the later stages of the differential diagnosis of ES and PNES. Due to low sensitivity, normal postictal CK levels do not exclude ES.

Apathy is a behavioural disturbance occurring alone or in concomitance with depression in Parkinson's disease (PD). Here we present a validation study for the self-report version of the Apathy Evaluation Scale (AES-S), carried out in a sample of 60 non-demented, non-depressed untreated, drug-naïve, de novo PD patients; 20 patients of the sample (33.3%) were classified as apathetic according to current clinical criteria. All enrolled patients completed the AES-S and a neurological and cognitive assessment. Mean AES-S score was 34.43. AES-S did not show floor or ceiling effect. Cronbach's alpha was 0.872. Principal component analysis revealed three factors: the first (34.4% of the variance) represented constitutive aspects of the construct of apathy; the second (8.5% of the variance) represented a social dimension; the third factor (7.9% of the variance) represented a dimension related to insight. With respect to clinical criteria for apathy considered as the gold standard, receiver operating characteristics curve analysis showed that a cut-off of 36/37 has the maximum discrimination power. High sensitivity and negative predictive values were obtained with cut-off scores of 33/34 or lower; high specificity and positive predictive values were obtained with cut-off scores of 38/39 or higher. AES-S score correlated with scores on frontal tasks, but not on Beck Depression Inventory, Unified Parkinson's Disease Rating Scale, Hoehn and Yahr scale. The AES-S is a reliable and valid questionnaire for detecting apathy in PD. For screening purposes a 33/34 cut-off score is indicated, but a 38/39 cut-off score is necessary when a high specificity is desired.

Tremor dominant (TD) and akinetic-rigid type (ART) are two motor subtypes of Parkinson's disease associated with different disease progression and neurochemical/neuropathological features. The role of presynaptic nigrostriatal dopaminergic damage is still controversial, poorly explored, and only assessed in medicated patients. In this study, we investigated with FP-CIT SPECT the striatal dopamine transporter (DAT) availability in drug-naïve PD patients with ART and TD phenotypes. Fifty-one de novo, drug-naïve patients with PD underwent FP-CIT SPECT studies. Patients were evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) part III and Hoehn and Yahr scale (H&Y) and divided into ART (24/51) and TD (27/51) according to UPDRS part III. ART and TD patients were not different with regard to age, gender, and disease duration. However, compared to TD, ART patients presented higher UPDRS part III (p = 0.01) and H&Y (p = 0.02) and lower DAT availability in affected and unaffected putamen (p = 0.008 and p = 0.007, respectively), whereas no differences were found in caudate. Moreover, in the whole group of patients, rigidity and bradykinesia, but not tremor scores of UPDRS part III were significantly related to FP-CIT binding in the putamen. These results suggest that in newly diagnosed drug-naïve PD patients DAT availability might be different between ART and TD in relation to different disease severity.

Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ (2) exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.

Much pre-clinical evidence show that insulin-like growth factor 1 (IGF-1) provides protection against loss of dopaminergic neurons. Recently, IGF-1 has been proposed as a possible biomarker for early diagnosis of Parkinson's disease (PD). We aimed to assess the relationship between serum IGF-1 levels and progression of motor symptoms in a cohort of drug-naïve PD patients. Serum IGF-1 was measured at baseline in 37 early, drug-naive PD patients; subsequently, patients were evaluated "on drug" by means of UPDRS-III, UPDRS dopa-resistant score and dopaminergic score at 12, 18 and 24 month follow-up. Repeated measures ANOVA was used both to evaluate progression of motor scores within time and differences between serum IGF-1 quartiles, age at onset and motor phenotype. Patients at the highest IGF-1 quartile were found to have significantly higher UPDRS-III (p < 0.001) and dopaminergic score (p < 0.001), as compared to patients at other quartiles. Mean serum IGF-1 level was moderately increased in PD as compared to healthy controls (p < 0.011). IGF-1 levels are related to those symptoms predominantly responsive to dopaminergic treatment. This is the first study to demonstrate a relationship between serum IGF-1 and progression of motor symptoms in the early stage of disease.

Epidermal growth factor (EGF) has been proposed as a candidate biomarker for cognitive impairment in Parkinson's disease (PD). We aimed to assess the relationship between serum EGF and cognitive functions in early, drug-naive PD patients and evaluate the predictive value of EGF on cognitive functions in a 2-year follow-up study. Serum EGF was measured in 65 early, drug-naive PD patients, that underwent a comprehensive neuropsychological battery. Motor symptoms were assessed by means of the Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III). Neuropsychological evaluation was repeated after 2 years. Spearman's rank correlation was used to assess the relationship between serum EGF levels and neuropsychological variables. Linear regression analysis was used to evaluate the relationship between EGF and neuropsychological scores as well as other variables (age, gender, UPDRS-III, levodopa equivalent dose, and type of treatment at follow-up) potentially affecting cognitive performance. Variation over time in cognitive scores was analyzed using repeated-measures ANOVA. At baseline, EGF was the only significant variable associated with performance on semantic fluency (R (2) = 0.131; p = 0.005). EGF levels (p = 0.025), together with UPDRS-III (p = 0.009) and age (p = 0.011), were associated with performance on frontal assessment battery (R (2) = 0.260). At 2-year follow-up, EGF was the only significant variable to predict performance on semantic fluency (R (2) = 0.147; p = 0.025) and color naming task of Stroop color-word test (R (2) = 0.121; p = 0.044). Serum EGF levels are related to frontal and temporal cognitive functions in early, drug-naive PD patients and predict performance on frontal and posterior cognitive functions at 2-year follow-up. EGF is proposed as a potential serum biomarker for early cognitive impairment in PD.

Little is known about the relationship between cognitive dysfunctions and the non-motor complex in subjects with newly diagnosed untreated Parkinson's disease (PD). The aim of this study was to explore the association between non-motor symptoms (NMS) and cognitive dysfunctions in an incident cohort of de novo, drug-naive, PD patients. Sixty-six non-demented, early, untreated PD patients completed a semi-structured interview on NMS and a battery of neuropsychological tests that assess verbal memory, visuospatial abilities, and attention/executive functions. Scores were age- and education-corrected. Patients who failed at least two tests for each cognitive domain were diagnosed as having mild cognitive impairment (MCI). All but three (95.4%) PD patients complained of at least one NMS. A total of 37.8% was diagnosed with MCI. There was a relationship between sleep-NMS and cognitive dysfunctions. Specifically, both REM behavioral sleep disorders (RBD) and insomnia were associated with lower scores on several cognitive tests. Moreover, RBD was closely related to MCI. NMS and MCI are very common even in the early phase of PD, before patients are treated. Given the correlation between sleep disturbances and cognitive impairment, it is possible that sleep symptoms in PD patients might be considered as an early marker of dementia.