Re-emergent Tremor in Parkinson's Disease: Evidence of Pathologic ß and Prokinetic γ Activity.

BACKGROUND: Re-emergent tremor is characterized as a continuation of resting tremor and is often highly therapy refractory. This study examines variations in brain activity and oscillatory responses between resting and re-emergent tremors in Parkinson's disease. METHODS: Forty patients with Parkinson's disease (25 males, mean age, 66.78 ± 5.03 years) and 40 age- and sex-matched healthy controls were included in the study. Electroencephalogram and electromyography signals were simultaneously recorded during resting and re-emergent tremors in levodopa on and off states for patients and mimicked by healthy controls. Brain activity was localized using the beamforming technique, and information flow between sources was estimated using effective connectivity. Cross-frequency coupling was used to assess neuronal oscillations between tremor frequency and canonical frequency oscillations. RESULTS: During levodopa on, differences in brain activity were observed in the premotor cortex and cerebellum in both the patient and control groups. However, Parkinson's disease patients also exhibited additional activity in the primary sensorimotor cortex. On withdrawal of levodopa, different source patterns were observed in the supplementary motor area and basal ganglia area. Additionally, levodopa was found to suppress the strength of connectivity (P < 0.001) between the identified sources and influence the tremor frequency-related coupling, leading to a decrease in ß (P < 0.001) and an increase in γ frequency coupling (P < 0.001). CONCLUSIONS: Distinct variations in cortical-subcortical brain activity are evident in tremor phenotypes. The primary sensorimotor cortex plays a crucial role in the generation of re-emergent tremor. Moreover, oscillatory neuronal responses in pathological ß and prokinetic γ activity are specific to tremor phenotypes. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Facial expressions and identities recognition in Parkinson disease.

Parkinson's Disease (PD) is associated with motor and non-motor symptoms. Among the latter are deficits in matching, identification, and recognition of emotional facial expressions. On one hand, this deficit has been attributed to a dysfunction in emotion processing. Another explanation (which does not exclude the former) links this deficit with reduced facial expressiveness in these patients, which prevents them from properly understanding or embodying emotions. To disentangle the specific contribution of emotion comprehension and that of facial expression processing in PD's observed deficit with emotions we performed two experiments on non-emotional facial expressions. In Experiment 1, a group of PD patients and a group of Healthy Controls (HC) underwent a task of non-emotional expression recognition in faces of different identity and a task of identity recognition in faces with different expression. No differences were observed between the two groups in accuracies. In Experiment 2, PD patients and Healthy Controls underwent a task where they had to recognize the identity of faces encoded through a non-emotional facial expression, through a rigid head movement, or as neutral. Again, no group differences were observed. In none of the two experiments hypomimia scores had a specific effect on expression processing. We conclude that in PD patients the observed impairment with emotional expressions is likely due to a specific deficit for emotions to a greater extent than for facial expressivity processing.

Validation of the Italian version of the Parkinson's Disease- Cognitive Functional Rating Scale.

A key distinguishing factor between mild cognitive impairment (MCI) and dementia in Parkinson's disease (PD) lies in the notable decrease in functioning due to cognitive impairment. The Parkinson's Disease-Cognitive Functional Rating Scale (PD-CRFS) was developed to assess functional limitations caused by cognitive impairment, while reducing the influence of motor impairment. The aim of this multicenter study was to (i) validate the Italian version of the PD-CFRS in PD, (ii) determine optimal cut-off scores for detecting MCI and dementia in PD, (iii) compare its performances with the most established functional assessment tool (IADL). Six hundred and sixty nine PD participants were recruited from 4 Italian Movement Disorders centers (Venice, Milan, Gravedona, and Salerno). They underwent Level-II cognitive evaluation, which resulted in 282 PD-NC, 310 PD-MCI, and 77 PDD. The PD-CFRS's psychometric and clinimetric properties, applicability, and responsiveness were analyzed. The PD-CFRS showed high acceptability. Floor and ceiling effects were acceptable. It also displayed strong internal consistency (Cronbach's α = 0.738), and test-retest reliability (ICC = .854). The PD-CFRS demonstrated higher coefficient of variation to detect dysfunction in PD-MCI patients in comparison to the IADL scale (PD-CFRS 96% vs IADL 22.5%). Convergent validity with the IADL was r = - 0.638 and - 0.527 in males and females, respectively. PD-CFRS total score negatively correlated with global cognition (MoCA corrected score r = - 0.61; p < 0.001). A cut-off score > 6.5 identified PDD with a sensitivity of 90% and specificity of 88% (AUC = .959). A cut-off value of > 1 detected PD-MCI with a sensitivity of 68% and specificity of 69% (AUC = .695). The Italian version of the PD-CFRS demonstrated to be an easy, valid and reliable tool that properly captures functional impairment due to cognitive decline in PD. It also proved to be particularly effective in the advanced stages of PD, and would be a useful support for the diagnosis of PD-MCI and PDD.

Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson's disease patients.

Highly specialized microtubules in neurons are crucial to both health and disease of the nervous system, and their properties are strictly regulated by different post-translational modifications, including α-Tubulin acetylation. An imbalance in the levels of acetylated α-Tubulin has been reported in experimental models of Parkinson's disease (PD) whereas pharmacological or genetic modulation that leads to increased acetylated α-Tubulin successfully rescues axonal transport defects and inhibits α-Synuclein aggregation. However, the role of acetylation of α-Tubulin in the human nervous system is largely unknown as most studies are based on in vitro evidence. To capture the complexity of the pathological processes in vivo, we analysed post-mortem human brain of PD patients and control subjects. In the brain of PD patients at Braak stage 6, we found a redistribution of acetylated α-Tubulin, which accumulates in the neuronal cell bodies in subcortical structures but not in the cerebral cortex, and decreases in the axonal compartment, both in putamen bundles of fibres and in sudomotor fibres. High-resolution and 3D reconstruction analysis linked acetylated α-Tubulin redistribution to α-Synuclein oligomerization and to phosphorylated Ser 129 α-Synuclein, leading us to propose a model for Lewy body (LB) formation. Finally, in post-mortem human brain, we observed threadlike structures, resembling tunnelling nanotubes that contain α-Synuclein oligomers and are associated with acetylated α-Tubulin enriched neurons. In conclusion, we support the role of acetylated α-Tubulin in PD pathogenesis and LB formation.

The Clinical Spectrum of ANO3-Report of a New Family and Literature Review.

BACKGROUND: Mutations in ANO3 are a rare cause of autosomal dominant isolated or combined dystonia, mainly presenting in adulthood. CASES: We extensively characterize a new, large ANO3 family with six affected carriers. The proband is a young girl who had suffered from tremor and painful dystonic movements in her right arm since the age of 11 years. She later developed a diffuse dystonic tremor and mild extrapyramidal signs (ie, rigidity and hypodiadochokinesis) in her right arm. She also suffered from psychomotor delay and learning difficulties. Repeated structural and functional neuroimaging were unremarkable. A dystonic tremor was also present in her two sisters. Her paternal aunt, father, and a third older sister presented episodic postural tremor in the arms. The father and one sister also presented learning difficulties. The heterozygous p.G6V variant in ANO3 was identified in all affected subjects. LITERATURE REVIEW: Stratification by age at onset divided ANO3 cases into two major groups, where younger patients displayed a more severe phenotype, probably due to variants near the scrambling domain. CONCLUSIONS: We describe the phenotype of a new ANO3 family and highlight the need for functional studies to explore the impact of ANO3 variants on its phospholipid scrambling activity.

Brain Noradrenergic Innervation Supports the Development of Parkinson's Tremor: A Study in a Reserpinized Rat Model.

The pathophysiology of tremor in Parkinson's disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um2, p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic-rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients.

Clinical and genetic correlations of scoliosis in Rett syndrome.

AIM: To identify the clinical features correlating with the presence and severity of scoliosis in girls with Rett syndrome (RTT). METHOD: Seventy-five girls with a clinical and genetically determined diagnosis of RTT participated in this cross-sectional study. Clinical scales administered included the Rett assessment rating scale, the modified Ashworth scale, the Rett syndrome motor evaluation scale, the PainAD, and the scale of evaluation of purposeful hand function. Multivariable analyses, such as ordinal logistic regression and ANCOVA, were used to assess the correlation between these scales and a clinical score of scoliosis. RESULTS: About 60% of patients had scoliosis, in general mild or moderate. The severity of scoliosis correlated with age and important neurological factors such as muscular hypertonus and hyperreflexia, standing, walking (level walking and on stairs), and postural transitions. No association was found with global disease severity, hand function, pain, or type of genetic mutation. INTERPRETATION: Scoliosis is a relevant problem in RTT. It should be carefully monitored along the life span, especially in conjunction with (loco-)motor impairment in these patients.

A Fully-Immersive Virtual Reality Setup to Study Gait Modulation.

Objective: Gait adaptation to environmental challenges is fundamental for independent and safe community ambulation. The possibility of precisely studying gait modulation using standardized protocols of gait analysis closely resembling everyday life scenarios is still an unmet need. Methods: We have developed a fully-immersive virtual reality (VR) environment where subjects have to adjust their walking pattern to avoid collision with a virtual agent (VA) crossing their gait trajectory. We collected kinematic data of 12 healthy young subjects walking in real world (RW) and in the VR environment, both with (VR/A+) and without (VR/A-) the VA perturbation. The VR environment closely resembled the RW scenario of the gait laboratory. To ensure standardization of the obstacle presentation the starting time speed and trajectory of the VA were defined using the kinematics of the participant as detected online during each walking trial. Results: We did not observe kinematic differences between walking in RW and VR/A-, suggesting that our VR environment per se might not induce significant changes in the locomotor pattern. When facing the VA all subjects consistently reduced stride length and velocity while increasing stride duration. Trunk inclination and mediolateral trajectory deviation also facilitated avoidance of the obstacle. Conclusions: This proof-of-concept study shows that our VR/A+ paradigm effectively induced a timely gait modulation in a standardized immersive and realistic scenario. This protocol could be a powerful research tool to study gait modulation and its derangements in relation to aging and clinical conditions.

Safety and Effectiveness of Cell Therapy in Neurodegenerative Diseases: Take-Home Messages From a Pilot Feasibility Phase I Study of Progressive Supranuclear Palsy.

Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field.

Clinical Outcome and Striatal Dopaminergic Function After Shunt Surgery in Patients With Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Participants with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [123I]-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years. RESULTS: We enrolled 115 patients with iNPH. Of 102 patients without significant levodopa response and no signs of atypical parkinsonism, 92 underwent FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery (p < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 (p < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in patients who declined surgery (p < 0.01). CONCLUSIONS: This prospective interventional study highlights the pathophysiologic relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and postsurgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with iNPH.

Striatal Dopamine Deficit and Motor Impairment in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus can present with parkinsonism. However, abnormalities of the striatal dopamine reuptake transporter are unclear. OBJECTIVES: To explore presence and features of striatal dopaminergic deficit in subjects with idiopathic normal pressure hydrocephalus as compared to Parkinson's disease (PD) patients and healthy controls. METHODS: We investigated 50 subjects with idiopathic normal pressure hydrocephalus, 25 with PD, and 40 healthy controls. All participants underwent [123 I]-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane and single-photon emission computed tomography to quantify the striatal dopamine reuptake transporter binding. All subjects with idiopathic normal pressure hydrocephalus underwent a levodopa (l-dopa) challenge test and magnetic resonance imaging to evaluate ventriculomegaly and white matter changes. Gait, cognition, balance, and continence were assessed with the Idiopathic Normal Pressure Hydrocephalus Rating Scale, and parkinsonism with the motor section of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale. All patients completed a 2-year follow-up. RESULTS: A total of 62% of patients with idiopathic normal pressure hydrocephalus featured a reduced striatal dopamine reuptake transporter binding, which correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike PD, this dopaminergic deficit in idiopathic normal pressure hydrocephalus was more symmetric and prominent in the caudate nucleus. CONCLUSIONS: Subjects with idiopathic normal pressure hydrocephalus can present a reduction of striatal dopamine reuptake transporter binding, which is consistent with the severity of parkinsonism and qualitatively differs from that found in PD patients. Longitudinal interventional studies are needed to prove a role for striatal dopamine reuptake transporter deficit in the pathophysiology of idiopathic normal pressure hydrocephalus. © 2020 International Parkinson and Movement Disorder Society.

Vocal cord electromyographic correlates of stridor in multiple system atrophy phenotypes.

INTRODUCTION: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by dysautonomia in combination with parkinsonian and cerebellar signs. Stridor may also occur and it is associated with life-threatening events and poor prognosis. The pathophysiology of stridor in MSA is still debated. OBJECTIVE: To define correlations between diurnal electromyographic (EMG) abnormalities of vocal cord muscles and stridor in MSA phenotypes. METHODS: We recruited 60 patients with "probable" MSA (45 with parkinsonian [MSA-P] and 15 with cerebellar phenotype [MSA-C]). Nocturnal stridor was detected with video-polysomnography, whereas diurnal stridor was clinically noted when present. A diurnal kinesiologic EMG study of the adductor thyroarytenoid and the abductor posterior cricoarytenoid muscles was also performed. RESULTS: Among subjects with nocturnal stridor, MSA-P patients predominantly showed a paradoxical burst-like activation of the adductor thyroarytenoid muscle during inspiration. This dystonic pattern was associated with nocturnal stridor in MSA-P (odds ratio [OR] = 23.64, 95% confidence interval [CI] 3.42-70.77, p < 0.001). Conversely, MSA-C patients with nocturnal stridor mainly had additional neurogenic findings of vocal cord muscles. This dystonic-plus pattern correlated with nocturnal stridor in MSA-C (OR = 17.21, 95% CI 4.17-74.92, p < 0.01). The findings of diurnal stridor paralleled the observations for nocturnal stridor. CONCLUSIONS: The pathophysiology of stridor may differ between MSA phenotypes, possibly related to dysfunctional supranuclear mechanisms in MSA-P (dystonic pattern) and to additional nuclear damage in MSA-C (dystonic-plus pattern).

A New Scale to Evaluate Motor Function in Rett Syndrome: Validation and Psychometric Properties.

BACKGROUND: We aim to describe and psychometrically validate the Rett Syndrome Motor Evaluation Scale, a 25-item ordinal scale examining (loco-)motor function across six sections: standing, sitting, transitions, walking, running, and walking up or downstairs. METHODS: We illustrate the process of item construction and validation, report findings and normative data obtained on a standardization sample of 60 patients with Rett syndrome. We investigate the validity and reliability of the scale and illustrate its psychometric properties using modern multivariate techniques of data analysis. RESULTS: Sixty patients with Rett syndrome were included (all female; mean age 12.45 (S.D. 8.75) years). The multidimensional latent structure of the scale was supported by the results of the confirmatory factor analysis. Rett Syndrome Motor Evaluation Scale showed strong internal consistency reliability as well as excellent inter-rater agreement. The Rett Syndrome Motor Evaluation Scale scores were not predicted by age, but were associated with disease severity, degree of spasticity, and hand dysfunction. We also identified three latent classes with different degrees of impairment. CONCLUSIONS: Rett Syndrome Motor Evaluation Scale is a new, valid, and reliable scale that can be introduced in clinical practice when assessing (loco-)motor function in Rett syndrome.

Sit-to-walk performance in Parkinson's disease: A comparison between faller and non-faller patients.

BACKGROUND: Falls are one of the main concerns in people with Parkinson's disease, leading to poor quality of life and increased mortality. The sit-to-walk movement is the most frequent postural transition task during daily life and is highly demanding in terms of balance maintenance and muscular strength. METHODS: With the aim of identifying biomechanical variables of high risk of falling, we investigated the sit-to-walk task performed by 9 Parkinson's disease patients with at least one fall episode in the six months preceding this study, 15 Parkinson's disease patients without previous falls, and 20 healthy controls. Motor performance was evaluated with an optoelectronic system and two dynamometric force plates after overnight suspension of all dopaminergic drugs and one hour after consumption of a standard dose of levodopa/benserazide. FINDINGS: Poor trunk movements critically influenced the execution of the sit-to-walk movement in patients with a history of falling. The peak velocity of the trunk in the anterior-posterior direction discriminated faller from non-faller patients, with high specificity and sensitivity in both the medication-off and -on state. INTERPRETATION: Our results confirm the difficulties in merging consecutive motor tasks in patients with Parkinson's disease. Trunk movements during the sit-to-walk can provide valuable measurements to monitor and possibly predict the risk of falling.

Phase matters: A role for the subthalamic network during gait.

The role of the subthalamic nucleus in human locomotion is unclear although relevant, given the troublesome management of gait disturbances with subthalamic deep brain stimulation in patients with Parkinson's disease. We investigated the subthalamic activity and inter-hemispheric connectivity during walking in eight freely-moving subjects with Parkinson's disease and bilateral deep brain stimulation. In particular, we compared the subthalamic power spectral densities and coherence, amplitude cross-correlation and phase locking value between resting state, upright standing, and steady forward walking. We observed a phase locking value drop in the ß-frequency band (≈13-35Hz) during walking with respect to resting and standing. This modulation was not accompanied by specific changes in subthalamic power spectral densities, which was not related to gait phases or to striatal dopamine loss measured with [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane and single-photon computed tomography. We speculate that the subthalamic inter-hemispheric desynchronization in the ß-frequency band reflects the information processing of each body side separately, which may support linear walking. This study also suggests that in some cases (i.e. gait) the brain signal, which could allow feedback-controlled stimulation, might derive from network activity.

Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy.

BACKGROUND: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. METHODS: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. RESULTS: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. CONCLUSIONS: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach. Trial registration ClinicalTrials.gov NCT01824121.

Dementia in Parkinson's disease: Is male gender a risk factor?

BACKGROUND: The rates of cognitive decline in patients with Parkinson's disease (PD) are higher than in the general population. Age and disease duration have been associated with increasing rates of dementia in PD. However, the role of other factors including gender has been poorly investigated. We investigated the relationship between dementia and gender along with other established risk factors, such as age and disease duration. METHODS: We conducted a cross-sectional retrospective study including all consecutive patients diagnosed with idiopathic PD attending a single out-patient tertiary clinic over an 18-year period (1995-2013). Dementia was diagnosed according to DSM-IV criteria. RESULTS: Prevalence of dementia was 11.5% (95%CI, 10.8-12.3) and 13.5% (95%CI, 12.7-14.5) in the whole population (N = 6599) and in those aged ≥60 years (N = 5373), respectively. Age and disease duration were independently associated with dementia, and the latter was associated with dementia up to 84 years of age. Male gender was an independent risk factor. In addition, while the rate of dementia increased in males over all age strata, we found that in females prevalence began to increase steadily after the age of 65 years, reaching male estimates only after 80 years of age. Higher rates in male gender were observed between 60 and 80 years of age. CONCLUSION: Age and PD duration are confirmed risk factors for dementia. However, disease duration appeared to be a less important factor in cognitive decline in patients aged ≥85 years. As opposed to gender-specific estimates in the general population, male gender is likely associated with higher rates of dementia in PD patients.

Movement preparation and bilateral modulation of beta activity in aging and Parkinson's disease.

In previous studies of young subjects performing a reaction-time reaching task, we found that faster reaction times are associated with increased suppression of beta power over primary sensorimotor areas just before target presentation. Here we ascertain whether such beta decrease similarly occurs in normally aging subjects and also in patients with Parkinson's disease (PD), where deficits in movement execution and abnormalities of beta power are usually present. We found that in both groups, beta power decreased during the motor task in the electrodes over the two primary sensorimotor areas. However, before target presentation, beta decreases in PD were significantly smaller over the right than over the left areas, while they were symmetrical in controls. In both groups, functional connectivity between the two regions, measured with imaginary coherence, increased before the target appearance; however, in PD, it decreased immediately after, while in controls, it remained elevated throughout motor planning. As in previous studies with young subjects, the degree of beta power before target appearance correlated with reaction time. The values of coherence during motor planning, instead, correlated with movement time, peak velocity and acceleration. We conclude that planning of prompt and fast movements partially depends on coordinated beta activity of both sensorimotor areas, already at the time of target presentation. The delayed onset of beta decreases over the right region observed in PD is possibly related to a decreased functional connectivity between the two areas, and this might account for deficits in force programming, movement duration and velocity modulation.

Swallowing disturbances in Parkinson's disease: a multivariate analysis of contributing factors.

BACKGROUND: Swallowing disturbances are an important issue in Parkinson's disease (PD) as several studies have shown that they are associated with increased risk of aspiration pneumonia and mortality. Information about factors related to swallowing disturbances, such as disease duration, age at assessment and concomitant dementia, is limited and would be useful for their management. METHODS: All consecutive PD out-patients evaluated at a movement disorders clinic over a 7-year period (2007-2014), were included in the present retrospective study. Presence of symptomatic swallowing disturbances was assessed using the specific item of the Non Motor Symptom Questionnaire. RESULTS: In the whole PD population (N = 6462), prevalence of symptomatic swallowing disturbances was 11.7% (95%CI, 10.9-12.5). Multivariable logistic regression analysis (adjusted for education) disclosed a significant interaction between disease duration and gender (P = 0.009). In both gender strata, swallowing disturbances were significantly associated with longer disease duration and dementia (P < 0.001 for all). A significant effect for age at assessment was also found in male patients. In non-demented patients, swallowing disturbances were associated with male gender, age and disease duration (P < 0.02 for all). In demented patients an association was found only with male gender (P = 0.018) and disease duration (P < 0.001). CONCLUSIONS: Gender, age, disease duration and dementia all seem to contribute to the occurrence of swallowing disturbances independently. However, the role played by these factors in sub-groups of patients stratified by gender and concomitant dementia suggests that swallowing disturbances are likely related to different neuro-degenerative patterns within the brain. The underlying mechanisms deserve further investigation.

Later age at onset in Parkinson's disease over twenty years in an Italian tertiary clinic.

BACKGROUND: Age is considered an important risk factor for Parkinson's disease (PD). However, although life-expectancy has increased considerably, incidence rates of PD appeared to be stable over the last two decades. Accordingly, an increase in mean age at onset over time could be expected. We investigated the changes in age at onset in PD over the last two decades. METHODS: All consecutive PD patients assessed over a 18-year period (1995-2013) in a single tertiary outpatient clinic were included in the present retrospective cohort study. RESULTS: After adjusting for several confounders (gender, positive family history for PD, education, smoking at onset and past exposure to environmental/occupational pollutants), 5-year cohorts of year of disease onset were associated with increasing age at onset in both prevalent (N = 6996) and incident (N = 4172) cases (for trend, P < 0.001). From 1995-2000 to 2010-2013 there was an increase in predicted age of 4.1 years (95% CI, 3.0-5.2) and 3.9 years (95% CI, 2.7-5.1) in prevalent and incident cases, respectively. However, the change in predicted age at PD onset, across cohorts of year at onset, showed a steeper increase than the corresponding sex and cohort-matched mean age from the official Italian statistics. CONCLUSIONS: Over the last two decades, age at onset of PD appeared to shift progressively towards more advanced age. However, sequential, high-quality population-based incidence studies are required. To establish whether there is a trend towards increase in age at onset over and above general population ageing and to assess whether the increase is associated with improved medical and socio-economic conditions.