Parkinsonian Signs Research Articles

Energy Decline May Predict Mild Parkinsonian Signs in Community-Dwelling Older Adults

Mild Parkinsonian Signs (MPS) are common in older adults without overt neurological disease. MPS are often progressive and predict disability and dementia, yet little is known about predictors for MPS. Low self-reported energy is associated with mobility impairment, which is a hallmark of MPS. Yet whether self-reported energy relates to MPS is unknown. We explored the association of changes in self-reported energy with MPS in 293 participants (aged 83 ± 2.8 years, 58% women, 61% White) free of dementia and Parkinson’s Disease in the Health, Aging and Body Composition Study. Self-reported energy was assessed on a 0-10 scale annually between Year 2 and Year 10 (mean follow-up: 8 years) and its slope was estimated via linear mixed effects models. MPS were evaluated at Year 10 based on the Unified Parkinson Disease Rating Scale motor component. On average, self-reported energy declined 0.06 points per year. In a linear regression model adjusted for age, fatigue, and comorbidities, those with MPS had steeper SEL decline (β [Standard Error] = -0.358 [0.119]) in the prior eight years than those without MPS. Thus, declining self-reported energy may be a risk factor for MPS. Self-reported energy is easily evaluated in routine clinic visits, and may be a modifiable risk factor that can be targeted to reduce the incidence of MPS.

Mild Parkinsonian Signs Are Related to Lower Cortico-Striatal Connectivity in Executive Networks

Mild Parkinsonian signs (MPS) affect up to 24% of community-dwelling older adults. We hypothesize that MPS are associated with Parkinson’s-like alterations of functional connectivity (FC) in sensorimotor, executive, and reward cortico-striatal networks. Participants (N=266; mean age=83; 57% female) without Parkinson’s completed resting-state fMRI and Unified Parkinsonian Disease Rating Scale (UPDRS). FC between striatum and cortex was measured within each network. Logistic regression tested associations of each network’s FC with MPS (UPDRS>0), adjusted for MPS risk factors, then including white matter hyperintensities (WMH). MPS was associated with lower cortical-striatal FC in the left executive cortico-striatal network (OR [95%CI]: 0.188 [0.043,0.824]). Association survived adjusting for risk factors (0.162 [0.030,0.874]) but was attenuated after including WMH (0.209 [0.036, 1.200]). In stratified analyses, left executive cortico-striatal FC was associated with MPS only for those with higher WMH (0.077 [0.010,0.599]). Future work should examine whether higher FC protects against the influence of WMH on MPS.

Mobility Performance in Old Age: A Window Into Brain Integrity

Over two decades of research has established brain aging as a critical component of mobility decline. Studies consistently report that motor slowing predicts cognitive decline and neurodegenerative diseases, but reported associations are often modest. Both mobility and brain aging are complex processes and steady-state assessments are typically used (usual pace gait and structural MRI). We aim to elucidate the complex relations between brain aging and mobility by considering (a) strategies to maintain function such as interlacing periods of activity and rest (fractionation), (b) interventions that target brain and body (motor skill training), (c) multimodal neuroimaging (functional connectivity and cerebral small vessel disease (cSVD)), (d) challenged walking (dual-tasks, uneven surfaces), and (e) reduced resources (hearing loss). This symposium focuses on community-dwelling older adults from observational and intervention studies using state-of-the-art and real-life assessments of gait (quality and fragmentation by tri-axial accelerometry) and brain (near-infrared spectroscopy (fNIRS), resting-state functional MRI). First, we examine activity strategies that modify the relation between slow gait and AD risk (Tian). Second, using fNIRS, we investigate the extent to which motor skill training increases automaticity of gait (Chen). Third, we examine how functional connectivity may compensate for the detrimental effects of cSVD on mild parkinsonian signs (Hengenius). Fourth, we investigate the effects of challenged walking on gait quality and the relation with cognitive function (Suri). Finally, we demonstrate relations of hearing and cognition with mobility (Pupo). We seek to generate discussions on shared pathways underlying motor slowing and the aging brain and future prevention and intervention strategies.

Remote Photobiomodulation Treatment for the Clinical Signs of Parkinson's Disease: A Case Series Conducted During COVID-19.

Objective: To assess whether remote application of photobiomodulation (PBM) is effective in reducing clinical signs of Parkinson's disease (PD). Background: PD is a progressive neurodegenerative disease for which there is no cure and few treatment options. There is a strong link between the microbiome-gut-brain axis and PD. PBM in animal models can reduce the signs of PD and protect the neurons from damage when applied directly to the head or to remote parts of the body. In a clinical study, PBM has been shown to improve clinical signs of PD for up to 1 year. Methods: Seven participants were treated with PBM to the abdomen and neck three times per week for 12 weeks. Participants were assessed for mobility, balance, cognition, fine motor skill, and sense of smell on enrolment, after 12 weeks of treatment in a clinic and after 33 weeks of home treatment. Results: A number of clinical signs of PD were shown to be improved by remote PBM treatment, including mobility, cognition, dynamic balance, spiral test, and sense of smell. Improvements were individual to the participant. Some improvements were lost for certain participants during at-home treatment, which coincided with a number of enforced coronavirus disease 2019 (COVID-19) pandemic lockdown periods. Conclusions: Remote application of PBM was shown to be an effective treatment for a number of clinical signs of PD, with some being maintained for 45 weeks, despite lockdown restrictions. Improvements in clinical signs were similar to those seen with the application of remote plus transcranial PBM treatment in a previous study. Clinical Trial Registration number: U1111-1205-2035.

Cardiovascular Metrics Associated With Prevention of Aging-Related Parkinsonian Signs Following Exercise Intervention in Sedentary Older Rats.

Preservation of motor capabilities is vital to maintaining independent daily living throughout a person's lifespan and may mitigate aging-related parkinsonism, a progressive and prevalent motor impairment. Physically active lifestyles can mitigate aging-related motor impairment. However, the metrics of physical activity necessary for mitigating parkinsonian signs are not established. Consistent moderate intensity (~10 m/min) treadmill exercise can reverse aging-related parkinsonian signs by 20 weeks in a 2-week on, 2-week off, regimen in previously sedentary advanced middle-aged rats. In this study, we initiated treadmill exercise in sedentary 18-month-old male rats to address two questions: (1) if a rest period not longer than 1-week off exercise, with 15 exercise sessions per month, could attenuate parkinsonian signs within 2 months after exercise initiation, and the associated impact on heart rate (HR) and mean arterial pressure (MAP) and (2) if continuation of this regimen, up to 20 weeks, will be associated with continual prevention of parkinsonian signs. The intensity and frequency of treadmill exercise attenuated aging-related parkinsonian signs by 8 weeks and were maintained till 23 months old. The exercise regimen increased HR by 25% above baseline and gradually reduced pre-intervention MAP. Together, these studies indicate that a practicable frequency and intensity of exercise reduces parkinsonian sign severity commensurate with a modest increase in HR after exercise. These cardiovascular changes provide a baseline of metrics, easily measured in humans, for predictive validity that practicable exercise intensity and schedule can be initiated in previously sedentary older adults to delay the onset of aging-related parkinsonian signs.

Survival and risk factors for premature mortality in patients with parkinson’s disease

Aim. To assess the survival rate and risk factors for premature mortality in patients with Parkinsons disease in Baku.
 Material and research methods. The observation was carried out retrospectively, information was collected on all patients (110 patients) in whom the diagnosis of Parkinsons disease was first established in 20092010. These patients are provided with drugs free of charge, which made it possible to provide them with diagnostic monitoring in polyclinics. During 20102019, 94 patients with a diagnosis of Parkinsons disease died. All medical death certificates were selected for analysis. The diagnoses in column a of these documents were accepted as direct causes of death, regardless of the presence or absence of a causal relationship of these diagnoses with Parkinsons disease. Therefore, the reported cases were interpreted not as death due to Parkinsons disease, but as the death of a patient diagnosed with Parkinsons disease.
 Results. Noteworthy is the prevalence of men (72.7%) and people without dementia (70.9%) among patients. Within 10 years, 85.5% of patients died from various causes. The immediate causes of death were acute cerebrovascular accidents (36.2%) and acute myocardial infarction (24.5%). The annual survival rate of the observed patients was high (94%; 95% confidence interval 51100%). The five-year survival rate is 76% (95% confidence interval 42100%).
 Conclusions. (1) The survival rate of patients with Parkinsons disease within 10 years after the onset of signs ranges from 0.94 to 0.41 (five-year survival rate is 0.76). (2) The immediate causes of mortality in patients with Parkinsons disease were cerebrovascular accidents (36.2%), myocardial infarction (24.5%), pulmonary embolism (11.7%), pneumonia (10.6%) and others (17%). (3) The effect of age of onset and signs of Parkinsons disease, gender, comorbidity and dementia on survival is statistically significant (p 0.05).

Blood neurofilament light, Parkinson’s disease, Parkinsonism, and physical function in a longitudinal population study

AbstractBackgroundBlood biomarkers of parkinsonism and Parkinson’s disease (PD) may allow for earlier identification of these conditions and improved longitudinal investigation of PD pathogenesis. Neurofilament light (Nf‐L), a neuronal cytoplasmic protein, is a biomarker of neurodegeneration measurable in CSF or blood. We examined the longitudinal association of serum Nf‐L with clinically diagnosed PD, parkinsonian signs, and physical functioning change over 16 years in a population‐based sample of Black and White older adults.MethodsData came from 1,327 older participants from the Chicago Health and Aging Project (CHAP), a longitudinal population‐based study of common chronic conditions of aging. Clinical evaluations included assessing parkinsonian signs in four domains, bradykinesia, parkinsonian gait, rigidity, and tremors using a structured version of the United Parkinson’s Disease Rating Scale. PD was diagnosed by board certified neurologists. Parkinsonian signs were reported as the four domain scores and a global parkinsonian score (combination of domain scores). Physical function was assessed by performance‐based tests. Serum Nf‐L was measured with an ultrasensitive immunoassay.ResultsAfter adjusting for demographic characteristics, the APOE‐e4 allele, and cognitive function, a 2‐fold higher concentration of serum Nf‐L was associated with the development of clinical PD (OR = 2.54, 95% CI: 1.70, 3.81), and global parkinsonian scores (OR = 2.44, 95% CI: 1.94, 2.94). This association was significant over five years before diagnosis. Compared to participants below 18.5 pg/mL of serum Nf‐L at baseline, participants in between 18.5–25.4 pg/mL, 25.4–37.3 pg/mL, and above 37.3 pg/mL had a higher odds ratio of clinical PD at all time intervals ranging from the time of diagnosis to greater than five years before diagnosis. A higher concentration of serum Nf‐L was associated with a faster decline in physical functioning over the duration of the study. In participants with 2‐fold higher concentrations of serum Nf‐L, the annual rate of decline in physical functioning increased by 0.15 units (95% CI: 0.21, 0.08).ConclusionsSerum Nf‐L predicted the development of clinically diagnosed PD, parkinsonian signs, and physical functioning decline in a population‐based sample. Our findings suggest that Nf‐L may serve as a potential biomarker for physical functioning outcomes in older adults.

Longitudinal motor decline in dementia with Lewy bodies and Parkinson’s disease dementia in a community autopsy cohort

AbstractBackgroundAlthough parkinsonism is a core feature of Parkinson’s Disease Dementia (PDD) and Dementia with Lewy bodies (DLB), its evolution is less delineated. We aimed to assess differences in severity and progression of parkinsonian motor symptoms and signs in a community autopsy cohort with clinicopathologic diagnosis of DLB, PDD or Alzheimer’s Disease (AD).MethodData included were from 194 participants in the Arizona study of Aging and Neurodegenerative Disorders with clinicopathologic diagnosis of DLB (n=48), PDD (n=98) (±AD co‐pathology) or pure AD (n=48), and at least two movement exams performed by movement disorders subspecialists who classified PD and parkinsonism according to MDS‐UPDRS criteria. DLB was subgrouped by presence or absence of parkinsonism at final exam (DLB+Park and DLB–Park). Between group trajectory of UPDRS‐II and UPDRS‐III scores were explored using piecewise‐linear and non‐linear MMRM multivariate analysis.ResultOver 1435 participant‐years of longitudinal data were included in the analyses (Figure 1). Mean±SD age at baseline movement exam and death were 76.0±7.5 and 83.4±6.8 years, respectively. At baseline, most participants did not have dementia or substantial motor abnormalities (except motor abnormalities in PDD). DLB (73.9%) and PDD (69.2%) groups had more males than AD (33.3%). Parkinsonism was present in 65.6% of DLB at last exam. Piecewise‐linear MMRM analysis showed baseline UPDRS‐II and UPDRS‐III scores were highest (p<0.001) for PDD (mean±SE: 14.3±0.78 and 27.4±1.64), followed by DLB+Park (5.0±1.05 and 17.4±3.10), DLB‐Park (3.7±2.54 and 3.8±1.35) and AD (3.2±0.88 and 8.0±1.94). Annual rate of increase in UPDRS‐II was greatest for DLB+Park (1.44±0.20) and PDD (1.04±0.08), followed by DLB‐Park (0.89±0.18) and AD (0.30±0.11). Annual rate of increase in UPDRS‐III was highest for PDD and DLB+Park (2.12±0.20 vs 2.64±0.42), followed by DLB‐Park and AD (1.31 ± 0.38 and 0.64 ± 0.22). Preliminary non‐linear MMRM models (Figure 2) further supported substantial between group/subgroup differences in motor trajectories, and progression in DLB‐Park.ConclusionThese preliminary results in a large, well‐characterized clinicopathological community‐based autopsy cohort support that DLB+Park experience comparable, or greater, parkinsonian motor progression to PDD. Future modeling/sensitivity analyses will better delineate expected trajectories of motor progression to add prognostication value in clinic and design of DLB clinical trials.

Longitudinal evaluation of patients with isolated head tremor

IntroductionIsolated head tremor, a pathological condition characterized by head tremor without dystonic postures or tremor in other body parts, has recently been suggested to be a form of dystonia. It is however still unclear whether isolated head tremor precedes dystonia or remains unmodified overtime. MethodsWe enrolled 20 patients with isolated head tremor. For each patient, we assessed videos recorded at enrollment and after 5 years. The videotapes were reviewed by two independent experienced movement disorder specialists who evaluated and scored tremor and CD severity using the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor and the revised Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), respectively. ResultsUpon enrollment, all 20 patients showed isolated head tremor. Mean tremor severity was 2.7 ± 0.9 as measured using the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor total score. At the 5-year follow-up examination, 15 (75%) of the 20 patients with isolated head tremor showed dystonic postures in the neck, while the remaining 5 patients (25%) had only isolated head tremor. Mean severity of dystonia as measured using the TWSTRS-2 total score was 11.8 ± 3.6. Head tremor severity was unchanged between baseline and the 5-year follow-up examination (p > 0.05). At the follow-up examination, no patients had tremor or dystonia in a body part other than the neck, nor did they develop bradykinesia or other parkinsonian signs. ConclusionsOur longitudinal study demonstrated that patients with isolated head tremor may develop cervical dystonia over time.

Зв’язок SWI-інтенсивності та легкої паркінсонічної симптоматики в пацієнтів із хворобою дрібних судин

Актуальність. Легка паркінсонічна симптоматика (ЛПС) (mild parkinsonian sіgns) може бути проявом нейродегенеративного процесу, результатом дисциркуляторної енцефалопатії або проявлятися як наслідок цих двох процесів, що перебігають паралельно та посилюють один одного. Мета дослідження: виявити, чи існує взаємозв’язок між зміною магнітної сприйнятливості підкіркових структур головного мозку та наявністю легкої паркінсонічної симптоматики в пацієнтів із хронічною ішeмією мозку. Матеріали та методи. Для дослідження були відібрані 82 пацієнти, у яких було діагностовано дисциркуляторну енцефалопатію та виключено нейродегенеративні захворювання. Усім пацієнтам було виконано магнітно­резонансну томографію (МРТ) у послідовностях T1­WI, T2­WI, TIRM, DWI, SWI. Наявність MPS діагностувалася за допомогою третьої секції шкали UPDRS. Результати. За допомогою U­критерію Манна — Уїтні було виявлено, що пацієнти з ЛПС мали вірогідно вищі рівні магнітної сприйнятливості підкіркових структур і, як наслідок, більшу кількість гіпоінтенсивних вокселів на МРТ­зображеннях у SWI­послідовності. Програмне забезпечення 3D Slicer використовувалося для сегментації підкіркових структур за рівнями інтенсивності сигналу. У пацієнтів із ЛПС було виявлено більшу кількість гіпоінтенсивних вокселів у блідих кулях, шкаралупі та чорних субстанціях обох півкуль. Після врегулювання за віком та балом шкали Fazekas було виявлено, що ЛПС найбільше асоційована із збільшенням кількості вокселів вираженої гіпоінтенсивності (SI < 75) у правій блідій кулі (OR 1,29, CI 1,08–1,55). Висновки. Підвищення рівнів гіпоінтенсивності підкіркових структур, що виявляються на SWI МРТ­знімках, можуть бути асоційовані з ЛПС у пацієнтів із хворобою дрібних судин головного мозку.

NIMG-57. MANAGEMENT OF TECTAL GLIOMAS IN ADULTS

Abstract BACKGROUND Tectal gliomas (TG) are rare tumors occurring primarily in children but also found in adults during workup of various neurological symptoms. Surgery is not required in asymptomatic cases, so histopathological information is sparse. No consensus on timing of imaging surveillance or management has been established. OBJECTIVE We seek to standardize neuroimaging, including MRI protocol and surveillance time intervals, and clinical management of symptoms and disease progression, including surgery, radiotherapy, and chemotherapy. METHODS At our institution, patients with TG were identified through a search of radiology reports and clinic notes between 1989 and 2020. Initial and serial MRI exams were evaluated for tumor size, enhancement, edema, hydrocephalus, and other radiographic features. When tissue was available, cellularity, mitotic activity, and morphology were described. We documented neurological symptoms and signs potentially related to the tumor. RESULTS 37 cases were identified: 22 female, 15 male; 5 children, 32 adults. Age of diagnosis ranged from 7 to 69 years. Presenting symptoms included headache (59%), visual symptoms (35%), and imbalance (14%), less commonly: seizure, weakness, nausea/vomiting, and dizziness. Surgical procedures included biopsy (9), resection (7), endoscopic third ventriculostomy (15), and shunt placement (11). Eight patients received radiotherapy, including IMRT, CyberKnife, GammaKnife, and Zap-X (all adults; 4 at diagnosis, 3 at progression, 1 at diagnosis and again at progression). Four patients received chemotherapy (all adults; 1 at diagnosis, 3 at progression), all with temozolomide. One additionally received bevacizumab for radionecrosis. Three patients died with progressive disease, two following treatment and one without. Of interest, 5 adult patients developed signs of parkinsonism during their follow-up period. CONCLUSION Management of TG encompasses both neoplastic progression and symptom control, either from local compression or infiltrative disease. We have developed an algorithm for imaging surveillance and treatment, including MRI protocol, definition of progressive disease, and indications for antineoplastic therapies.

Brain Volume Alterations Using 3tesla Magnetic Resonance and Neuropsychological Findings in Gaucher Disease Patients

▪Gaucher Disease (GD) is a metabolic inherited disorder, that classically includes three clinical phenotypes. Type I GD (GD1) is considered as a non-neuronopathic variant and can mimic a hematologic disease; type II (GD2) is classified as an acute neuropathic form and type III (GD3) is characterized by a slower and progressive neurological involvement. A protective role of N370S mutation against neurological impairment had been previously hypothesized in GD1, however, increasing data and our experience show that patients with GD1 may present clinical signs of parkinsonism, frequently combined with cognitive impairment and behavioral alterations. Structural brain changes associated with cognitive impairments in GD patients, especially type I, has not yet been reported.The prospective study, called SENOPRO_GAUCHER, has investigated in depth, the neurological status in GD patients using a multidisciplinary approach, including 3Tesla magnetic resonance (3T MR). This study was approved by our Ethics Committee. Baseline data on neurological, psychological, psychiatric, somatosensory, and motor evaluations, and electroencephalography (EEG) surprisingly revealed two, or more, clinical and/or instrumental, neurological signs in all GD1 patients, and a wide spectrum of neurological abnormalities in all GD3 patients.We, hereby, report the results of investigations on brain structure of GD patients, compared to that of healthy subjects, using 3T MR, in order to evaluate whether brain alterations can predict neurocognitive impairment in GD patients, especially GD1. Out of 22 GD patients, assessed for neuropsychological and psychiatric functions, 19 (17 GD1, 2 GD3, median age = 44, range 17 - 68 years) underwent 3T MR examination. Regarding genotyping, all but one of the 17 GD1 patients was N370S mutation heterozygous.A Voxel-based Morphometry (VBM) analysis was performed to investigate brain structure in the 19 GD patients and in 19 healthy subjects with no neurological or neuropsychiatric disease. The healthy subjects, matched to patients by age, sex, and education, in addition to 3T MR, underwent neuropsychological assessment using Mini-Mental State Exam and Mental Deterioration Battery, to evaluate cognitive functions and mental deterioration, respectively. Qualitative MR examinations revealed unspecific abnormalities in 7/17 GD1 patients. In particular, cortical and/or subcortical areas of gliosis (4 patients), vascular ectasia extended from the left frontal surface of the brain to the lateral ventricle (1 patient), dilation of perivascular spaces in the sub-cortical and nucleus-basal area (1 patient), diffuse suffering of the brain white matter due to a chronic ischemic vascular damage (1 patient) were found. Concurrently, results of the VBM analysis revealed that a set of regions, mostly located in the prefrontal and parieto-occipital cortex, were significantly reduced in GD patients, compared to healthy subjects. The most affected regions included the frontal eye fields, the dorso-lateral prefrontal cortex, the posterior cingulate cortex, and the V3B area. Psychological and psychiatric evaluations underlined anxiety, depression, and somatic concerns in 10/17 GD1 patients, combined with cognitive impairments in two of them. Moreover, 1/2 GD3 and 5/17 GD1 patients showed cognitive impairments in attention, language, short-term memory, and executive cognitive functions. The local brain volume reductions, detected in GD1 patients, were in line with the cognitive impairments resulted in the neuropsychological assessment. Cortical reductions of fronto-parietal regions, responsible for the planning and execution of movements, are compatible with impairments in executive functions (digit-span) and visuo-spatial memory, found in GD1 patients. Moreover, impairments in short-term memory observed in GD1 patients are compatible with cortical reductions in the frontal cortex found by the VBM analysis.In conclusion, focal brain differences found between GD1 patients and healthy subjects may predict and clarify the cognitive impairments and behavioural alterations observed in GD patients. The brain structural analyses, associated with neuropsychological assessment, suggest that a multidisciplinary approach is necessary in evaluating GD1 patients. DisclosuresGiona: Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Consultancy.

Manipulation of vocal communication and anxiety through pharmacologic modulation of norepinephrine in the Pink1-/- rat model of Parkinson disease

Vocal deficits and anxiety are common, co-occurring, and interacting signs of Parkinson Disease (PD) that have a devastating impact on quality of life. Both manifest early in the disease process. Unlike hallmark motor signs of PD, neither respond adequately to dopamine replacement therapies, suggesting that their disease-specific mechanisms are at least partially extra-dopaminergic. Because noradrenergic dysfunction is also a defining feature of PD, especially early in the disease progression, drug therapies targeting norepinephrine are being trialed for treatment of motor and non-motor impairments in PD. Research assessing the effects of noradrenergic manipulation on anxiety and vocal impairment in PD, however, is sparse. In this pre-clinical study, we quantified the influence of pharmacologic manipulation of norepinephrine on vocal impairment and anxiety in Pink1-/- rats, a translational model of PD that demonstrates both vocal deficits and anxiety. Ultrasonic vocalization acoustics, anxiety behavior, and limb motor activity were tested twice for each rat: after injection of saline and after one of three drugs. We hypothesized that norepinephrine reuptake inhibitors (atomoxetine and reboxetine) and a β receptor antagonist (propranolol) would decrease vocal impairment and anxiety compared to saline, without affecting spontaneous motor activity. Our results demonstrated that atomoxetine and reboxetine decreased anxiety behavior. Atomoxetine also modulated ultrasonic vocalization acoustics, including an increase in vocal intensity, which is almost always reduced in animal models and patients with PD. Propranolol did not affect anxiety or vocalization. Drug condition did not influence spontaneous motor activity. These studies demonstrate relationships among vocal impairment, anxiety, and noradrenergic systems in the Pink1-/- rat model of PD.

Amantadine: an old drug reborn

In my opinion, amantadine is the most under-appreciated, under-utilised, and under prescribed oral medication in the treatment of patients with Parkinson's disease. I applaud Olivier Rascol and colleagues 1 Rascol O Fabbri M Poewe W Amantadine in the treatment of Parkinson disease and other movement disorders. Lancet Neurol. 2021; (published online Oct 19)https://doi.org/10.1016/S1474-4422(21)00249-0 Google Scholar for providing a timely update on the uses of amantadine in the treatment of Parkinson's disease and other movement disorders. Their Personal View also provides insight into the reasons why amantadine is not so widely used and emphasises the fact that, even though this drug has been available for 50 years, its complex pharmacology is still not fully understood nor are the mechanisms behind its beneficial effects. Amantadine in the treatment of Parkinson's disease and other movement disordersThe efficacy of amantadine in the symptomatic treatment of patients with Parkinson's disease, discovered serendipitously more than 50 years ago, has stood the test of time and the drug is still commonly used by neurologists today. Its pharmacological actions are unique in combining dopaminergic and glutamatergic properties, which account for its dual effect on parkinsonian signs and symptoms and levodopa-induced dyskinesias. Furthermore, amantadine has additional and less well-defined pharmacological effects, including on anticholinergic and serotonergic activity. Full-Text PDF

Parkinson's Disease and the Gut: Symptoms, Nutrition, and Microbiota.

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, characterized by symptoms of bradykinesia, rigidity, postural instability, and tremor. Recently, there has been a growing focus on the relationship between the gut and the development of PD. Emerging to the forefront, an interesting concept has developed suggesting that the initial pathophysiological changes occur in the gastrointestinal tract before changes are seen within the brain. This review is aimed at highlighting the relationship between PD and the gastrointestinal tract, along with the supporting evidence for this. Firstly, we will focus on the gastrointestinal conditions and symptoms which commonly affects patients, including both upper and lower gastrointestinal issues. Secondly, the impact of nutrition and diet on neurological health and PD physiology, with particular emphasis on commonly consumed items including macronutrients and micronutrients. Finally, variability of the gut microbiome will also be discussed and its link with both the symptoms and signs of PD. The evidence presented in this review highly suggests that the initial pathogenesis in the gut may proceed the development of prodromal PD subtypes, and therefore building on this further could be imperative and lead to earlier diagnosis with new and improved therapeutics.

Investigation of oropharyngeal swallowing and swallowing-breathing coordination in patients with Parkinsonian syndromes. An electrokinesiographic approach

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by dysautonomia in combination with parkinsonian and cerebellar signs. Dysphagia typically occurs in the early stages of the disease also representing a life-threatening condition that is at least in part responsible for the poorer prognosis with respect to Parkinson's disease (PD). The pathophysiology of dysphagia in MSA is still poor understood. Aim: To investigate with an electrokinesiographic approach abnormality of swallowing and coordination between swallowing and breathing in different MSA phenotypes in comparison with PD and age-matched normal subjects.

A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data.

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease.Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD.Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial Registration: NCT03100149.

Association Between Metabolic Syndrome and Mild Parkinsonian Signs Progression in the Elderly.

Background: This study investigated the impact of metabolic syndrome on the progression from mild parkinsonian signs (MPS) to Parkinson's disease (PD).Methods: A total of 1,563 participants with MPS completed 6 years of follow-up. The diagnosis of metabolic syndrome was made according to Adult Treatment Panel III of the National Cholesterol Education Program. The evaluations of MPS and PD were based on the motor portion of the Unified Parkinson's Disease Rating Scale. Cox proportional hazard models were used to identify the association between metabolic syndrome and PD conversion.Results: Of the 1,563 participants, 482 (30.8%) with MPS developed PD at the end of the follow-up. Metabolic syndrome (HR: 1.69, 95% CI: 1.29–2.03) was associated with the risk of PD conversion. Metabolic syndrome was associated with the progression of bradykinesia (HR: 1.85, 95% CI: 1.43–2.34), rigidity (HR: 1.36, 95% CI: 1.19–1.57), tremor (HR: 1.98, 95% CI: 1.73–2.32), and gait/balance impairment (HR: 1.66, 95% CI: 1.25–2.11). The effect of metabolic syndrome on the progression of bradykinesia and tremor was nearly two fold. Participants treated for two or three to four components of metabolic syndrome, including high blood pressure, high fasting plasma glucose, hypertriglyceridemia, and low HDL-C, had a lower risk of PD conversion.Conclusion: Metabolic syndrome increased the risk of progression from MPS to PD. Participants treated for two or more components of metabolic syndrome had a lower risk of PD conversion.

Mild Parkinsonian Signs: A Systematic Review of Clinical, Imaging, and Pathological Associations.

Mild parkinsonian signs (MPS) have been widely studied during the past 3 decades and proposed as a risk marker for neurodegenerative disease. This systematic review explores the epidemiology, clinical and prognostic associations, radiological features, and pathological findings associated with MPS in older adults free from neurodegenerative disease. We find that MPS as currently defined are strongly associated with increasing age and increased risk of development of Parkinson's disease (PD), all-cause dementia, disability, and death. Positive associations with later PD are found mainly in younger populations and those with other features of prodromal PD. There are currently no consistent radiological findings for MPS, and pathological studies have shown that MPS, at least in the oldest old, are often underpinned by mixed neuropathologies, including those associated with Alzheimer's disease, cerebrovascular disease, nigral neuronal loss, and Lewy bodies. Different subcategories of MPS appear to convey varying risk and specificity for PD and other outcomes. MPS overall are not specific for parkinsonian disorders and, although associated with increased risk of PD, can reflect multiple pathologies, particularly in older individuals. "Mild motor signs" appears a more appropriate term to avoid prognostic and pathological implications, and larger future studies to prospectively examine outcomes and associations of specific MPS subcategories are required. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Shift of musical hallucinations to visual hallucinations after correction of the hearing deficit in a patient with Lewy body dementia: a case report

BackgroundMusical hallucinations are a particular type of auditory hallucination in which the patient perceives instrumental music, musical sounds, or songs. Musical hallucinations are associated with acquired hearing loss, particularly within the elderly. Under conditions of reduced auditory sensory input, perception-bearing circuits are disinhibited and perceptual traces released, implying an interaction between peripheral sensory deficits and central factors related to brain dysfunction.Case presentationA 71-year-old Caucasian man with hearing loss complained of memory difficulties and resting tremor of the right upper limb in the previous 2 years. He already had difficulties in instrumental activities of daily life. Neurological examination showed Parkinsonian signs and hypoacusia. Neuropsychological examination identified deficits in executive functions and memory tests. Brain computerized tomography and nuclear magnetic resonance scans showed mild cortical and subcortical atrophy. The clinical diagnosis of possible dementia with Lewy bodies was established. Five years later, the patient began complaining of musical hallucinations. There had been no previous change in medication. An otorhinolaryngologist diagnosed age-related hearing loss and prescribed bilateral hearing aids. After using the hearing aids, the patient did not hear the songs any longer, only some tinnitus, described as a whistle. However, at the same time, the patient started experiencing visual hallucinations he never had before.DiscussionTo our knowledge, the immediate shift of hallucinations from one sensory modality to another sensory modality when perception is improved has not been previously described. This report emphasizes the interaction between brain pathology and sensory deficits for the genesis of hallucinations, and reinforces the theory that attention and control networks must couple properly to the default mode network, as well as integrate and select adequately peripheral signals to the somatosensory cortices, in order to keep a clear state of mind.ConclusionThe clinician should bear in mind and let the patient know that improving one sensory modality to ameliorate hallucinations may sometimes paradoxically lead to hallucinations in a different sensory modality.