Developing a Staging Scheme for Essential Tremor: A Discussion of Organizing Principles.

Essential tremor (ET) is a chronic, progressive neurological disease that may negatively affect patients' lives. While there has been considerable progress in ET research, some fundamental issues remain unaddressed. One such issue is disease staging. Staging schemes have inherent value and are part of the dialogue that clinicians have with other movement disorders patients. We highlight the value of and challenges with developing a staging system for ET and organize a discussion around the potential steps in developing such a system. Diseases for which there are staging schemes generally have a number of shared characteristics. ET has numerous features that would lend themselves to a staging scheme: emerging evidence supporting the existence of a premotor phase of disease, insidious onset, progressive worsening of arm tremor, spread of tremor to other body regions, the observation that patients seem to be at increased risk for other conditions within the same organ (i.e., emergence of Parkinson's disease and Alzheimer's disease in excessive numbers of ET patients), pathological changes in the cerebellum whose evolution can be ordered from (i) those that compromise the physical integrity and physiological function of Purkinje cells, (ii) subsequent changes that are reparative and regenerative, and (iii) eventual cell death. Challenges to formulating a staging scheme are the absence of both a biological marker and an "end stage" of disease. The sum of combined evidence suggests that a staging scheme would be of value. We provide initial thoughts as to how to begin to structure such a staging scheme.

A video-atlas of levodopa-induced dyskinesia in Parkinson's disease: terminology matters.

Dyskinesia is a common complication of long-term levodopa therapy in patients with Parkinson's disease (PD), which often worsens the quality of life. It is usually dose-dependent and emerges possibly due to pulsatile stimulation of dopamine receptors. Delineating the pattern of dyskinesia is crucial for determining the most effective therapeutic approach, a task that often presents challenges for numerous neurologists. This article comprehensively describes various patterns of dyskinesia in PD patients and features video demonstration of some of the common forms of dyskinesia. We have used a real case scenario as an example to lead the discussion on the phenomenology, distinguishing features, and management of various types of dyskinesia. A comprehensive literature search was conducted in PubMed using "dyskinesia" as a keyword. The prototype case with videos highlights the differentiating features of dyskinesia along with the treatment strategies. A wide range of descriptive rubrics have been used for certain dyskinesia which are described in detail in this article. The newer types of dyskinesia associated with continuous dopaminergic stimulation in patients with advanced PD and their implications have been described. As there are distinct ways of managing various types of dyskinesia, understanding the phenomenology and chronology of dyskinesia is vital for the optimal management of dyskinetic PD patients. We suggest that dyskinesia should be classified broadly into peak-dose dyskinesia (PDD), biphasic dyskinesia (BD), and OFF-period dystonia. The occurrence of low-dose dyskinesia and complex dyskinesia of continuous dopaminergic treatments should be known to specialists and will require additional studies.

Cardiac 18F-dopamine positron emission tomography predicts the type of phenoconversion of pure autonomic failure.

PURPOSE: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), no known secondary cause, and lack of a neurodegenerative movement or cognitive disorder. Clinically diagnosed PAF can evolve ("phenoconvert") to a central Lewy body disease [LBD, e.g., Parkinson's disease (PD) or dementia with Lewy bodies (DLB)] or to the non-LBD synucleinopathy multiple system atrophy (MSA). Since cardiac 18F-dopamine-derived radioactivity usually is low in LBDs and usually is normal in MSA, we hypothesized that patients with PAF with low cardiac 18F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA. METHODS: We reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 with a clinical diagnosis of PAF and data about 18F-dopamine positron emission tomography (PET). RESULTS: Nineteen patients (15 with low 18F-dopamine-derived radioactivity, 4 with normal radioactivity) met the above criteria and had follow-up data. Nine (47%) phenoconverted to a central synucleinopathy over a mean of 6.6 years (range 1.5-18.8 years). All 6 patients with low cardiac 18F-dopamine-derived radioactivity who phenoconverted during follow-up developed a central LBD, whereas none of 4 patients with consistently normal 18F-dopamine PET phenoconverted to a central LBD (p = 0.0048), 3 evolving to probable MSA and 1 upon autopsy having neither a LBD nor MSA. CONCLUSION: Cardiac 18F-dopamine PET can predict the type of phenoconversion of PAF. This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs.

Dystonia and tremor: Do they have a shared biology?

Dystonia and tremor are the two most commonly encountered hyperkinetic movement disorders encountered in clinical practice. While there has been substantial progress in the research on these two disorders, there also exists a lot of gray areas. Entities such as dystonic tremor and tremor associated with dystonia occupy a major portion of the "gray zone". In addition, there is a marked clinical heterogeneity and overlap of several clinical and epidemiological features among dystonia and tremor. These facts raise the possibility that dystonia and tremor could be having shared biology. In this chapter, we revisit critical aspects of this possibility that may have important clinical and research implications in the future. We comprehensively review the points in favor and against the theory that dystonia and tremor have shared biology from clinical, epidemiological, genetic and neuroimaging studies.

Cardiac 18F-Dopamine Positron Emission Tomography Predicts the Type of Phenoconversion of Pure Autonomic Failure.

Background: Pure autonomic failure (PAF) is a rare disease characterized clinically by neurogenic orthostatic hypotension (nOH) and biochemically by peripheral noradrenergic deficiency. Clinically diagnosed PAF can evolve ("phenoconvert") to a central Lewy body disease (LBD, e.g., Parkinson's disease (PD) or dementia with Lewy bodies (DLB)) or to the non-LBD synucleinopathy multiple system atrophy (MSA). We examined whether cardiac 18F-dopamine positron emission tomography (PET) predicts the trajectory of phenoconversion in PAF. Since cardiac 18F-dopamine-derived radioactivity always is decreased in LBDs with nOH and usually is normal in MSA, we hypothesized that PAF patients with low cardiac 18F-dopamine-derived radioactivity may phenoconvert to a central LBD but do not phenoconvert to MSA. Methods: We reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 with a clinical diagnosis of PAF and data about serial 18F-dopamine PET. Results: Twenty patients met the above criteria. Of 15 with low cardiac 18F-dopamine-derived radioactivity, 6 (40%) phenoconverted to PD or DLB and none to MSA. Of 5 patients with consistently normal 18F-dopamine PET, 4 phenoconverted to MSA, and the other at autopsy had neither a central LBD nor MSA. Conclusion: In this case series, 40% of patients with nOH and low cardiac 18F-dopamine-derived radioactivity phenoconverted to PD or DLB during follow-up; none phenoconverted to MSA. Cardiac 18F-DA PET therefore can predict the type of phenoconversion in PAF. This capability could refine eligibility criteria for entry into disease-modification trials aiming to prevent evolution of PAF to symptomatic central LBDs.

A multicentre study on grey matter morphometric biomarkers for classifying early schizophrenia and parkinson's disease psychosis.

Psychotic symptoms occur in a majority of schizophrenia patients and in ~50% of all Parkinson's disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little is known, however, about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as in schizophrenia and PD. The present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals in at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms. SCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD, PDN and Con-PD, as well as PDN and PDP, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC ~0.80) of FEP and Con-Psy, and fair performance (AUC ~0.72) when differentiating PDP from Con-PD. Importantly, the best performance was found in partly the same networks, including the thalamus. Alterations within selected SCNs may be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP.

Peripherally-induced Movement Disorders: An Update.

Background: Peripherally-induced movement disorders (PIMD) should be considered when involuntary or abnormal movements emerge shortly after an injury to a body part. A close topographic and temporal association between peripheral injury and onset of the movement disorders is crucial to diagnosing PIMD. PIMD is under-recognized and often misdiagnosed as functional movement disorder, although both may co-exist. Given the considerable diagnostic, therapeutic, and psychosocial-legal challenges associated with PIMD, it is crucial to update the clinical and scientific information about this important movement disorder. Methods: A comprehensive PubMed search through a broad range of keywords and combinations was performed in February 2023 to identify relevant articles for this narrative review. Results: The spectrum of the phenomenology of PIMD is broad and it encompasses both hyperkinetic and hypokinetic movements. Hemifacial spasm is probably the most common PIMD. Others include dystonia, tremor, parkinsonism, myoclonus, painful leg moving toe syndrome, tics, polyminimyoclonus, and amputation stump dyskinesia. We also highlight conditions such as neuropathic tremor, pseudoathetosis, and MYBPC1-associated myogenic tremor as examples of PIMD. Discussion: There is considerable heterogeneity among PIMD in terms of severity and nature of injury, natural course, association with pain, and response to treatment. As some patients may have co-existing functional movement disorder, neurologists should be able to differentiate the two disorders. While the exact pathophysiology remains elusive, aberrant central sensitization after peripheral stimuli and maladaptive plasticity in the sensorimotor cortex, on a background of genetic (two-hit hypothesis) or other predisposition, seem to play a role in the pathogenesis of PIMD.

How should future clinical trials be designed in the search for disease-modifying therapies for Parkinson's disease?

INTRODUCTION: Although there has been substantial progress in research and innovations in symptomatic treatments, similar success has not been achieved in disease-modifying therapy (DMT) for Parkinson's disease (PD). Considering the enormous motor, psychosocial and financial burden associated with PD, safe and effective DMT is of paramount importance. AREAS COVERED: One of the reasons for the lack of progress in DMT for PD is poor or inappropriate design of clinical trials. In the first part of the article, the authors focus on the plausible reasons why the previous trials have failed and in the latter part, they provide their perspectives on future DMT trials. EXPERT OPINION: There are several potential reasons why previous trials have failed, including broad clinical and etiopathogenic heterogeneity of PD, poor definition and documentation of target engagement, lack of appropriate biomarkers and outcome measures, and short duration of follow-up. To address these deficiencies, future trials may consider- (i) a more customized approach to select the most suitable participants and therapeutic approaches, (ii) explore combination therapies that would target multiple pathogenetic mechanisms, and (iii) moving beyond targeting only motor symptoms to also assessing non-motor features of PD in well-designed longitudinal studies.

Cognitive Correlates of Visual and Minor Hallucinations in Parkinson's Disease.

INTRODUCTION: Psychosis is one of the incapacitating nonmotor symptoms of Parkinson's disease (PD). Although several risk factors that include older age, rapid eye movement sleep behavior disorder, depression, and cognitive dysfunction have been identified, the exact neural correlates remain elusive. As cognitive impairment has a close association with psychosis in PD, it is useful to know the spectrum of cognitive impairment in PD patients with psychosis (PD-P). METHODS: This cross-sectional study compared various cognitive parameters of PD-P (visual/minor hallucinations) and PD patients with no psychosis (PD-NP). A neuropsychological battery encapsulating several cognitive domains (executive, visuospatial, learning, and memory) was used for the cognitive assessment of 37 PD-P and 51 PD-NP patients who were matched for age, gender, education, and disease duration. RESULTS: The two groups were comparable in terms of disease severity and stage. Although the groups had a comparable mean score on Montreal cognitive assessment, the PD-P group performed poorly in tests focused on executive function (color trail test, forward digit span), verbal learning and memory (Rey auditory and verbal learning test), and visuospatial functions (complex figure test, corsi block tapping test). Those with complex visual hallucinations performed poorly in the color trial test (part A) compared to those with minor hallucinations. CONCLUSION: Psychosis is associated with a multidomain cognitive dysfunction in PD. All PD patients should undergo detailed cognitive assessment as cognitive dysfunction may be a marker of psychosis in the future. Additional longitudinal studies are warranted to obtain detailed insights into this issue.

Orthostatic Hypotension in Parkinson Disease: What Is New?

Purpose of the Review: Orthostatic hypotension (OH) is the primary manifestation of cardiovascular autonomic dysfunction in Parkinson disease (PD) and can be a prodromal feature of the disease. We review the recent progress in the field of autonomic dysfunction in PD. Recent Findings: Individuals with isolated neurogenic OH should be followed up frequently because they may evolve into PD, dementia with Lewy bodies, or multiple system atrophy. The prevalence of OH in PD increases with disease stages, but the role of levodopa remains unclear. Measurement of supine and standing heart rate and blood pressure allows for accurate identification of neurogenic OH in the clinic. Summary: Accurate identification of neurogenic OH in the clinic is crucial for identification of individuals who may benefit from participation in neuroprotective trials in the future. The treatment of OH in PD should be individualized and may reduce the risk of falls, cognitive impairment, and death.

Retinal Changes in Parkinson's Disease: A Longitudinal Follow-up Study.

Background: There is definite evidence for the involvement of retina in Parkinson's disease (PD). However, a specific pattern has not been clear due to the cross-sectional nature of the majority of the previous studies. Objective: The aim of this work was to study the pattern of changes in the retinal layers in patients with PD on longitudinal follow-up. Materials and Methods: Twelve patients with PD (23 eyes) were evaluated at baseline with complete history, clinical examination, Unified Parkinson's Disease Rating Scale (UPDRS) motor part, visual acuity, and retinal imaging with spectral-domain Optical Coherence Tomography. After a mean duration of 3.7 ± 0.46 years, patients were re-evaluated. Results: The Central Macular Thickness (CMT) of the right eye was found to be significantly thicker during the follow-up (P = 0.002). The outer retinal layer in the temporal quadrant at 0.5 centimeters from the fovea of the left eye was found to be significantly thinner (P = 0.001). Conclusion: The serial evaluation of the retinal layers in patients with PD suggests a progressive loss of thickness of the outer retinal layer. The involvement of non-dopaminergic mechanisms, especially glutamatergic pathways, may be responsible for these changes.

Essential Tremor: Five New Things.

Purpose of the Review: To highlight five new things in the research and clinical aspects of essential tremor (ET). Recent Findings: The introduction of a new definition of ET and a new category "ET plus" were the major themes of the recent consensus statement. This new change demands a change in the approach to the clinical diagnosis of ET and related diseases. From the pathogenesis standpoint, the cerebellar neurodegenerative model seems to have abundant evidence in its favor compared with the olivary model, which has largely fallen out of favor. From the standpoint of therapeutics, magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has enriched the therapeutic armamentarium. Summary: There has been considerable progress in the field of ET. We discuss five new things in this article, which include (1) new definition, (2) ET plus, (3) approach to the diagnosis of ET, (4) cerebellar degeneration, and (5) MRgFUS thalamotomy.

Practical pearls to improve the efficacy and tolerability of levodopa in Parkinson's disease.

INTRODUCTION: Levodopa is the most effective medication for the treatment of motor symptoms of Parkinson's disease (PD). Several factors may affect the efficacy and tolerability of levodopa. These include the timing, dosage and administration of levodopa, concomitant drugs, food, PD-associated non-motor symptoms, and various neurologic and non-neurologic comorbidities. If not appropriately addressed, these issues may limit levodopa efficacy, tolerability, and compliance. AREAS COVERED: This article reviews the basics of the metabolism of orally administered levodopa, its side effects, and the factors that may affect its tolerability and efficacy. We provide several practical pearls to improve the tolerability and efficacy of levodopa. EXPERT OPINION: Protein-rich food delays and reduces levodopa absorption. Hence, levodopa should preferably be administered in a relatively empty stomach. Carbidopa dosing is crucial as it not only enhances the entry of levodopa into the central nervous system but also reduces levodopa's peripheral adverse effects. Patients experiencing the early side effects such as nausea/vomiting should be prescribed with anti-nausea medications that do not block dopamine receptors. Non-oral routes of administration can be used to obviate persistent gastrointestinal side effects. Implementation of these and other tips may help improve the tolerability and efficacy of levodopa.

Tremor Syndromes: An Updated Review.

Tremor is the most commonly encountered movement disorder in clinical practice. A wide range of pathologies may manifest with tremor either as a presenting or predominant symptom. Considering the marked etiological and phenomenological heterogeneity, it would be desirable to develop a classification of tremors that reflects their underlying pathophysiology. The tremor task force of the International Parkinson Disease and Movement Disorders Society has worked toward this goal and proposed a new classification system. This system has remained a prime topic of scientific communications on tremor in recent times. The new classification is based on two axes: 1. based on the clinical features, history, and tremor characteristics and 2. based on the etiology of tremor. In this article, we discuss the key aspects of the new classification, review various tremor syndromes, highlight some of the controversies in the field of tremor, and share the potential future perspectives.

Cardiac 18F-Dopamine PET Distinguishes PD with Orthostatic Hypotension from Parkinsonian MSA.

BACKGROUND: Parkinson's disease with orthostatic hypotension (PD + OH) can be difficult to distinguish clinically from the parkinsonian form of multiple system atrophy (MSA-P). Previous studies examined cardiac sympathetic neuroimaging to differentiate PD from MSA but without focusing specifically on PD + OH versus MSA-P, which often is the relevant differential diagnostic issue. OBJECTIVE: To investigate the utility of cardiac sympathetic neuroimaging by 18F-dopamine positron emission tomographic (PET) scanning for separating PD + OH from MSA-P. METHODS: Cardiac 18F-dopamine PET data were analyzed from 50 PD + OH and 68 MSA-P patients evaluated at the NIH Clinical Center from 1990 to 2020. Noradrenergic deficiency was defined by interventricular septal 18F-dopamine-derived radioactivity <6000 nCi-kg/cc-mCi in the 5' frame with mid-point 8' after initiation of 3' tracer injection. RESULTS: 18F-Dopamine PET separated the PD + OH from the MSA-P group with a sensitivity of 92% and specificity of 96%. CONCLUSION: Cardiac 18F-dopamine PET scanning efficiently distinguishes PD + OH from MSA-P.

Differential abnormalities of cerebrospinal fluid dopaminergic versus noradrenergic indices in synucleinopathies.

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), DHPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen 18 F-DOPA and cardiac 18 F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.