Delayed levodopa-responsive parkinsonism following acute midbrain injury.

Acute midbrain injury may cause both hyperkinetic movement disorders and parkinsonism. The temporal interval between the insult and the emergence of hyperkinetic disorders can last years. A delayed appearance of parkinsonism, on the other hand, was rarely described. We present three cases of male patients (50-, 58- and 28-year-old) who developed levodopa-responsive parkinsonism 20, 8 and two years, respectively, after acute brain insult involving the midbrain. Insults included subcortical intracerebral hemorrhage dissecting into the midbrain, embolic basilar occlusion and trauma. A fluorodopa scan, performed in two cases, revealed reduced striatal uptake. All individuals improved on low doses of levodopa and developed motor fluctuations shortly after levodopa was introduced. We conclude that delayed, levodopa-responsive parkinsonism following midbrain injury should be recognized in the relevant clinical setup. Possible mechanisms include age-related loss of dopaminergic neurons superimposed on acute injury and secondary neurodegeneration.

Purpose in Life and Its Association to Parkinsonism.

OBJECTIVES: Purpose in life has been associated with diverse health outcomes; however, few studies have examined its associations with progressive motor decline in older adults. We tested if higher purpose would be associated with lower likelihood of incident parkinsonism as well as with lower levels and slower rates of increase in parkinsonian signs. METHODS: Participants were 2,626 older adults from the Rush Memory and Aging Project and Minority Aging Research Study followed for an average of 7.2 years (standard deviation [SD] = 4.6). Purpose was measured using the purpose in life subscale of the modified Ryff's and Keyes's measure of psychological well-being. Four parkinsonian signs (i.e., parkinsonian gait, rigidity, bradykinesia, and tremor) were assessed using the United Parkinson's Disease Rating Scale. We examined purpose with risk of developing incident parkinsonism using Cox proportional hazards models. We also used linear mixed-effect models to assess the association between purpose and parkinsonian sign trajectories. RESULTS: After including demographics, health conditions, and health behaviors in the model, for a 1-SD increase in purpose, the hazards ratio for incident parkinsonism was 0.88 (95% confidence interval [CI] 0.80, 0.97). A 1-SD increase in purpose was associated with a -0.19 (95% CI -0.24, -0.15) point lower score in the global parkinsonian summary score at baseline but no differences in rate of change were evident. DISCUSSION: Higher purpose was associated with lower hazards of incident parkinsonism and lower levels of parkinsonian signs at baseline. Associations were seen even after adjustment for a wide range of covariates. Findings suggest higher purpose may contribute to maintenance of healthy physical function among older adults.

The Vocal Flutter of Multiple System Atrophy: A Parkinsonian-Type Phenomenon?

BACKGROUND: Early features of multiple system atrophy (MSA) are similar to those in Parkinson's disease (PD), which can challenge differential diagnosis. Identifying clinical markers that help distinguish MSA from forms of parkinsonism is essential to promptly implement the most appropriate management plan. In the context of a thorough neurological evaluation, the presence of a vocal flutter might be considered a potential feature of MSA-parkinsonian type (MSA-P). CASES: This case series describes clinical histories of 3 individuals with MSA-P. In each case, vocal flutter was detected during neurological and motor speech evaluations. It seemed to be a concomitant feature with the constellation of other signs and symptoms that led to the clinical diagnosis. LITERATURE REVIEW: The vocal flutter may be described as pitch and loudness fluctuations during phonation. Different from a vocal tremor, the flutter phenomenon has higher oscillation frequencies. The neuropathological underpinnings of vocal flutter may be related to generalized laryngeal dysfunction that is commonly described in MSA-P. CONCLUSION: Vocal flutter may be a unique speech feature in some individuals who have MSA-P. Future studies using perceptual and acoustic measures of speech are warranted to quantify these observations and directly compare to other MSA variants, PD, and a control group.

Non-Motor Disorders in Parkinson Disease and Other Parkinsonian Syndromes.

Parkinsonism is an umbrella term that refers to multisystemic neurodegenerative disorders characterized by a broad spectrum of motor and non-motor symptoms (NMSs) [...].

Long-Term Longitudinal Course of Cognitive and Motor Symptoms in Patients With Cerebral Small Vessel Disease.

BACKGROUND AND OBJECTIVES: Patients with cerebral small vessel disease (SVD) show a heterogenous clinical course. The aim of the current study was to investigate the longitudinal course of cognitive and motor function in patients who developed parkinsonism, dementia, both, or none. METHODS: Participants were from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study, a prospective cohort of patients with SVD. Parkinsonism and dementia were, respectively, diagnosed according to the UK Parkinson's Disease Society brain bank criteria and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for major neurocognitive disorder. Linear and generalized linear mixed-effect analyses were used to study the longitudinal course of motor and cognitive tasks. RESULTS: After a median follow-up of 12.8 years (interquartile range 10.2-15.3), 132 of 501 (26.3%) participants developed parkinsonism, dementia, or both. Years before diagnosis of these disorders, participants showed distinct clinical trajectories from those who developed none: Participant who developed parkinsonism had an annual percentage of 22% (95% CI 18%-27%) increase in motor part of the Unified Parkinson's Disease Rating Scale score. This was significantly higher than the 16% (95% CI 14%-18%) of controls, mainly because of a steep increase in bradykinesia and posture and gait disturbances. When they developed dementia as well, the increase in Timed Up and Go Test time of 0.73 seconds per year (95% CI 0.58-0.87) was significantly higher than the 0.20 seconds per year increase (95% CI 0.16-0.23) of controls. All groups, including the participants who developed parkinsonism without dementia, showed a faster decline in executive function compared with controls: Annual decline in Z-score was -0.07 (95% CI -0.10 to -0.05), -0.09 (95% CI -0.11 to -0.08), and -0.11 (95% CI -0.14 to -0.08) for participants who developed, respectively, parkinsonism, dementia, and both parkinsonism and dementia. These declines were all significantly faster than the annual decline in Z-score of 0.07 (95% CI -0.10 to -0.05) of controls. DISCUSSION: A distinct pattern in deterioration of clinical markers is visible in patients with SVD, years before the diagnosis of parkinsonism and dementia. This knowledge aids early identification of patients with a high risk of developing these disorders.

Structural Network Efficiency Predicts Conversion to Incident Parkinsonism in Patients With Cerebral Small Vessel Disease.

BACKGROUND: To investigate whether structural network disconnectivity is associated with parkinsonian signs and their progression, as well as with an increased risk of incident parkinsonism. METHODS: In a prospective cohort (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study) consisting of 293 participants with small vessel disease (SVD), we assessed parkinsonian signs and incident parkinsonism over an 8-year follow-up. In addition, we reconstructed the white matter network followed by graph-theoretical analyses to compute the network metrics. Conventional magnetic resonance imaging markers for SVD were assessed. RESULTS: We included 293 patients free of parkinsonism at baseline (2011), with a mean age 68.8 (standard deviation [SD] 8.4) years, and 130 (44.4%) were men. Nineteen participants (6.5%) developed parkinsonism during a median (SD) follow-up time of 8.3 years. Compared with participants without parkinsonism, those with all-cause parkinsonism had higher Unified Parkinson's Disease Rating scale (UPDRS) scores and lower global efficiency at baseline. Baseline global efficiency was associated with UPDRS motor scores in 2011 (ß = -0.047, p < .001) and 2015 (ß = -0.84, p < .001), as well as with the changes in UPDRS scores during the 4-year follow-up (ß = -0.63, p = .004). In addition, at the regional level, we identified an inter-hemispheric disconnected network associated with an increased UPDRS motor score. Besides, lower global efficiency was associated with an increased risk of all-cause and vascular parkinsonism independent of SVD markers. CONCLUSIONS: Our findings suggest that global network efficiency is associated with a gradual decline in motor performance, ultimately leading to incident parkinsonism in the elderly with SVD. Global network efficiency may have the added value to serve as a useful marker to capture changes in motor signs.

Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum.

BACKGROUND AND OBJECTIVE: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders. METHODS: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia. RESULTS: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block. CONCLUSION: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.

Management of lower urinary tract symptoms in Parkinsonian disorders.

INTRODUCTION: The aim of the study was to present a narrative review of the literature on the management of lower urinary tract symptoms (LUTS) in patients presenting Parkinsonian disorders (PD). MATERIAL AND METHODS: We carried out a literature search in PubMed and Embase database, without time restriction. We used keywords and free-text words around "Parkinsonian disorders" AND "lower urinary tracts symptoms" without language restriction. We focused mainly on papers less than 10 years old. We included all studies evaluating LUTS in patients with PD. RESULTS: For the diagnostic management, authors emphasized the importance of differentiating Parkinson's disease with symptoms of bladder overactivity from multiple system atrophy with symptoms of bladder hypoactivity. Urodynamic evaluation was noted as the key element of diagnostic management. The therapeutic management proposed was symptomatic, based on functional urology techniques for the treatment of LUTS, both with drugs (especially anticholinergics) or surgery (intradetrusor injections of botulinum toxin, neuromodulation). Moreover, it was pointed out that it is always necessary to take into account the existence of a possible associated uropathy (prostate adenoma or pelvic prolapse). CONCLUSION: Urodynamic evaluation is the cornerstone of diagnostic management of LUTS in patients with PD. Therapeutic management is above all symptomatic and must be done in a collegial way involving the urologist, neurologist, gynecologist, and physical medicine and rehabilitation physician.

Neurological gait assessment.

Gait disorders are a common feature of neurological disease. The gait examination is an essential part of the neurological clinical assessment, providing valuable clues to a myriad of causes. Understanding how to examine gait is not only essential for neurological diagnosis but also for treatment and prognosis. Here, we review aspects of the clinical history and examination of neurological gait to help guide gait disorder assessment. We focus particularly on how to differentiate between common gait abnormalities and highlight the characteristic features of the more prevalent neurological gait patterns such as ataxia, waddling, steppage, spastic gait, Parkinson's disease and functional gait disorders. We also offer diagnostic clues for some unusual gait presentations, such as dystonic, stiff-person and choreiform gait, along with red flags that help differentiate atypical parkinsonism from Parkinson's disease.

Corticobasal syndrome mimicking Foix-Chavany-Marie syndrome with suggested 4-repeat tauopathy by tau PET.

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative disease diagnosed based on clinical manifestations such as asymmetrical parkinsonism, limb apraxia, and speech and language impairment. The background pathology of CBS is commonly a variety of proteinopathies, but association with cerebrovascular disease has also been reported. Foix-Chavany-Marie syndrome (FCMS) is a rare neurological disorder characterized by facio-pharyngo-glossal diplegia with automatic-voluntary movement dissociation presenting with bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles. FCMS is commonly attributable to stroke. Transactive response DNA binding protein of 43 kD (TDP-43) proteinopathy is also known as the pathological background of FCMS, while the pathological background of the majority of CBS cases consists of diverse tauopathies instead of TDP-43 proteinopathy. In this report, we describe a case mimicking FCMS that was finally diagnosed as CBS with suggested 4-repeat tauopathy. CASE PRESENTATION: A 68-year-old female started experiencing difficulty speaking followed by difficulty writing, and especially texting, several years before her visit. Her impairment had been gradually worsening, and she came to our hospital. On neurological examination, she demonstrated the facial apraxia, frontal lobe dysfunction, and upper motor neuron signs. She presented some characteristics suggestive of FCMS. Her symptoms exhibited rapid progression and myoclonus, parkinsonism, and left-side dominant cortical sensory deficit occurred, resulting in the fulfillment of diagnostic criteria for CBS after 9 months. Tau PET imaging displayed notable ligand uptake in the brainstem, subthalamic nuclei, basal ganglia, and bilateral subcortical frontal lobe, suggesting that her pathological background was 4-repeat tauopathy. As a result of her progressive dysphagia, she became unable to eat and passed away after 12 months. CONCLUSION: We hereby present an atypical case of CBS showing clinical features mimicking FCMS at first presentation. TDP-43 proteinopathy was suspected based on the clinical symptoms in the early stages of the disease; however, the clinical course and imaging findings including tau PET suggested that her pathological background was 4-repeat tauopathy.

Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold.

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.

Monoaminergic Degeneration and Ocular Motor Abnormalities in De Novo Parkinson's Disease.

BACKGROUND: Evaluating eye movements in Parkinson's disease (PD) provides valuable insights into the underlying pathophysiological changes. OBJECTIVE: The aim was to investigate the relationship between monoaminergic degeneration and ocular motor abnormalities in de novo PD. METHODS: Drug-naive PD patients who underwent N-(3-[18 F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane positron emission tomography scans and video-oculography at diagnosis were eligible. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected. Patients underwent Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and detailed cognitive tests. We investigated the associations between ocular motor measurements and specific tracer uptake ratios (SUR) in the caudate nucleus, anterior and posterior putamen, thalamus, and dorsal raphe nuclei, along with motor and cognitive symptoms. RESULTS: One-hundred twenty-four subjects were included in this study. Saccadic accuracy was positively associated with parkinsonian motor severity expressed as Hoehn and Yahr stages, MDS-UPDRS Part III scores, and subscores for bradykinesia and rigidity but not with tremor scores (PFDR < 0.05). Saccadic accuracy correlated with poor performances in the Rey-Complex-Figure copy, and latency with the Digit Symbol Coding and the Montreal Cognitive Assessment scores (PFDR < 0.05). Prolonged saccadic latency correlated with reduced thalamic SUR, whereas decreased saccadic accuracy correlated with reduced SUR in the anterior and posterior putamen (PFDR < 0.05). Reduced smooth pursuit gain showed associations with reduced SUR in the dorsal raphe, a serotonin-predominant region, but did not correlate with parkinsonism severity scores. CONCLUSION: Defective dopaminergic and nondopaminergic neural systems may discretely influence ocular motor function in de novo PD patients. © 2023 International Parkinson and Movement Disorder Society.

ATP1A3 related disease manifesting as rapid onset dystonia-parkinsonism with prominent myoclonus and exaggerated startle.

We report ATP1A3-associated rapid-onset dystonia-parkinsonism with an atypical presentation including myoclonus and exaggerated startle in four patients. Their prominence over parkinsonism prompted consideration of a syndromic diagnosis of myoclonus dystonia. ATP1α3 dysfunction in GABAergic neurons could explain these examination findings. The spectrum of ATP1A3-associated movement disorders includes myoclonus-dystonia.

An Overview of Gastrointestinal Dysfunction in Parkinsonian Syndromes.

Gastrointestinal (GI) dysfunction is a common nonmotor symptom in Parkinson's disease (PD) as well as other parkinsonian syndromes and may precede the onset of motor symptoms by decades. Involvement of all segments of the GI tract can lead to altered responses to medications and worsened quality of life for patients. While some GI symptoms occur in isolation, others overlap. Therefore, understanding the changes in different segments of the GI tract and how they relate to altered responses to PD treatment can guide both diagnostic and pharmacological interventions. Gut microbiota plays a critical role in immune activity and modulation of the enteric and central nervous systems. Understanding this bidirectional relationship helps to elucidate the pathogenesis of neurodegeneration. This review will describe the current understanding of how GI dysfunction develops in parkinsonian syndromes, common symptoms in PD and related disorders, and available treatments.

[Parkinson-dementia and amyotrophic lateral sclerosis association (complex of Guam). Diagnostic challenge, Mexican patient]. / Asociación Parkinson-demencia y esclerosis lateral amiotrófica (complejo Guam). Reto diagnóstico, paciente mexicano.

Background: The Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex (ALS-PDC) was first described in the islands of Guam. This pathology presented its peak incidence in the 1950s. Due to the rarity of the association, we report a clinical case with this complex. The objective was to describe the nosological and pathogenic implications of these neurodegenerative disorder, since they are not frequent to find in our population. Clinical case: We present a case of Latinoamerican origin who initially manifested systemic symptoms of more than 6 years of evolution, with subsequent cognitive alterations. Later, patient began with gait disturbances and motor symptoms suggestive of parkinsonism with atypical data and data of motor neurone disease (MND). More studies were carried out and confirmed findings compatible with upper and lower motor neuron involvement. A mutation in the POLG gene was observed, related to mitochondrial depletion syndrome. Conclusion: Despite the knowledge of this association, it is an entity whose clinical diagnosis could be very difficult to achieve. In addition, molecular mechanisms have not been fully identified, the most common genes related to Parkinsonism and ALS have been excluded, and even attempts to locate the locus were made, without achieving accurate results. Unfortunately, being a neurodegenerative disease, the prognosis is fatal, with no disease-modifying treatment.

Introducción: el complejo parkinsonismo-demencia-esclerosis lateral amiotrófica fue descrito por primera vez en las islas de Guam. Esta patología presentó su pico de incidencia en los años 50. Debido a la rareza de la asociación, informamos sobre un caso clínico que la presenta. El objetivo fue describir las implicaciones nosológicas y patogénicas de este trastorno neurodegenerativo, ya que no es frecuente encontrar esta asociación en nuestra población. Caso clínico: presentamos un caso de origen latinoamericano que inicialmente se manifestó con síntomas sistémicos de más de 6 años de evolución, con posteriores alteraciones cognitivas. Después presentó alteraciones de la marcha y síntomas motores sugestivos de parkinsonismo con datos atípicos y datos de enfermedad de motoneurona. Se hicieron estudios de extensión que confirmaron hallazgos compatibles con afectación en motoneurona superior e inferior. Observamos mutación en gen POLG, relacionada con síndrome de depleción mitocondrial. Conclusión: a pesar del conocimiento de esta asociación, es una entidad cuyo diagnóstico clínico puede ser muy difícil de obtener. Además, no se han identificado del todo los mecanismos moleculares, se han excluido los genes más comunes relacionados con parkinsonismos y esclerosis lateral amiotrófica e incluso se intentó localizar el locus, sin lograr resultados certeros. Desafortunadamente al ser una enfermedad neurodegenerativa el pronóstico es fatal, sin que haya tratamiento modificador de la enfermedad.

The prevalence of sarcopenia in Parkinson's disease and related disorders- a systematic review.

BACKGROUND: The prevalence of sarcopenia (reduced skeletal muscle strength and mass), Parkinson's disease (PD) and Parkinson's related disorders (PRD) all increase with age. They also share risk factors and pathogenetic features. An increased prevalence of sarcopenia in PD and PRD than the general population was thus postulated. METHODS: Four databases were searched using predefined literature search strategies. Studies conducted in participants with PD or PRD reporting the prevalence of sarcopenia and those providing data to compute the prevalence were included. Pre-sarcopenia, probable/possible sarcopenia and confirmed sarcopenia were defined according to the main sarcopenia working groups. Risk of bias was assessed using the AXIS tool. RESULTS: 1978 studies were identified; 97 assessed in full; 14 met inclusion criteria. The median study quality score was 15/20. The range of probable sarcopenia was 23.9 to 66.7%, and it did not change after excluding PRD participants. The prevalence of confirmed sarcopenia in participants with any parkinsonian disorder ranged from 2 to 31.4%. Including just PD participants, the range was 10.9 to 31.4%. In studies with controls, sarcopenia was more prevalent in PD and PRD. There was a positive non-significant trend between severity of motor symptoms and prevalence of sarcopenia or components of sarcopenia. High heterogeneity precluded meta-analysis, therefore there was insufficient evidence to conclude whether sarcopenia is more prevalent in PD or PRD. CONCLUSIONS: Probable and confirmed sarcopenia are common in PD and PRD and they may be associated with disease severity. This co-occurrence supports the value of screening for sarcopenia in parkinsonian populations.

Wilson Disease: A Case Report of Psychosis Preceding Parkinsonism.

BACKGROUND A first psychotic episode requires the exclusion of toxic-metabolic, inflammatory, infective, and neoplastic causes. Wilson disease is a rare, autosomal recessive disorder of copper metabolism and can present with neuropsychiatric symptoms secondary to copper accumulation in the brain. CASE REPORT We describe the case of a 48-year-old man with parkinsonism on a background of longstanding schizophrenia and psychotic depression in the setting of previously undiagnosed Wilson disease. The common history of neuropsychiatric disturbance and neuroleptic use complicated the assessment of parkinsonism. However, close attention to the temporal appearance of symptoms and signs differentiated his case from drug-induced parkinsonism, which commonly develops hours to weeks after commencement or uptitration of antipsychotic medication. The early features of sialorrhea and dysarthria were also atypical for idiopathic Parkinson disease. The diagnosis was confirmed by serum copper testing and supported by Kayser-Fleischer rings on bedside ophthalmological examination. Magnetic resonance imaging (MRI) of the brain demonstrated copper accumulation in the basal ganglia and pons, contributing to the characteristic neurological manifestations of an akinetic-rigid syndrome with dysarthria. CONCLUSIONS Serum copper testing is easily obtained and should be considered as part of the first-line investigations for new neuropsychiatric disturbances. Although rare, Wilson disease, if diagnosed early, is a potentially treatable and reversible cause of psychosis. With advanced disease, extrapyramidal findings on examination correlate with MRI brain changes, aiding the clinical assessment in differentiating the disease from drug-induced parkinsonism.