Monash-Alfred protocol for assessment of atypical parkinsonian syndromes (MAP-APS).

Introduction: Atypical parkinsonian syndromes (APS) are rare neurodegenerative syndromes for which parkinsonism is one significant feature. APS includes progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS). The diagnosis of APS remains reliant on clinical features with no available diagnostic or prognostic biomarker. Clinical scales remain the gold standard assessment measures in clinical trials and research. The lack of standardised approach for research cohorts has contributed to shortcomings in disease understanding and limits collaboration between researchers. The primary objectives of this study are to (1) establish an assessment protocol for parkinsonian syndromes and (2) to implement it at a single site to establish the viability and utility of populating a clinical and biological databank of patients with APS. Methods: The Monash Alfred Protocol for Assessment of APS was devised by expert consensus within a broad multidisciplinary team. Eligible patients are diagnosed as possible or probable PSP, MSA or CBS by a consultant neurologist with expertise in movement disorders. Participants will be assessed at recruitment and then annually for up to 3 years; individuals within 5 years of index symptom onset will also undergo a once-off 6-month assessment. Ethics and dissemination: Each participant or their legally authorised representative will provide informed written consent prior to commencement of the study. Data will be stored on a locally hosted Research Electronic Data Capture database. Trial registration number: Australian New Zealand Clinical Trials Registry (ANZCTN 12622000923763).

Brain Networks Involved in Sensory Perception in Parkinson's Disease: A Scoping Review.

Parkinson's Disease (PD) has historically been considered a disorder of motor dysfunction. However, a growing number of studies have demonstrated sensory abnormalities in PD across the modalities of proprioceptive, tactile, visual, auditory and temporal perception. A better understanding of these may inform future drug and neuromodulation therapy. We analysed these studies using a scoping review. In total, 101 studies comprising 2853 human participants (88 studies) and 125 animals (13 studies), published between 1982 and 2022, were included. These highlighted the importance of the basal ganglia in sensory perception across all modalities, with an additional role for the integration of multiple simultaneous sensation types. Numerous studies concluded that sensory abnormalities in PD result from increased noise in the basal ganglia and increased neuronal receptive field size. There is evidence that sensory changes in PD and impaired sensorimotor integration may contribute to motor abnormalities.

Automated measurement of inter-arytenoid distance on 4D laryngeal CT: A validation study.

Changes to the voice are prevalent and occur early in Parkinson's disease. Correlates of these voice changes on four-dimensional laryngeal computed-tomography imaging, such as the inter-arytenoid distance, are promising biomarkers of the disease's presence and severity. However, manual measurement of the inter-arytenoid distance is a laborious process, limiting its feasibility in large-scale research and clinical settings. Automated methods of measurement provide a solution. Here, we present a machine-learning module which determines the inter-arytenoid distance in an automated manner. We obtained automated inter-arytenoid distance readings on imaging from participants with Parkinson's disease as well as healthy controls, and then validated these against manually derived estimates. On a modified Bland-Altman analysis, we found a mean bias of 1.52 mm (95% limits of agreement -1.7 to 4.7 mm) between the automated and manual techniques, which improves to a mean bias of 0.52 mm (95% limits of agreement -1.9 to 2.9 mm) when variability due to differences in slice selection between the automated and manual methods are removed. Our results demonstrate that estimates of the inter-arytenoid distance with our automated machine-learning module are accurate, and represents a promising tool to be utilized in future work studying the laryngeal changes in Parkinson's disease.

Two Rare Cases of Long Surviving Riboflavin Transporter Deficiency with Co-Existing Adenosine Monophosphate Deaminase (AMP) Deficiency.

(1) Background: Riboflavin transporter deficiency (RTD), formerly known as Brown−Vialetto−Van Laere syndrome, is a rare condition that causes a progressive neurological syndrome in early life with features of auditory and optic neuropathy, weakness of bulbar muscles and the diaphragm and sensorimotor neuropathy. Pathologic mutations in the genes that code for riboflavin transporters have been identified as the genetic basis of RTD, and the majority of the genetically confirmed cases are caused by mutations of SLC52A3, a riboflavin transporter 2 coding gene or compound mutations in SLC52A2, encoding riboflavin transporter 3. Fatality in childhood is common if the condition is left untreated, but survival into adulthood has been reported in cases treated with high-dose oral riboflavin. (2) Case summary: We report two long-term survivors of RTD type 2 due to compound heterozygous 185T> G and 1258G>A mutations in gene SLC2A2. They are two brothers in a family in which two female siblings died in childhood from a similar neurological disorder. Brother one, the older RTD survivor, is aged 71, and brother two is aged 58. Both have significant visual impairment from optic nerve atrophy and sensory ataxia. Their muscle biopsies showed decreased muscle adenosine monophosphate (AMP) deaminase activity. No AMPD1 mutation was detected through whole-genome sequencing. (3) Conclusion: Co-existing riboflavin transporter deficiency (RTD) type 2 and muscle AMP deaminase deficiency has not been previously reported. Apart from the possibility that there is a milder phenotype associated with these mutations in SLC2A2, AMP deaminase deficiency might have contributed to a survival benefit by preserving muscle function through accumulating intracellular AMP.

Patient care standards for primary mitochondrial disease in Australia: an Australian adaptation of the Mitochondrial Medicine Society recommendations.

This document provides consensus-based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus-based recommendations will continue to evolve, but current standards of care are summarised in this document.

Radiological correlates of vocal fold bowing as markers of Parkinson's disease progression: A cross-sectional study utilizing dynamic laryngeal CT.

OBJECTIVE: To determine whether arytenoid cartilage position and dynamics change with advancing duration and severity (as graded by MDS-UPDRS part III scores) in Parkinson's disease, in a cross-sectional study design, we performed laryngeal four-dimensional computed tomography (4D-CT) in people with Parkinson's disease and controls. METHODS: 31 people with Parkinson's disease covering a range of disease duration and severity and 19 controls underwent laryngeal 4D-CT whilst repeatedly vocalizing. We measured on each CT volume the glottic area (GA), inter-arytenoid distance (IAD), IAD-Area index (IAI) and arytenoid cartilage velocity ([Formula: see text]). RESULTS: People with Parkinson's disease had reductions in the mean/effective minimum IAD when compared to controls, while mean/effective minimum GA and mean/effective maximum IAI were increased. Arytenoid cartilage velocities showed no difference. On Spearman correlation analyses, advancing disease duration and severity of PD showed moderately strong and significant correlations with increasing mean/effective minimum GA, increasing mean/effective maximum IAI and decreasing effective minimum IAD. Linear mixed models which considered the effects of intra and inter-individual variation showed that both disease duration (b = -0.011, SEb = 0.053, 95% CI [-0.022, 0], t(27) = -2.10, p = 0.045) and severity (b = -0.069, SEb = 0.032, 95% CI [-0.14,-0.0039], t(27) = -2.17, p = 0.039) were significant predictors for IAD, and also for transformed values of the GA and IAI. CONCLUSIONS: There are progressive alterations in phonatory posturing as Parkinson's disease advances. The increases in GA despite reductions in IAD are concordant with prior observations of vocal fold bowing. Our study provides a basis for using laryngeal 4D-CT to assess disease progression in Parkinson's disease.

"He's Back so I'm Not Alone": The Impact of Deep Brain Stimulation on Personality, Self, and Relationships in Parkinson's Disease.

Deep brain stimulation (DBS) for Parkinson's disease successfully alleviates motor symptoms, but unanticipated changes in personality, self, and relationships can occur. Little is known about how these nonmotor outcomes affect patients and families. We prospectively examined the experience and meaning of DBS-related changes in personality and self for patients and caregivers. In-depth, semi-structured interviews were conducted with 22 participants (11 patient-caregiver dyads) before and 9 months after DBS and analyzed using thematic analysis. We identified three themes present prior to DBS that reflected a time of anticipation, while three themes present after DBS reflected a process of adjustment. Participants noted both positive and negative personality changes, with some, but not all, attributing them to the stimulation. The risk of stimulation-related personality change should be weighed against the procedure's motor benefits and considered in the context of disease- and medication-related personality changes. Clinical implications including perioperative education and follow-up management are discussed.

Voice changes in Parkinson's disease: What are they telling us?

Emerging evidence suggests voice dysfunction is the earliest sign of motor impairment in Parkinson's disease (PD). The complexity and fine motor control involved in vocalization may result in dysfunction here before the limbs. The voice in PD demonstrates characteristic changes on perceptual and acoustic analyses. The physiological and anatomical correlates of these have been investigated through laryngoscopy, stroboscopy, photoglottography, laryngeal electromyography, computed-tomography, pulmonary function testing and aerodynamic assessments. These have revealed numerous abnormalities including incomplete glottic closure and vocal fold hypoadduction/bowing to account for these voice changes. Many of these phenomena are likely related to rigidity or bradykinesia of the laryngeal muscles. The early onset of voice changes is resonant with the pathophysiological insights offered by Braak's hypothesis and murine models of the disease. These physiological abnormalities and pathological models largely stand to support dopaminergic and non-dopaminergic mechanisms being implicated in the pathogenesis of voice dysfunction. This review focuses on characterizing the voice changes in PD. These stand as a promising area of enquiry to further our understanding of the pathophysiology of the disease and offer potential to be utilized as an early diagnostic biomarker or marker of disease progression.

Genetic prion disease: D178N with 129MV disease modifying polymorphism-a clinical phenotype.

BACKGROUND: Human prion diseases are a group of rare neurological diseases with a minority due to genetic mutations in the prion protein (PRNP) gene. The D178N mutation is associated with both Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotype modified by a polymorphism at codon 129 with the methionine/valine (MV) polymorphism associated with atypical presentations leading to diagnostic difficulty. CASE: We present a case of fatal familial insomnia secondary to a PRNP D178N mutation with 129MV disease modifying polymorphism who had no family history, normal MRI, electroencephalography (EEG), cerebrospinal fluid (CSF) and positron emission tomography findings and a negative real-time quaking-induced conversion result. CONCLUSION: Patients with genetic prion disease may have no known family history and normal EEG, MRI brain and CSF findings. PRNP gene testing should be considered for patients with subacute progressive neurological and autonomic dysfunction.

CNS imaging studies in cystic fibrosis patients presenting with sudden neurological events.

Background: Acute neurological events may present as an extrapulmonary complication in patients with cystic fibrosis (CF). These events can be secondary to a range of different aetiologies. Methods: A retrospective analysis of 476 medical records of CF patients attending a large teaching hospital between 2000 and 2018 was performed. Patients presenting with acute neurological events who had MRI brain imaging were evaluated. Patients who had headaches without associated neurological symptoms were excluded from this analysis. Results: Acute neurological presentations, excluding headaches without associated neurological symptoms, were reported in 27 index patients out of the 476 patients. Of these, 16 patients had MRI brain imaging for review. Three patients suffered pathology secondary to vascular events, both ischaemic and haemorrhagic; four patients had evidence of ischaemia or infarction not consistent with a vascular territory stroke and the remaining patients experienced a range of different neurological events. The most common presentation among these patients was seizure activity, followed by a transient motor or sensory deficit. Conclusions: Neurological complications are recognised among individuals with CF. Although rare, they can be secondary to a range of different aetiologies, including dysfunctional cell energetics. Additional studies are required to further evaluate this association.

Dopamine restores cognitive motivation in Parkinson's disease.

Disorders of motivation, such as apathy, are common in Parkinson's disease, and a key feature of such disorders is a greater aversion to effort. In humans, the experience of cognitive effort is ubiquitous, and cognitive apathy has traditionally been considered distinct and separable from other subtypes. Surprisingly, however, the neurobiology of cognitive motivation is poorly understood. In particular, although dopamine has a well-characterized role in incentivizing physically effortful behaviour, a critical, unresolved issue is whether its facilitatory role generalizes to other domains. Here, we asked how dopamine modulates the willingness of patients with Parkinson's disease to invest cognitive effort in return for reward. We tested 20 patients with idiopathic Parkinson's disease across two counterbalanced sessions-ON and OFF their usual dopaminergic medication-and compared their performance to 20 healthy age-matched controls. We applied a novel task in which we manipulated cognitive effort as the number of rapid serial visual presentation streams to which participants had to attend. After training participants to ceiling performance, we then asked them to choose between a low-effort/low-reward baseline option, and a higher-effort/higher-reward offer. Computational models of choice behaviour revealed four key results. First, patients OFF medication were significantly less cognitively motivated than controls, as manifest by steeper cognitive effort discounting functions in the former group. Second, dopaminergic therapy improved this deficit, such that choices in patients ON medication were indistinguishable from controls. Third, differences in motivation were also accompanied by independent changes in the stochasticity of individuals' decisions, such that dopamine reduced the variability in choice behaviour. Finally, choices on our task correlated uniquely with the subscale of the Dimensional Apathy Scale that specifically indexes cognitive motivation, which suggests a close relationship between our laboratory measure of cognitive effort discounting and subjective reports of day-to-day cognitive apathy. Importantly, participants' choices were not confounded by temporal discounting, probability discounting, physical demand, or varying task performance. These results are the first to reveal the central role of dopamine in overcoming cognitive effort costs. They provide an insight into the computational mechanisms underlying cognitive apathy in Parkinson's disease, and demonstrate its amenability to dopaminergic therapy. More broadly, they offer important empirical support for prominent frameworks proposing a domain-general role for dopamine in value-based decision-making, and provide a critical link between dopamine and multidimensional theories of apathy.

Deep Brain Stimulation for Parkinson's disease changes perception in the Rubber Hand Illusion.

Parkinson's disease (PD) alters cortico-basal ganglia-thalamic circuitry and susceptibility to an illusion of bodily awareness, the Rubber Hand Illusion (RHI). Bodily awareness is thought to result from multisensory integration in a predominantly cortical network; the role of subcortical connections is unknown. We studied the effect of modulating cortico-subcortical circuitry on multisensory integration for bodily awareness in 24 PD patients treated with subthalamic nucleus (STN) deep brain stimulation (DBS), in comparison to 21 healthy volunteers, using the RHI experiment. Typically, synchronous visuo-tactile cues induce a false perception of touch on the rubber hand as if it were the subject's hand, whereas asynchronous visuo-tactile cues do not. However, we found that in the asynchronous condition, patients in the off-stimulation state did not reject the RHI as strongly as healthy controls; patients' rejection of the RHI strengthened when STN-DBS was switched on, although it remained weaker than that of controls. Patients in the off-stimulation state also misjudged the position of their hand, indicating it to be closer to the rubber hand than controls. However, STN-DBS did not affect proprioceptive judgements or subsequent arm movements altered by the perceptual effects of the illusion. Our findings support the idea that the STN and subcortical connections have a key role in multisensory integration for bodily awareness. Decision-making in multisensory bodily illusions is discussed.

Perioperative risk assessment for successful kidney transplant in leigh syndrome: a case report.

BACKGROUND: Leigh syndrome (LS) is a rare neurodegenerative mitochondrial disorder which typically presents in childhood but has a varied clinical course. Renal involvement such as proximal tubulopathy in patients with mitochondrial disorders has been described. However, end stage renal disease (ESRD) is uncommon and literature regarding patients undergoing kidney transplantation is limited. Successful deceased donor renal transplant has not been previously described in a patient with Leigh Syndrome. CASE PRESENTATION: We report a 21-year-old Han Chinese man who presented with limb weakness and unsteady gait, which progressed rapidly over a period of months until he was wheelchair-bound. He subsequently developed ESRD and was commenced on hemodialysis. Investigations revealed a m.13513G > A mutation with clinical and radiological features consistent with LS. His mitochondrial disease stabilised and he underwent a multidisciplinary assessment for deceased donor kidney transplantation to identify and minimise the LS-associated perioperative risks and potential negative effects of immunosuppressants on his LS. Successful kidney transplantation followed with excellent graft function three and a half years post-transplant and improvement in the patient's physical function. CONCLUSION: This case highlights the importance of careful pre-transplant perioperative risk assessment and post-transplant care in a rare and heterogeneous neurological disease to achieve an ultimately excellent clinical outcome. To our knowledge, this is the first report of successful deceased donor kidney transplant in a patient with known LS.

Emotion recognition in Parkinson's disease: Static and dynamic factors.

OBJECTIVE: The authors tested the hypothesis that Parkinson's disease (PD) participants would perform better in an emotion recognition task with dynamic (video) stimuli compared to a task using only static (photograph) stimuli and compared performances on both tasks to healthy control participants. METHOD: In a within-subjects study, 21 PD participants and 20 age-matched healthy controls performed both static and dynamic emotion recognition tasks. The authors used a 2-way analysis of variance (controlling for individual participant variance) to determine the effect of group (PD, control) on emotion recognition performance in static and dynamic facial recognition tasks. RESULTS: Groups did not significantly differ in their performances on the static and dynamic tasks; however, the trend was suggestive that PD participants performed worse than controls. CONCLUSIONS: PD participants may have subtle emotion recognition deficits that are not ameliorated by the addition of contextual cues, similar to those found in everyday scenarios. Consistent with previous literature, the results suggest that PD participants may have underlying emotion recognition deficits, which may impact their social functioning. (PsycINFO Database Record

Arytenoid cartilage movements are hypokinetic in Parkinson's disease: A quantitative dynamic computerised tomographic study.

BACKGROUND: Voice change is one of the earliest features of Parkinson's disease. However, quantitative studies of vocal fold dynamics which are needed to provide insight into disease biology, aid diagnosis, or track progression, are few. METHODS: We therefore quantified arytenoid cartilage movements and glottic area during repeated phonation in 15 patients with Parkinson's disease (symptom duration < 6 years) and 19 controls, with 320-slice computerised tomography (CT). We related these measures to perceptual voice evaluations and spirometry. We hypothesised that Parkinson's disease patients have a smaller inter-arytenoid distance, a preserved or larger glottic area because vocal cord bowing has previously been reported, less variability in loudness, more voice dysdiadochokinesis and breathiness and a shortened phonation time because of arytenoid hypokinesis relative to glottic area. RESULTS: Inter-arytenoid distance in Parkinson's disease patients was moderately smaller (Mdn = 0.106, IQR = 0.091-0.116) than in controls (Mdn = 0.132, IQR = 0.116-0.166) (W = 212, P = 0.015, r = -0.42), normalised for anatomical and other inter-subject variance, analysed with two-tailed Wilcoxon's rank sum test. This finding was confirmed in a linear mixed model analysis-Parkinson's disease significantly predicted a reduction in the dependent variable, inter-arytenoid distance (b = -0.87, SEb = 0.39, 95% CI [-1.66, -0.08], t(31) = -2.24, P = 0.032). There was no difference in glottic area. On perceptual voice evaluation, patients had more breathiness and dysdiadochokinesis, a shorter maximum phonation time, and less variability in loudness than controls. There was no difference in spirometry after adjustment for smoking history. CONCLUSIONS: As predicted, vocal fold adduction movements are reduced in Parkinson's disease on repeated phonation but glottic area is maintained. Some perceptual characteristics of Parkinsonian speech reflect these changes. We are the first to use 320-slice CT to study laryngeal motion. Our findings indicate how Parkinson's disease affects intrinsic laryngeal muscle position and excursion.

Arytenoid cartilage feature point detection using laryngeal 3D CT images in Parkinson's disease.

Parkinson's disease is a neurodegenerative disorder that results in progressive degeneration of nerve cells. It is generally associated with the deficiency of dopamine, a neurotransmitter involved in motor control of humans and thus affects the motor system. This results in abnormal vocal fold movements in majority of the Parkinson's patients. Analysis of vocal fold abnormalities may provide useful information to assess the progress of Parkinson's disease. This is accomplished by measuring the distance between the arytenoid cartilages during phonation. In order to automate this process of identifying arytenoid cartilages from CT images, in this work, a rule-based approach is proposed to detect the arytenoid cartilage feature points on either side of the airway. The proposed technique detects feature points by localizing the anterior commissure and analyzing airway boundary pixels to select the optimal feature point based on detected pixels. The proposed approach achieved 83.33% accuracy in estimating clinically-relevant feature points, making the approach suitable for automated feature point detection. To the best of our knowledge, this is the first such approach to detect arytenoid cartilage feature points using laryngeal 3D CT images.

Optokinetic nystagmus reflects perceptual directions in the onset binocular rivalry in Parkinson's disease.

Optokinetic nystagmus (OKN), the reflexive eye movements evoked by a moving field, has recently gained interest among researchers as a useful tool to assess conscious perception. When conscious perception and stimulus are dissociated, such as in binocular rivalry-when dissimilar images are simultaneously presented to each eye and perception alternates between the two images over time-OKN correlates with perception rather than with the physical direction of the moving field. While this relationship is well established in healthy subjects, it is yet unclear whether it also generalizes to clinical populations, for example, patients with Parkinson's disease. Parkinson's disease is a motor disorder, causing tremor, slow movements and rigidity. It may also be associated with oculomotor deficits, such as impaired saccades and smooth pursuit eye movements. Here, we employed short-duration, onset binocular rivalry (2 s trial of stimulus presentation followed by 1 s inter-trial interval) with moving grating stimuli to assess OKN in Parkinson's disease patients (N = 39) and controls (N = 29) of a similar age. Each trial was either non-rivalrous (same stimuli presented to both eyes) or rivalrous, as in binocular rivalry. We analyzed OKN to discriminate direction of stimulus and perception on a trial-by-trial basis. Although the speed of slow-phase OKN was slower in the patients, discriminability of conscious perception based on OKN was comparable between the groups. Treatment with anti-Parkinson drugs and deep brain stimulation improved motor ability of patients, but did not impact on OKN. Furthermore, OKN-based measures were robust and their latencies were shorter than manual button-based measures in both groups and stimulus conditions. To our knowledge, our study is the first to demonstrate that OKN can be used as a reliable indicator of conscious perception in binocular rivalry even in Parkinson's disease patients in whom impaired manual dexterity may render button-press reports less reliable.

Parkinson's disease alters multisensory perception: Insights from the Rubber Hand Illusion.

BACKGROUND: Manipulation of multisensory integration induces illusory perceptions of body ownership. Patients with Parkinson's disease (PD), a neurodegenerative disorder characterised by striatal dopamine deficiency, are prone to illusions and hallucinations and have sensory deficits. Dopaminergic treatment also aggravates hallucinations in PD. Whether multisensory integration in body ownership is altered by PD is unexplored. OBJECTIVE: To study the effect of dopamine neurotransmission on illusory perceptions of body ownership. METHODS: We studied the Rubber Hand Illusion (RHI) in 21 PD patients (on- and off-medication) and 21 controls. In this experimental paradigm, synchronous stroking of a rubber hand and the subject's hidden real hand results in the illusory experience of 'feeling' the rubber hand, and proprioceptive mislocalisation of the real hand towards the rubber hand ('proprioceptive drift'). Asynchronous stroking typically attenuates the RHI. RESULTS: The effect of PD on illusory experience depended on the stroking condition (b = -2.15, 95% CI [-3.06, -1.25], p < .0001): patients scored questionnaire items eliciting the RHI experience higher than controls in the illusion-attenuating (asynchronous) condition, but not in the illusion-promoting (synchronous) condition. PD, independent of stroking condition, predicted greater proprioceptive drift (b = 15.05, 95% CI [6.05, 24.05], p = .0022); the longer the disease duration, the greater the proprioceptive drift. However, the RHI did not affect subsequent reaching actions. On-medication patients scored both illusion (critical) and mock (control) questionnaire items higher than when off-medication, an effect that increased with disease severity (log (OR) =.014, 95% CI [.01, .02], p < .0001). CONCLUSION: PD affects illusory perceptions of body ownership in situations that do not typically induce them, implicating dopamine deficit and consequent alterations in cortico-basal ganglia-thalamic circuitry in multisensory integration. Dopaminergic treatment appears to increase suggestibility generally rather than having a specific effect on own-body illusions, a novel finding with clinical and research implications.