Automating the analysis of eye movement for different neurodegenerative disorders.

The clinical observation and assessment of extra-ocular movements is common practice in assessing neurodegenerative disorders but remains observer-dependent. In the present study, we propose an algorithm that can automatically identify saccades, fixation, smooth pursuit, and blinks using a non-invasive eye tracker. Subsequently, response-to-stimuli-derived interpretable features were elicited that objectively and quantitatively assess patient behaviors. The cohort analysis encompasses persons with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), Parkinson's disease mimics (PDM), and controls (CTRL). Overall, results suggested that the AD/MCI and PD groups had significantly different saccade and pursuit characteristics compared to CTRL when the target moved faster or covered a larger visual angle during smooth pursuit. These two groups also displayed more omitted antisaccades and longer average antisaccade latency than CTRL. When reading a text passage silently, people with AD/MCI had more fixations. During visual exploration, people with PD demonstrated a more variable saccade duration than other groups. In the prosaccade task, the PD group showed a significantly smaller average hypometria gain and accuracy, with the most statistical significance and highest AUC scores of features studied. The minimum saccade gain was a PD-specific feature different from CTRL and PDM. These features, as oculographic biomarkers, can be potentially leveraged in distinguishing different types of NDs, yielding more objective and precise protocols to diagnose and monitor disease progression.

Interpretable speech features vs. DNN embeddings: What to use in the automatic assessment of Parkinson's disease in multi-lingual scenarios.

Speech-based approaches for assessing Parkinson's Disease (PD) often rely on feature extraction for automatic classification or detection. While many studies prioritize accuracy by using non-interpretable embeddings from Deep Neural Networks, this work aims to explore the predictive capabilities and language robustness of both feature types in a systematic fashion. As interpretable features, prosodic, linguistic, and cognitive descriptors were adopted, while x-vectors, Wav2Vec 2.0, HuBERT, and TRILLsson representations were used as non-interpretable features. Mono-lingual, multi-lingual, and cross-lingual machine learning experiments were conducted leveraging six data sets comprising speech recordings from various languages: American English, Castilian Spanish, Colombian Spanish, Italian, German, and Czech. For interpretable feature-based models, the mean of the best F1-scores obtained from each language was 81% in mono-lingual, 81% in multi-lingual, and 71% in cross-lingual experiments. For non-interpretable feature-based models, instead, they were 85% in mono-lingual, 88% in multi-lingual, and 79% in cross-lingual experiments. Firstly, models based on non-interpretable features outperformed interpretable ones, especially in cross-lingual experiments. Specifically, TRILLsson provided the most stable and accurate results across tasks and data sets. Conversely, the two types of features adopted showed some level of language robustness in multi-lingual and cross-lingual experiments. Overall, these results suggest that interpretable feature-based models can be used by clinicians to evaluate the deterioration of the speech of patients with PD, while non-interpretable feature-based models can be leveraged to achieve higher detection accuracy.

Perry Disease: Expanding the Genetic Basis.

Background: Perry disease (or Perry syndrome [PS]) is a hereditary neurodegenerative disorder inevitably leading to death within few years from onset. All previous cases with pathological confirmation were caused by mutations within the cytoskeleton-associated protein glycine-rich (CAP-Gly) domain of the DCTN1 gene. Objectives: This paper presents the first clinicopathological report of PS due to a novel DCTN1 mutation outside the CAP-Gly domain. Methods: Clinical and pathological features of the new variant carrier are compared with another recently deceased PS case with a well-known pathogenic DCTN1 mutation and other reported cases. Results and Conclusions: We report a novel DCTN1 mutation outside the CAP-Gly domain that we demonstrated to be pathogenic based on clinical and autopsy findings.

Multilingual evaluation of interpretable biomarkers to represent language and speech patterns in Parkinson's disease.

Motor impairments are only one aspect of Parkinson's disease (PD), which also include cognitive and linguistic impairments. Speech-derived interpretable biomarkers may help clinicians diagnose PD at earlier stages and monitor the disorder's evolution over time. This study focuses on the multilingual evaluation of a composite array of biomarkers that facilitate PD evaluation from speech. Hypokinetic dysarthria, a motor speech disorder associated with PD, has been extensively analyzed in previously published studies on automatic PD evaluation, with a relative lack of inquiry into language and task variability. In this study, we explore certain acoustic, linguistic, and cognitive information encoded within the speech of several cohorts with PD. A total of 24 biomarkers were analyzed from American English, Italian, Castilian Spanish, Colombian Spanish, German, and Czech by conducting a statistical analysis to evaluate which biomarkers best differentiate people with PD from healthy participants. The study leverages conceptual robustness as a criterion in which a biomarker behaves the same, independent of the language. Hence, we propose a set of speech-based biomarkers that can effectively help evaluate PD while being language-independent. In short, the best acoustic and cognitive biomarkers permitting discrimination between experimental groups across languages were fundamental frequency standard deviation, pause time, pause percentage, silence duration, and speech rhythm standard deviation. Linguistic biomarkers representing the length of the narratives and the number of nouns and auxiliaries also provided discrimination between groups. Altogether, in addition to being significant, these biomarkers satisfied the robustness requirements.

Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65-Associated Stiff Person Syndrome Spectrum Disorder.

ABSTRACT: A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild-moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a wide-based stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and real-time quaking-induced conversion (RT-QuIC). However, her anti-glutamic acid decarboxylase-65 (GAD65) immunoglobulin G (IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0-5 IU/mL) and in CSF to 18.1 nmol/L (reference range <0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cerebellar workup should be considered.

Parkinsonics: A Randomized, Blinded, Cross-Over Trial of Group Singing for Motor and Nonmotor Symptoms in Idiopathic Parkinson Disease.

Introduction: Parkinson's disease (PD) frequently causes communication difficulties due to various voice impairments and there are few treatment options for vocal/communication complaints. We assessed the effects of weekly group singing on PD patients' objective vocal and motoric function, cognition, mood, self-efficacy, and quality of life. Methods: Thirty-two participants were randomly assigned to either a singing group or a facilitated discussion group weekly over 12 weeks. After 12 weeks, participants crossed over for an additional 12 weeks. Evaluations were performed at baseline and every six weeks for 30 weeks. Objective voice measures included volume/loudness (decibels), held vowel duration, jitter, shimmer, and harmonic-to-noise ratio. Additional outcome measures included patient-centered quality of life, voice-related quality of life, MDS-UPDRS, Montreal Cognitive Assessment, and questionnaires assessing depression, self-efficacy, and overall well-being. Results: Twenty-six participants (16 M/10F; Hoehn & Yahr stage 2.3 (range 2-3); and age 68.6 (55-89)) completed the study. Across participants in both groups (intention-to-treat analyses), there was significant improvement from baseline in average loudness on the Cookie Theft picture description at 24 weeks (end of interventions), corresponding with improved minimal reading volumes at 24 weeks and 30 weeks (end of study). Similarly, there were improvements in minimal loudness on Rainbow passage reading at 24 and 30 weeks. There were improvements observed in the Emotional Well-Being (mean delta -12.7 points, p = 0.037) and Body Discomfort (mean delta -18.6 points, p = 0.001) domains of the PDQ-39 from baseline to week 24 in the overall cohort and greater improvement in the Communication domain for Group S than Group D after 12 weeks of singing (delta -12.9 points, p = 0.016). Baseline differences between the participant groups (age, gender, Hoehn & Yahr stage, and several voice loudness measures) and observed improvements during the weekly discussion group period limited our ability to attribute all of the above results specifically to singing (per-protocol analyses). No significant changes in other assessed outcome measures were found. Conclusions: Weekly group singing may improve some aspects of conversational voice volume and quality of life in PD. Some improvements were sustained at least six weeks after interventions ended. Further investigations of the mechanism of benefit and randomized controlled studies (without crossover) to assess the longitudinal effects of singing in PD are necessary.

Pearls & Oy-sters: Deep Phenotyping of Abnormal Eye Movements Advances the Detection of Gerstmann-Sträussler-Scheinker Syndrome.

A 58-year-old previously healthy woman presents with 3 years of rapidly progressive ataxia, parkinsonism, dysautonomia, peripheral neuropathy, leg weakness, spasticity, hyperreflexia, and mild vertical-gaze palsy. She has a matrilineal family history of neurodegenerative diseases. She was initially postulated to have spinocerebellar ataxia or atypical parkinsonism with cerebellar features. However, on closer inspection, her abnormal extraocular eye movements suggested rare mimicking disorders such as prion disease as part of the differential diagnosis, requiring further evaluation. This case highlights how deep phenotyping can open new diagnostic considerations, inform additional workup, and yield the precise diagnosis of Gerstmann-Sträussler-Scheinker syndrome (GSS).

The association between educational attainment and SCA 3 age of onset and disease course.

BACKGROUND: The number of trinucleotide CAG repeats is inversely correlated with the age at onset (AAO) of motor symptoms in individuals with Spinocerebellar Ataxia type 3 (SCA 3) and may be responsible for 50%-60% of the variability in AAO. Drawing from a social determinants of health model, we sought to determine if educational attainment further contributes to the AAO and motor symptom progression of SCA 3. METHODS: We performed a retrospective chart review in which twenty individuals met criteria for inclusion and had been seen by an ataxia specialist at our hospital between January 2005 and July 2019. AAO of motor symptoms and Scale for Assessment and Rating of Ataxia (SARA) scores were used as primary outcome measures. RESULTS: Using a linear regression, we found that having greater CAG repeat length and greater than 16 years of education results in an earlier AAO. The importance of the CAG repeat length on AAO, however, is greater amongst individuals with lower education. Using a linear mixed model evaluating SARA score over time with AAO, we found that less than 16 years of education is associated with faster progression of the disease. CONCLUSION: In our group of SCA 3 patients, level of education correlated with both the AAO and SARA scores. Though our findings need to be confirmed with a larger cohort, our study suggests that level of education can have a strong influence on health outcomes in SCA 3 and possibly other groups of patients with ataxia.

Global Variability in Deep Brain Stimulation Practices for Parkinson's Disease.

INTRODUCTION: Deep brain stimulation (DBS) has become a standard treatment option for select patients with Parkinson's disease (PD). The selection process and surgical procedures employed have, to date, not been standardized. METHODS: A comprehensive 58-question web-based survey was developed with a focus on DBS referral practices and peri-operative management. The survey was distributed to the Parkinson's Foundation Centers of Excellence, members of the International Parkinson's Disease and Movement Disorders Society, and the Parkinson Study Group (Functional Neurosurgery Working Group) between December 2015 and May 2016. RESULTS: There were 207 individual respondents (20% response rate) drawn from 59 countries and 6 continents, of whom 64% received formal training in DBS. Thirteen percent of centers reported that DBS could proceed despite a confidence level of < 50% for PD diagnosis. A case-based approach to DBS candidacy was applied in 51.3% of centers without a cut-off for levodopa-responsiveness. Surprisingly, 33% of centers regularly used imaging for diagnostic confirmation of idiopathic PD. Thirty-one percent of centers reported that neuropsychological evaluation did not affect DBS target selection. Approximately half of the respondents reported determination of DBS candidacy based on a multidisciplinary committee evaluation and 1/3 rd reported that a committee was used for target selection. Eight percent of respondents felt that psychosocial factors should not impact DBS candidacy nor site selection. Involvement of allied health professionals in the preoperative process was sparse. There was high variability in preoperative education about DBS outcome expectations. Approximately half of the respondents did not utilize a "default brain target," though STN was used more commonly than GPi. Specific DBS procedure techniques applied, as well as follow-up timelines, were highly variable. CONCLUSION: Results revealed high variability on the best approaches for DBS candidate selection, brain target selection, procedure type, and postoperative practices. Cognitive and mood assessments were underutilized. There was low reliance on multidisciplinary teams or psychosocial factors to impact the decision-making process. There were small but significant differences in practice across global regions, especially regarding multidisciplinary teams. The wide variability of responses across multiple facets of DBS care highlights the need for prospective studies to inform evidence-based guidelines.

Brainstem Pathologies Correlate With Depression and Psychosis in Parkinson's Disease.

BACKGROUND: The pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus. METHODS: The brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants' history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation. RESULTS: Of the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ2 = 7.1, p = 0.008, df = 1) and depression (χ2 = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5-6.4, χ2 = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3-5.0, χ2 = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra. CONCLUSION: These results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.

Non-staged bilateral Globus Pallidus Internus deep brain stimulation lead revision using intraoperative MRI: a case report and literature review.

BACKGROUND: Deep brain stimulation (DBS) lead revision due to suboptimal therapy is common but there is no standardised protocol. We describe a novel technique using iMRI to perform concurrent new Globus Pallidus Internus (GPi) DBS lead implantation and old lead removal in a dystonia patient.Case-description: A 60-year-old woman with medication and neurotoxin-refractory isolated cervical dystonia underwent awake bilateral GPi DBS surgery with MER-guided lead implantation. She initially had a favourable response but later reported suboptimal benefit despite reprogramming. MRI demonstrated suboptimal lead placement and MRI-guided revision surgery under general anesthesia was planned. The goal was to place new leads superior and medial to the existing leads. Using a 1.5 T iMRI and the ClearPoint® NeuroNavigation system, new leads were placed through the existing burr holes, into the new targets with radial errors < 0.08mm bilaterally without crossing the old leads. The old leads were then removed and the new leads connected to the existing pulse generator. The patient tolerated the procedure well and had improved side-effect profile at all contacts at 1-month follow-up. CONCLUSIONS: Non-staged iMRI-guided DBS revision surgery under general anesthesia is technically feasible and is an alternative strategy to a staged iMRI-guided revision surgery or an awake MER-guided revision surgery in select patients.

Neuropsychiatric aspects of Parkinson disease psychopharmacology: Insights from circuit dynamics.

Parkinson disease (PD) is a neurodegenerative disorder with a complex pathophysiology characterized by the progressive loss of dopaminergic neurons within the substantia nigra. Persons with PD experience several motoric and neuropsychiatric symptoms. Neuropsychiatric features of PD include depression, anxiety, psychosis, impulse control disorders, and apathy. In this chapter, we will utilize the National Institutes of Mental Health Research Domain Criteria (RDoC) to frame and integrate observations from two prevailing disease constructions: neurotransmitter anomalies and circuit physiology. When there is available evidence, we posit how unified translational observations may have clinical relevance and postulate importance outside of PD. Finally, we review the limited evidence available for pharmacologic management of these symptoms.

MAPT p.V363I mutation: A rare cause of corticobasal degeneration.

OBJECTIVE: Patients with corticobasal syndrome (CBS) present with heterogeneous clinical features, including asymmetric parkinsonism, dyspraxia, aphasia, and cognitive impairment; to better understand the genetic etiology of this rare disease, we undertook a genetic analysis of microtubule-associated protein tau (MAPT). METHODS: We performed a genetic evaluation of MAPT mutations in 826 neurologically healthy controls and 173 cases with CBS using the Illumina NeuroChip genotyping array. RESULTS: We identified 2 patients with CBS heterozygous for a rare mutation in MAPT (p.V363I) that is located in the highly conserved microtubule-binding domain. One patient was pathologically confirmed and demonstrated extensive 4-repeat-tau-positive thread pathology, achromatic neurons, and astrocytic plaques consistent with corticobasal degeneration (CBD). CONCLUSIONS: We report 2 CBS cases carrying the rare p.V363I MAPT mutation, one of which was pathologically confirmed as CBD. Our findings support the notion that this rare coding change is pathogenic.

Expansion of the clinical spectrum associated with AARS2-related disorders.

Biallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl-tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult-onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51-year-old man with adult-onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34-year-old man with childhood-onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57-year-old woman with childhood-onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2-related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult-onset AARS2-related neurological decline without leukodystrophy, and the third is biallelic AARS2-related disorder involving a partial gene deletion.

Suicide in Parkinson's disease.

Persons with Parkinson's disease (PwP) have many known risk factors for suicide and suicidal ideation (SI). Despite this, there is limited understanding of suicidality in this population. We conducted a systematic review to synthesise the available literature on suicidality in PwP and highlight areas for potential intervention and further research. We identified 116 articles discussing SI, suicidal behaviours, suicide attempts and/or fatal suicide in PwP. These articles describe prevalence, suicide methods, risk factors for suicide and SI and treatment of suicidality. In this review, we summarise the current literature and provide suggestions for how clinicians can identify and treat PwP who are at risk for suicide, for example, through aggressive treatment of depression and improved screening for access to lethal means.

Dopamine transporter availability reflects gastrointestinal dysautonomia in early Parkinson disease.

BACKGROUND: Constipation is a prodromal feature of Parkinson's disease (PD) and the gastrointestinal (GI) tract is implicated in the pathogenesis of PD. However, no studies have demonstrated ante-mortem relationships between nigrostriatal dysfunction and GI dysautonomia in PD. METHODS: The Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOPA-AUT) assesses dysautonomia in the multi-center Parkinson's Progression Marker Initiative (PPMI). We used linear mixed-effects models and reliable change indices (RCIs) to examine longitudinal associations between dysautonomia and dopamine transporter (DAT) striatal binding ratios (SBRs) measured by single-photon emission computerized tomography in PPMI participants over four years (n = 397 at baseline). RESULTS: Adjusted mixed-models of longitudinal data showed that constipation-but not orthostatic hypotension or urinary dysfunction-was associated with reduced SBR in both caudate (P < 0.001) and putamen (P = 0.040). In both regions, SBR reductions between baseline and 4-year follow-up were significant and measurable (P < 0.0001), with larger decline and variance in the caudate nucleus. Four-year change in caudate-but not putaminal-SBR was significantly associated with RCI-indicated progression of GI dysautonomia (P = 0.031), but not other types of dysautonomia. These associations remained after adjusting for the use of medications or supplements to control constipation. Consistent with prior PPMI reports, motor impairment progression was not associated with SBR reduction. CONCLUSIONS: GI dysautonomia correlates with reductions in DAT availability; constipation is most closely associated with caudate-DAT reduction. Worsening GI-dysautonomia and reduced bowel movements may accompany advancing nigral degeneration or changes in nigrostriatal dopamine function.

MR-Guided Functional Neurosurgery: Laser Ablation and Deep Brain Stimulation.

Intraoperative magnetic resonance imaging (iMRI) is increasingly implemented for image-guided procedures in functional neurosurgery. iMRI facilitates accurate electrode implantation for deep brain stimulation (DBS) and is currently an alternative method for DBS electrode targeting. The application of iMRI also allows for greater accuracy and precision in laser-induced thermal therapy (LITT). The expanding use of functional neurosurgical procedures makes safety and feasibility of iMRI important considerations, particularly in patients with comorbidities or complex medical histories. We review here the applications of iMRI and discuss its safety, feasibility, and limitations in functional neurosurgery.To motivate discussion of this topic, we also present a 52-year-old patient with an implanted cardioverter-defibrillator (ICD) who successfully underwent iMRI-guided DBS electrode implantation for advanced Parkinson disease (PD). Neither iMRI nor the passage of electrical current through the implanted DBS electrodes demonstrated detectable interference in ICD function. This case demonstrates that, even in complex clinical contexts, iMRI is a promising tool that merits further exploration for procedures requiring highly accurate and precise identification of target structures.