AI-based differential diagnosis of dementia etiologies on multimodal data.

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an AI model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a micro-averaged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the micro-averaged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in various clinical settings and drug trials, with promising implications for person-level management.

Genetic Mapping and Phenotypic Analysis of GstE14 E.4.1 on Eye and Antennae Development in Drosophila melanogaster.

Genetic screens are valuable for identifying novel genes involved in the regulation of developmental processes. To identify genes associated with cell growth regulation in Drosophila melanogaster , a mutagenesis screen was performed. Undergraduate students participating in Fly-CURE phenotypically characterized the E.4.1 mutant which is associated with rough eyes and antennae overgrowth. Following complementation analysis and subsequent genomic sequencing, E.4.1 was identified as a novel mutant allele of GstE14 , a gene involved in ecdysone biosynthesis important for the timing of developmental events. The abnormal eye and antenna phenotypes observed resulting from the loss of GstE14 suggest its role in tissue growth.

Global Epidemiology of Movement Disorders: Rare or Underdiagnosed?

In this manuscript, we review the epidemiology of movement disorders including Parkinson's disease (PD), atypical parkinsonism, essential tremor, dystonia, functional movement disorders, tic disorders, chorea, and ataxias. We emphasize age-, sex-, and geography-based incidence and prevalence, as well as notable trends including the rising incidence and prevalence of PD. Given the growing global interest in refining clinical diagnostic skills in recognizing movement disorders, we highlight some key epidemiological findings that may be of interest to clinicians and health systems tasked with diagnosing and managing the health of patients with movement disorders.

COVID19-associated new-onset movement disorders: a follow-up study.

BACKGROUND: Neurological symptoms are common manifestation in acute COVID-19. This includes hyper- and hypokinetic movement disorders. Data on their outcome, however, is limited. METHODS: Cases with new-onset COVID-19-associated movement disorders were identified by searching the literature. Authors were contacted for outcome data which were reviewed and analyzed. RESULTS: Movement disorders began 12.6 days on average after the initial onset of COVID-19. 92% of patients required hospital admission (mean duration 23 days). In a fraction of patients (6 of 27; 22%; 4 males/2 females, mean age 66.8 years) the movement disorder (ataxia, myoclonus, tremor, parkinsonism) was still present after a follow-up period of 7.5 ± 3 weeks. Severe COVID-19 in general and development of encephalopathy were risk factors, albeit not strong predictors, for the persistence. CONCLUSIONS: The prognosis of new-onset COVID-19-associated movement disorder appears to be generally good. The majority recovered without residual symptoms within several weeks or months. Permanent cases may be due to unmasking of a previous subclinical movement disorder or due to vascular/demyelinating damage. Given the relatively low response rate of one third only and the heterogeneity of mechanisms firm conclusions on the (long-term) outome cannot, however, be drawn.

'One student might get one opportunity and then the next student won't get anything like that': Inequities in Australian career education and recommendations for a fairer future.

Access to quality career advice is important for economic, personal and equity reasons, yet, in many countries around the world, career-education provision is of varying quality and quantity within school settings. Given the inconsistencies in career-education resourcing and provision, what is not clearly understood is how students from low socioeconomic status (low SES) backgrounds experience career-education provision and the extent to which it shapes their post-school futures. Drawing on Australian research, this paper explores the career-education experiences of high-school students from low SES backgrounds. Bourdieu's tools of field, habitus and capital are used as a theoretical framework to understand how career education can influence students' imagining and achieving their career goals. The findings reported in this paper contribute nuanced understandings of career education to students from low SES backgrounds and recommends how all students can benefit from an embedded approach to career education in schools.

Multimodal deep learning for Alzheimer's disease dementia assessment.

Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer's disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis.

Neurogenetic disorders across the lifespan: from aberrant development to degeneration.

Intellectual disability and autism spectrum disorder (ASD) are common, and genetic testing is increasingly performed in individuals with these diagnoses to inform prognosis, refine management and provide information about recurrence risk in the family. For neurogenetic conditions associated with intellectual disability and ASD, data on natural history in adults are scarce; however, as older adults with these disorders are identified, it is becoming clear that some conditions are associated with both neurodevelopmental problems and neurodegeneration. Moreover, emerging evidence indicates that some neurogenetic conditions associated primarily with neurodegeneration also affect neurodevelopment. In this Perspective, we discuss examples of diseases that have developmental and degenerative overlap. We propose that neurogenetic disorders should be studied continually across the lifespan to understand the roles of the affected genes in brain development and maintenance, and to inform strategies for treatment.

Neuropathological Findings in a Case of Parkinsonism and Developmental Delay Associated with a Monoallelic Variant in PLXNA1.

BACKGROUND: PLXNA1 encodes for Plexin-A, a transmembrane protein expressed in the developing nervous system. Mutations in this gene have been associated with developmental delay but have not been previously associated with the development of parkinsonism. OBJECTIVES: To describe the case of a 38-year-old patient with developmental delay who developed parkinsonism later in life. METHODS: Post-mortem exome sequencing was performed with confirmation by Sanger sequencing. Brain autopsy was also performed. RESULTS: Post-mortem exome sequencing on the proband identified a heterozygous predicted nonsense PLXNA1 variant (c.G3361T:p.Glu1121Ter). Pathology demonstrated arhinencephaly with brainstem heterotopia, diffuse Lewy body disease, and frontotemporal lobar dementia-tau. CONCLUSIONS: This case of a patient with developmental delay and parkinsonism with PLXNA1 mutation highlights a need for assessing long-term outcomes of individuals with neurodevelopmental disorders, as well as the need for genetic testing in adults. It also suggests that the link between PLXNA1 and α-synuclein should be explored in the future. © 2021 International Parkinson and Movement Disorder Society.

Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.

PURPOSE: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. METHODS: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. RESULTS: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. CONCLUSION: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.

Neuropathological correlation supports automated image-based differential diagnosis in parkinsonism.

PURPOSE: Up to 25% of patients diagnosed as idiopathic Parkinson's disease (IPD) have an atypical parkinsonian syndrome (APS). We had previously validated an automated image-based algorithm to discriminate between IPD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). While the algorithm was accurate with respect to the final clinical diagnosis after long-term expert follow-up, its relationship to the initial referral diagnosis and to the neuropathological gold standard is not known. METHODS: Patients with an uncertain diagnosis of parkinsonism were referred for 18F-fluorodeoxyglucose (FDG) PET to classify patients as IPD or as APS based on the automated algorithm. Patients were followed by a movement disorder specialist and subsequently underwent neuropathological examination. The image-based classification was compared to the neuropathological diagnosis in 15 patients with parkinsonism. RESULTS: At the time of referral to PET, the clinical impression was only 66.7% accurate. The algorithm correctly identified 80% of the cases as IPD or APS (p = 0.02) and 87.5% of the APS cases as MSA or PSP (p = 0.03). The final clinical diagnosis was 93.3% accurate (p < 0.001), but needed several years of expert follow-up. CONCLUSION: The image-based classifications agreed well with autopsy and can help to improve diagnostic accuracy during the period of clinical uncertainty.

Training in Neurology: Feedback from Graduates About the Psychiatry Component of Residency Training.

OBJECTIVE: To obtain feedback from early career adult and pediatric neurologists about the psychiatry component of residency training. METHODS: A survey was developed and administered electronically to 4 cohorts of recently certified American Board of Psychiatry and Neurology diplomates. RESULTS: The response rate was 16% (431/2,677) and included 330 adult neurologists and 101 pediatric neurologists. Fewer than half of the respondents described themselves as extremely or quite satisfied with their psychiatry training whereas 26% of the adult neurologists and 33% of the pediatric neurologists felt slightly or not at all prepared for this component of practice. Four themes were identified in the respondents' suggestions for improving psychiatry training: provide more outpatient experience; provide more time/teaching in psychiatry; provide more experience with both pharmacologic and nonpharmacologic psychiatric treatments; and provide more exposure to patients with conditions likely to be encountered in neurology/child neurology practice. CONCLUSION: These recent graduates of adult and pediatric neurology residency programs felt underprepared for the psychiatric issues they encountered in their patients. They suggested a number of strategies for better alignment of psychiatry training with the likely demands of practice. A model curriculum recently developed by the American Academy of Neurology's Consortium of Neurology Program Directors and the American Association of Directors of Psychiatric Residency Training also provides guidance for both neurology and psychiatry program directors.

Vulnerable learners in the age of COVID-19: A scoping review.

This scoping review provides an overview of COVID-19 approaches to managing unanticipated school closures and available literature related to young people learning outside-of-school. A range of material has been drawn upon to highlight educational issues of this learning context, including psychosocial and emotional repercussions. Globally, while some countries opted for a mass school shut-down, many schools remained open for students from disadvantaged backgrounds. This partial closure not only enabled learning in smaller targeted groups but also offered a safe sanctuary for those who needed a regulated and secure environment. In Australia, if full school closures were to be enforced over a long period, a significant proportion of students from more vulnerable backgrounds would likely experience persistent disadvantage through a range of barriers: long-term educational disengagement, digital exclusion, poor technology management, and increased psychosocial challenges. This scoping review combines research on technology availability and learning, with analysis of the long-term educational impacts of navigating the COVID-19 disruption.

Myoclonus in Patients With Coronavirus Disease 2019: A Multicenter Case Series.

OBJECTIVES: To describe the risk factors for and outcomes after myoclonus in a cohort of patients with coronavirus disease 2019. DESIGN: Multicenter case series. SETTING: Three tertiary care hospitals in Massachusetts, Georgia, and Virginia. PATIENTS: Eight patients with clinical myoclonus in the setting of coronavirus disease 2019. INTERVENTIONS & MEASUREMENTS AND MAIN RESULTS: Outcomes in patients with myoclonus were variable, with one patient who died during the study period and five who were successfully extubated cognitively intact and without focal neurologic deficits. In five cases, the myoclonus completely resolved within 2 days of onset, while in three cases, it persisted for 10 days or longer. Seven patients experienced significant metabolic derangements, hypoxemia, or exposure to sedating medications that may have contributed to the development of myoclonus. One patient presented with encephalopathy and developed prolonged myoclonus in the absence of clear systemic provoking factors. CONCLUSIONS: Our findings suggest that myoclonus may be observed in severe acute respiratory syndrome coronavirus 2 infected patients, even in the absence of hypoxia. This association warrants further evaluation in larger cohorts to determine whether the presence of myoclonus may aid in the assessment of disease severity, neurologic involvement, or prognostication.

Patients With Vestibular Migraine are More Likely to Have Occipital Headaches than those With Migraine Without Vestibular Symptoms.

OBJECTIVE: To determine whether patients with vestibular migraine are more likely to suffer from an occipital headache than patients with migraine without vestibular symptoms. BACKGROUND: Vestibular migraine is an underdiagnosed disorder in which migraine is associated with vestibular symptoms. Anatomical evidence and symptomatology hint at the involvement of brain structures in the posterior fossa (back of the head location). We hypothesized that vestibular migraine patients are more likely than migraineurs without vestibular symptoms to experience headaches located in the back of the head, that is, occipital headaches. METHODS: A retrospective cross-sectional study was conducted at the University of Iowa Hospital and Clinics. Chart analysis of 169 patients was performed. The primary outcome was the location of the headache in vestibular migraine patients and migraineurs without vestibular symptoms. The secondary outcomes included the association of vestibular migraine with gender, age at onset of headache, age at onset of vestibular symptoms (such as vertigo, head motion-induced dizziness), aura, motion sickness, other associated symptoms, family history of headaches, and family history of motion sickness. RESULTS: In vestibular migraine group, 45/103 (44%) had occipital location for their headaches vs 12/66 (18%) in migraine patients without vestibular symptoms, for an odd's ratio of 3.5 (95% CI = 1.7-7.2, P < .001). Additionally, the age at onset of headache was greater in the vestibular migraine group (28 ± 12 vs 18 ± 9 years, P < .001) and motion sickness was more common (41/98 (42%) in the vestibular migraine group, 1/64 (2%) in the migraine without vestibular symptoms group, P < .001). CONCLUSIONS: This study suggests that patients with vestibular migraine are more likely to have occipital headaches than patients with migraine without vestibular symptoms. Our data support the initiation of a prospective study to determine whether a patient presenting with occipital headaches, with late onset of age of headache, and with a history of motion sickness is at an increased risk for the possible development of vestibular migraine.

Holmes Tremor due to Artery of Percheron Infarct: Clinical Case and Treatment Using Deep Brain Stimulation of the Vim and ZI Targets.

Background: Holmes tremor (HT) arises from disruption of the cerebellothalamocortical pathways. A lesion can interrupt the projection at any point, resulting in this tremor. We describe a case of HT due to the rare artery of Percheron infarct and its successful treatment using deep brain stimulation. Case report: A 62-year-old woman with a right medial cerebral peduncle and bilateral thalamic stroke developed HT. Ventral intermediate nucleus (Vim) zona incerta (ZI) deep brain stimulation (DBS) surgery was performed, with improvement in her tremor. Discussion: Our case supports the theory that the more caudal ZI target in combination with Vim is beneficial in treating poorly DBS-responsive tremors such as HT.

Urinary incontinence in adults with cerebral palsy: prevalence, type, and effects on participation.

OBJECTIVE: To assess the prevalence, type, and impact of urinary problems in adults with cerebral palsy and their relation with the Gross Motor Function Classification System for cerebral palsy. DESIGN: A cross-sectional prospective survey study. SETTING: An outpatient, urban, academic rehabilitation clinic. PARTICIPANTS: Ninety-one adults with cerebral palsy (45 women, 46 men). INTERVENTIONS: Subjects were approached at clinic presentation and were interviewed regarding current function, type and incidence of bladder issues, and concerns with bladder problems. MAIN OUTCOME MEASURES: The International Consultation on Incontinence Questionnaire-Female, or the International Consultation on Incontinence Questionnaire-Male Lower Urinary Tract Symptoms Module, Gross Motor Function Classification System, employment, and type of residence. RESULTS: The mean age for both women and men was 36 years (range, 18-79 years). The subjects were currently assessed with the Gross Motor Function Classification System scales I-V: I, 4.4%; II, 19.8%; III, 13.2%; IV, 40.7%; and V, 22.0%. 95.6% of females and 84.7% of males were living at home. Twenty-three percent were currently employed. Twenty percent of the women indicated that they had bladder urgency most to all of the time and 46.7% of the women had leakage that occurred 2-3 times per week to several times per day. In men, urgency that occurred more often than "occasionally" was reported by 45.7%, and 19.6% reported this occurred "most to all of the time." Multivariable analyses found that obesity compared with normal weight was significantly related to leaking before reaching a toilet (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.3-14.7), to leaking with cough, exercise, or sneeze (OR 5.6, 95% CI 1.3-23.1), and to nocturia (OR 5.4, 95% CI 1.2-25.1). Women were more likely to leak with cough, exercise, or sneeze (OR 5.5, 95% CI 1.5-20.0). On scales that indicate symptom interference with life, high levels of interference were reported for women with symptoms of leaking and for men with urgency and leaking. No significant differences in living situation or employment were related to incontinence scores for women or men. CONCLUSION: There are high levels of incontinence in adults with cerebral palsy, and these individuals report interference with quality of life. Despite these issues, most participants were living in the community, and incontinence scores were not related to employment.

Open pancreatic necrosectomy in the multidisciplinary management of postinflammatory necrosis.

OBJECTIVE: To examine clinical outcome in a consecutive cohort of patients undergoing open necrosectomy for postinflammatory necrosis. BACKGROUND INFORMATION: The last decade has witnessed major developments in the surgical management of pancreatic necrosis. Minimally invasive approaches have become established. However, there are limited data from contemporary open necrosectomy, in particular where multidisciplinary care and aggressive interventional radiology are used. This report provides data on outcome from open necrosectomy in a tertiary referral Hepatobiliary unit over the last decade. METHODS: During the period January 1, 2000 to July 31, 2008, 1535 patients were admitted with a final discharge code of acute pancreatitis. Twenty-eight (1.8%) of all admissions underwent open surgical necrosectomy. Twenty-four (86%) were tertiary referral patients. RESULTS: The median APACHE II score on admission was 10.5 (5-26). Median logistic organ dysfunction score on admission was 3 (0-10). Median LODS score after surgery was 2 (0-8). Twenty patients (71%) underwent radiologically guided drainage of collections before surgery. Thirty-day mortality occurred in 2 (7%), 4 further deaths occurred in patients after discharge from intensive care resulting in a total of 6 (22%) episode-related deaths. CONCLUSIONS: Modern open necrosectomy can be performed without the procedure-related deterioration in organ dysfunction associated with major debridement. Multidisciplinary care with an emphasis on aggressive radiologic intervention before and after surgery results in acceptable outcomes in this cohort of critically ill patients. Newer laparoscopic techniques must demonstrate similar outcomes in the setting of stage-matched severity before wider acceptance.

Iatrogenic addiction in patients treated for acute or subacute pain: a systematic review.

We conducted a systematic review of the literature on the evidence for iatrogenic addiction in patients treated for acute and subacute pain. Literature searches yielded 1,943 articles, 53 of which were reviewed in detail, and 41 of which met criteria for inclusion in the review of iatrogenic addiction. Two authors independently reviewed and summarized the findings of each article. Discrepancies of ratings were resolved by discussion. We identified no randomized trials or comparative longitudinal studies. The results of nine studies of low methodological quality suggest conflicting findings. This manuscript discusses some possible mechanisms of iatrogenic addiction and concludes with suggestions for methodologically stronger studies to provide more definitive data regarding the evidence for or against iatrogenic addiction in patients treated for acute and subacute pain. The systematic review of the literature could not adequately answer the study questions; thus, it is not known whether the risk for iatrogenic addiction among patients treated with opioids for acute or subacute pain is relatively high (> 10 percent) or low (< 0.1 percent).