Faculty Bibliography

OBJECTIVE:To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program. METHODS:Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established post-mortem. RESULTS:Using VirScan, enrichment of dengue viral antibodies were detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but post-mortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months ante-mortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system. INTERPRETATION/CONCLUSIONS:Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Further, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiologies. This article is protected by copyright. All rights reserved.

Cognitive impairment is frequent in progressive supranuclear palsy (PSP) and less common in multiple system atrophy (MSA), but characteristics and progression compared with Parkinson's disease (PD) need to be properly defined. We evaluated 35 PSP with Richardson's syndrome (PSP-RS), 30 MSA as well as 65 age-, sex-, and education-matched PD with an extensive clinical and neuropsychological assessment, allowing Level II cognitive diagnosis. Eighteen PSP, 12 MSA and 30 PD had a second evaluation between 12 and 18 months (mean 15 months) after the first assessment. PSP performance at Montreal Cognitive Assessment (MoCA), verbal fluencies (phonemic and semantic tasks), Stroop test (Error and Time), Digit Span Sequencing (DSS), incomplete letters of Visual Object and Space Perception (VOSP) and Benton's Judgment of Line Orientation (JLO) performance were significantly poorer at baseline compared to PD and MSA. Executive, language and visuospatial abilities declined longitudinally in PSP, but not in PD and MSA. After 1.5 year, 16% of PSP converted to dementia. Our study provides evidence that cognitive progression is more severe and rapid in PSP-RS than PD and MSA. Further, we observed that MoCA, verbal fluency (particularly semantic), DSS and Benton's JLO are valuable tests to detect cognitive progression in PSP-RS and may be proposed as possible biomarker to assess efficacy of disease modification strategies.

BACKGROUND:H MRS with the ability to separate tissue-type partial volume contribution(s). PURPOSE/OBJECTIVE:H MRSI voxel averaging is sensitive to regional WM metabolic abnormalities. STUDY TYPE/METHODS:Retrospective cross-sectional cohort study. POPULATION/METHODS:Twenty-seven subjects: 15 symptomatic mTBI patients, 12 matched controls. FIELD STRENGTH/SEQUENCE/UNASSIGNED:. ASSESSMENT/RESULTS:N-acetyl-aspartate (NAA), creatine, choline, and myo-inositol concentrations estimated in predominantly WM regions: body, genu, and splenium of the corpus callosum, corona radiata, frontal, and occipital WM. STATISTICAL TESTS/UNASSIGNED:Analysis of covariance (ANCOVA) to compare patients with controls in terms of regional concentrations. The effect sizes (Cohen's d) of the mean differences were compared across regions and with previously published global data obtained with linear regression of the WM over the entire VOI in the same dataset. RESULTS:Despite patients' global VOI WM NAA being significantly lower than the controls', no regional differences were observed for any metabolite. Regional NAA comparisons, however, were all unidirectional (patients' NAA concentrations < controls') within a narrow range: 0.3 ≤ Cohen's d ≤ 0.6. DATA CONCLUSION/UNASSIGNED:H MRS studies, given that these results are confirmed in other cohorts. LEVEL OF EVIDENCE/METHODS:2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019.

OBJECTIVE:To report a case of petrous apicitis that manifested as chronic migraine without aura and to discuss the pathophysiological mechanisms behind this presentation. BACKGROUND:Petrous apicitis is a rare complication of acute otitis media with varied clinical presentations that stem from the close proximity of the petrous apex to numerous neurovascular structures. Headache is among the common symptoms of petrous apicitis. METHODS:A case of new onset headache in the setting of petrous apicitis with symptomatic response to antibiotic therapy was reported. We provided a brief review of peripheral pathophysiological mechanisms of migraine and correlated to mechanism of headache in petrous apicitis. RESULTS:A 65-year-old man with chronic otitis externa/media presented with ongoing headache fulfilling International Classification of Headache Disorders 3rd edition (ICHD-3) criteria for chronic migraine without aura that persisted despite undergoing right mastoidectomy and tympanoplasty with multiple courses of oral antibiotic therapy for his chronic otitis. MRI brain revealed petrous apicitis, otomastoiditis, and clival osteomyelitis. His imaging findings improved and his migraine-like headache completely resolved after treatment with a prolonged course of antibiotics. CONCLUSIONS:Petrous apicitis can present as a headache with features of migraine, and in this case in particular, as chronic migraine without aura. The pathophysiological mechanisms that may underlie the generation of migraine-like headache in petrous apicitis may include the activation of nociceptive fibers within the periosteum of the petrous apex and clivus whose cell bodies originate in the trigeminal ganglion and upper cervical dorsal root ganglia. By treating the peripheral pathology, resolution of the headache may be achieved.

Cerebellar abnormalities are commonly reported in autism spectrum disorder (ASD). Dentate nuclei (DNs) are key structures in the anatomical circuits linking the cerebellum to the extracerebellum. Previous resting-state functional connectivity (RsFc) analyses reported DN abnormalities in high-functioning ASD (HF-ASD). This study examined the RsFc of the DN in young adults with HF-ASD compared with healthy controls (HCs) with the aim to expand upon previous findings of DNs in a dataset using advanced, imaging acquisition methods that optimize spatiotemporal resolution and statistical power. Additional seed-to-voxel analyses were carried out using motor and nonmotor DN coordinates reported in previous studies as seeds. We report abnormal dentato-cerebral and dentato-cerebellar functional connectivity in ASD. Our results expand and, in part, replicate previous descriptions of DN RsFc abnormalities in this disorder and reveal correlations between DN-cerebral RsFc and ASD symptom severity.

Myelin has traditionally been considered a static structure that is produced and assembled during early developmental stages. While this characterization is accurate in some contexts, recent studies have revealed that oligodendrocyte generation and patterns of myelination are dynamic and potentially modifiable throughout life. Unique structural and biochemical properties of the myelin sheath provide opportunities for the development and implementation of multimodal label-free and fluorescence optical imaging approaches. When combined with genetically encoded fluorescent tags targeted to distinct cells and subcellular structures, these techniques offer a powerful methodological toolbox for uncovering mechanisms of myelin generation and plasticity in the live brain. Here, we discuss recent advances in these approaches that have allowed the discovery of several forms of myelin plasticity in developing and adult nervous systems. Using these techniques, long-standing questions related to myelin generation, remodeling, and degeneration can now be addressed.

BACKGROUND:Recent studies estimate nearly half of the US population can access mobile medical applications (apps) on their smartphones. The are no systematic data available on apps focused on stroke survivors/caregivers. OBJECTIVE:To identify apps (a) designed for stroke survivors/caregivers, (b) dealing with a modifiable stroke risk factor (SRF), or (c) were developed for other purposes but could potentially be used by stroke survivors/caregivers. METHODS:A systematic review of the medical apps in the US Apple iTunes store was conducted between August 2013 and January 2016 using 18 predefined inclusion/exclusion criteria. SRFs considered were: diabetes, hypertension, smoking, obesity, atrial fibrillation, and dyslipidemia. RESULTS:Out of 30,132 medical apps available, 843 (2.7%) eligible apps were identified. Of these apps, (n = 74, 8.7%) apps were specifically designed for stroke survivors/caregivers use and provided the following services: language/speech therapy (n = 28, 37%), communication with aphasic patients (n = 19, 25%), stroke risk calculation (n = 11, 14%), assistance in spotting an acute stroke (n = 8, 10%), detection of atrial fibrillation (n = 3, 4%), direction to nearby emergency room (n = 3, 4%), physical rehabilitation (n = 3, 4%), direction to the nearest certified stroke center (n = 1, < 2%), and visual attention therapy (n = 1, <2%). 769 apps identified that were developed for purposes other than stroke. Of these, the majority (n = 526, 68%) addressed SRFs. CONCLUSIONS:Over 70 medical apps exist to specifically support stroke survivors/caregivers and primarily targeted language and communication difficulties. Apps encompassing most stroke survivor/caregiver needs could be developed and tested to ensure the issues faced by these populations are being adequately addressed.

AIM/OBJECTIVE:To assess the accuracy of consumer available wrist-based and hip-based activity trackers in quantitatively measuring ambulation in children with cerebral palsy (CP). METHOD/METHODS:Thirty-nine children (23 males, 16 females; mean age [SD] 9y 7mo [3y 5mo]; range 4-15y) with CP were fitted with trackers both on their wrist and hip. Each participant stood for 3 minutes, ambulated in a hallway, and sat for 3 minutes. The number of steps and distance were recorded on trackers and compared to manually counted steps and distance. Pearson correlation coefficients were determined for the number of steps during ambulation from each tracker and a manual count. Mean absolute error (MAE) and range of errors were calculated for steps during ambulation for each tracker and a manual count and for distance for each tracker and hallway distance. RESULTS:For the number of steps, a weak inverse relationship (r=-0.033) was found for the wrist-based tracker and a strong positive relationship (r=0.991) for the hip-based tracker. The MAE was 88 steps for the wrist-based and seven steps for the hip-based tracker. The MAE for distance was 0.06 miles for the wrist-based and 0.07 miles for the hip-based tracker. INTERPRETATION/CONCLUSIONS:Only the hip-based tracker provided an accurate step count; neither tracker was accurate for distance. Thus, ambulation of children with CP can be accurately quantified with readily available trackers.

Application of molecular neuroimaging using positron emission tomographic techniques to assess pediatric neurodegenerative disorders has been limited, unlike in adults where positron emission tomography has contributed to clinical diagnosis, monitoring of neurodegenerative disease progression, and assessment of novel therapeutic approaches. Yet, there is a huge unexplored potential of molecular imaging to improve our understanding of the pathophysiology of neurodegenerative disorders in children and provide radiological biomarkers that can be applied clinically. The obstacles in performing PET scans on children include sedation, radiation exposure, and access but, as will be illustrated, these barriers can be easily overcome. In this review, we summarize findings from PET studies that have been performed over the past three decades on children with various neurodegenerative disorders, including the neuronal ceroid lipofuscinoses, juvenile Huntington disease, Wilson disease, Niemann-Pick disease type C, Dravet syndrome, dystonia, mitochondrial disorders, inborn errors of metabolism, lysosomal storage diseases, dysmyelinating disorders, Rett syndrome, neurotransmitter disorders, glucose transporter Glut 1 deficiency, and Lesch-Nyhan disease. Because positron emission tomographic scans have often been clinically useful and have contributed to the management of these disorders, we suggest that the time has come for glucose metabolism positron emission tomographic scans to be reimbursed by insurance carriers for children with neurodegenerative disorders, and not restricted only to epilepsy surgery evaluation.

OBJECTIVE:Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies. METHODS:We searched PubMed (January 2007-February 2019) for human studies of OH and RBD evaluating cognitive impairment, postural instability, and survival in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Included studies were analysed for design, key results and limitations as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS:OH and RBD showed a positive association with cognitive impairment in PD and DLB, conflicting association in PAF, and no association in MSA. OH was correlated with incident falls and postural instability in PD and DLB but not in MSA. The association between RBD and postural instability was inconclusive; positive in five studies, negative in seven. OH, but not RBD, correlated with reduced survival in PD, DLB and MSA. The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability. CONCLUSIONS:OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a 'malignant' phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei.