Faculty Bibliography

Technological and methodological innovations are equipping researchers with unprecedented capabilities for detecting and characterizing pathologic processes in the developing human brain. As a result, ambitions to achieve clinically useful tools to assist in the diagnosis and management of mental health and learning disorders are gaining momentum. To this end, it is critical to accrue large-scale multimodal datasets that capture a broad range of commonly encountered clinical psychopathology. The Child Mind Institute has launched the Healthy Brain Network (HBN), an ongoing initiative focused on creating and sharing a biobank of data from 10,000 New York area participants (ages 5-21). The HBN Biobank houses data about psychiatric, behavioral, cognitive, and lifestyle phenotypes, as well as multimodal brain imaging (resting and naturalistic viewing fMRI, diffusion MRI, morphometric MRI), electroencephalography, eye-tracking, voice and video recordings, genetics and actigraphy. Here, we present the rationale, design and implementation of HBN protocols. We describe the first data release (n=664) and the potential of the biobank to advance related areas (e.g., biophysical modeling, voice analysis).

Background: Reduced pain and temperature sensation with varying degrees of autonomic dysfunction are characteristic features of patients with hereditary sensory and autonomic neuropathies (HSAN). At least seven HSAN phenotypes have been described for which 14 gene mutations have been identified. In many patients presenting with congenital sensory and autonomic deficits, however, traditional genetic testing is unable to detect genetic mutations. Objective: To identify novel genetic causes of congenital impaired sensation to pain with autonomic dysfunction with whole exome sequencing and evaluate genotype-phenotype correlations. Methods: We enrolled 10 patients with impaired or absent sensation to pain and temperature sensation with onset at birth without a previously identified molecular diagnosis from a HSAN gene panel. We performed detailed phenotypic assessment including presentation, autonomic testing, and comprehensive neurological and ophthalmo-logical examinations. Whole exome sequencing was performed in all patients as well as in, at least, one family member. Results: In 9 of 10 (90%) patients with congenital impaired pain sensation, we identified variants predicted to be pathogenic in NGF (n = 2, siblings), SMPDL3A (n = 2, siblings), SCN11A (n = 1), SCN10A (n = 1), SCN9A (n = 1), LIFR (n = 1), and TECPR2 (n = 1). Only in one patient, whole exome sequencing was not useful to identify potential pathogenic variants. Autonomic deficits included anhidrosis (SCN9A, NGF), hypohidrosis (TECPR2), hyperhidrosis (SCN11A, SCN10A, TECPR2, LIFR), alacrima or hypolacrima (SMPDL3A, TECPR2, LIFR), neurogenic dysphagia (TECPR2, SMPDL3A, SCN11A), gastroesophageal reflux (SCN11A), vomiting episodes (LIFR), and central sleep apnea (TECPR2). The subject with LIFR had episodes of hypertension, tachycardia, severe hyperhidrosis and hypernatremia. Sensorineural hearing loss was present in TECPR2 and one of the subjects with SMPDL3A. Conclusions: We characterize and expand the genetic landscape of HSAN, and demonstrate the feasibility of genetic diagnosis with clinically whole exome sequencing in 90% of our cohort

Background: Symptoms of psychosis, including hallucinations and delusions, are relatively frequent in Parkinson disease and Lewy body dementia, particularly in patients receiving levodopa and dopamin-ergic agonists. However, the prevalence of psychosis in multiple system atrophy (MSA) is unknown. We aimed to determine the prevalence and characteristics of psychotic symptoms in patients with MSA, and factors associated with their development. Methods: Consecutive patients with probable MSA without previous history of psychiatric disorders were prospectively enrolled in a longitudinal observational study. The presence of hallucinations and delusions was determined during a standardized clinical interview and quantified with the Scale for the Assessment of Positive Symptoms in Parkinson disease (SAPS-PD). Patients also underwent full evaluation of visual acuity, cognition (Montreal Cognitive Assessment, MoCA), motor function and disease severity [United Multiple System Atrophy Rating Scale (UMSARS)]. Results: Of the 31 consecutive patients with probable MSA (17 men; mean age 64 +/- 8 years; 13 MSA-P and 14 MSA-C), 6 (19%) had positive symptoms of psychosis including delusions and/or hallucinations. All but one patient had the cerebellar phenotype of the disease (MSA-C). Auditory hallucinations occurred in 4 patients, visual hallucinations in 4, persecutory delusions in 3, and jealousy delusions in 3. No patients reported somatic or tactile hallucinations. Psychosis symptoms were extremely severe and refractory to treatment in 2 cases with MSA-C, both of whom died within 12 months of psychosis onset. Psychotic symptoms were not associated with levodopa or other antiparkinsonian medication treatment, visual acuity, cognitive score, depression score, or duration of illness. Conclusions: Psychotic symptoms occur in *20% of patients with MSA, the vast majority of whom have MSA-C. Severe refractory psychotic symptoms appear to be associated with poor prognosis (death < 1 year). Our results suggest that psychotic symptoms in MSA are unrelated to visual system abnormalities

Introduction: Patients with pure autonomic failure (PAF) typically present with symptoms of sympathetic insufficiency, with anhidrosis frequently reported. We here report an unusual patient with PAF who presented with cold-induced sweating. Methods: Case report. Results: A 73-year-old man had a 5-year history of frequent lightheadedness, dizziness and syncope on standing. He also had erectile dysfunction, nocturia, constipation, and dream reenactment. He also reported a significant increase in sweating in his torso, back, and both arms (particularly the left) induced by cold temperatures. Autonomic testing showed a supine hypertension (193/105 mmHg) with resting bradycardia (50 bpm). Blood pressure overshoot after release of the Valsalva strain was absent, indicating impaired baroreflex-mediated sympathetic activation. After 14-min of head-up tilt his blood pressure had dropped to 124/83 mmHg with a blunted increase in heart rate to 73 bpm. His norepinephrine levels failed to increase appropriately upon head-up tilt (supine 376 pg/mL; tilted 404 pg/mL), indicating a neurogenic cause for his orthostatic hypotension. Electrochemical skin conductance was reduced in palms and soles. An iodine-starch test was performed with a room temperature of 90degreeF and repeated after the temperature was decreased to 78degreeF. When the ambient temperature was reduced, the starch powder turned dark purple, more intensely in the left side, indicating the release of sweat. Conclusion: Cold-induced sweating can be a manifestation of autonomic failure. Possible mechanisms include cold-induced sudomotor supersensitivity triggered by the remaining fibers innervating the sweat glands

Our genome encodes for all proteins in the body and controls our biological functions. Mutations in DNA sequences that encode for proteins highly expressed in nerve tissue can result in specific lesions within the autonomic pathways. Mutations that result in a deficiency in a protein important for the survival of autonomic neurons at key developmental stages are usually expressed at birth or in early childhood. Hereditary sensory and autonomic neuropathies (HSAN) are a group of inherited diseases with insensitivity to pain. There are currently 6 major HSAN subtypes and at least 12 known gene-causing mutations. The severity of autonomic involvement is most profound in types 3 and 4, which are both autosomal recessive, but their autonomic phenotypes are distinctly different. Genetic mutations that result in the overexpression of proteins expressed in autonomic neurons typically present later in life and follow a more degenerative course. Familial amyloid polyneuropathies are a group of disorders caused by deposits of amyloid fibrils, most commonly due to mutations within the transthyretin (TTR) gene. This results in a length-dependent sensorimotor and autonomic neuropathy affecting unmyelinated and small myelinated fibers. The most common auto-nomic features are orthostatic hypotension, erectile dysfunction and gastrointestinal dysmotility, and can sometimes be a presenting sign. Genetic factors may also play a role in susceptibility to neurode-generative diseases. A recent genome wide association study found several genes that may emerge as genetic players in synucleinopathies including multiple system atrophy. For now, clinical trials are underway to explore whether modifying gene expression can influence the survival of autonomic neurons in HSAN3 and transthyretin-related hereditary amyloidosis. In the future, it may be possible to modify our future risk of developing an autonomic disorder with genetic therapy

Introduction: Familial dysautonomia (FD) is a rare autosomal recessive disorder caused by a point mutation in the IKBKAP gene, resulting in reduction of the IkappaB Kinase-associated protein/Elongator protein 1 (IKAP/ELP1). ELP1 is a transcriptional regulator that targets downstream genes involved with cell migration, stability and survival. We hypothesized that ELP1-associated abnormalities may increase the incidence and prevalence of neoplasia and cancer in FD. Methods: Retrospective chart review of the New York University FD Patient International Registry, which contains standardized clinical information on patients with genetically confirmed FD since 1970. We identified cases with neoplasia or cancer, and reviewed their demographics, tumor type and age at diagnosis. Results: At the time of writing, of the 674 patients with FD reviewed, we identified 25 cases of neoplasia, which included 12 cases of cancer. The prevalence of neoplasia in the FD population was 3.7% and the prevalence of cancer was 1.8%. Average age at cancer diagnosis was 29 years, significantly younger than in the general population (66 years). Additionally, 16% of all neoplasia were tumors derived from neural crest cells. There was no association between growth hormone treatment and the prevalence of neoplasia or cancer. Conclusions: Patients with FD have higher rates of neoplasia and cancer than previously reported in the literature. Overall, the FD population develops cancer and tumors at a much younger atypical age than the general population. Our results suggest that ELP1 plays an important role in tumor genesis and may explain the high prevalence of neoplasia and cancer in patients with FD

Background: The arterial baroreflex buffers blood pressure to prevent it from rising or falling excessively. Afferent baroreflex failure occurs in patients with genetic or acquired lesions of the afferent (sensory) baroreceptor nerves relaying information to the brain or within the central connections of the medulla. Patients with afferent baroreflex failure have extremely volatile high and quite low pressures. Review of the literature reveals that acquired forms of afferent baroreflex failure have never been described in children or young adults. Aim: To define the cause, clinical spectrum, and treatment of acquired baroreflex failure in children and young adults. Methods: We prospectively studied consecutive pediatric and young adult patients (<30 years old) who were diagnosed with afferent baroreflex failure. Each patient underwent a detailed clinical history, neurological examination, autonomic testing, plasma catecholamine measurements, and ambulatory blood pressure monitoring. Results: We identified 6 patients (3 males and 3 females; age range: 11-28 years old). All presented with severe, labile hypotension with syncope and hypertension often accompanied by headache, and flushing. Office blood pressure ranged from a maximum of 198/138 to 143/90 mmHg and a minimum of 70/40 to 102/68 mmHg. Plasma norepinephrine levels failed to increase appropriately during head-up. On ambulatory monitoring, 24-h systolic blood pressure standard deviation was markedly exaggerated (from 17.5 to 20.8 mmHg). In all cases, patients had excessive pressor and tachycardic responses to cognitive arousal (mental-arithmetic). The underlying causes of the afferent baroreflex failure included surgery and radiotherapy of head or neck cancer (n = 4), posterior reversible leukoencephalopathy (n = 1), and Moebius syndrome (n = 1). Conclusions: Acquired afferent baroreflex failure should be considered in children and young adults with otherwise unexplained labile hypertension, particularly in those with a history of head or neck cancer

Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in β-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the β-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αβ-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αβ-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.

Amyloid-β (Aβ) and tau pathologies are intertwined in Alzheimer's disease, and various immunotherapies targeting these hallmarks are in clinical trials. To determine if tau pathology influences Aβ burden and to assess prophylactic benefits, 3xTg and wild-type mice received tau immunization from 2-6 months of age. The mice developed a high IgG titer that was maintained at 22 months of age. Pronounced tau and Aβ pathologies were primarily detected in the subiculum/CA1 region, which was therefore the focus of analysis. The therapy reduced histopathological tau aggregates by 70-74% overall (68% in males and 78-86% in females), compared to 3xTg controls. Likewise, western blot analysis revealed a 41% clearance of soluble tau (38-76% in males and 48% in females) and 42-47% clearance of insoluble tau (47-58% in males and 49% in females) in the immunized mice. Furthermore, Aβ burden was reduced by 84% overall (61% in males and 97% in females). These benefits were associated with reductions in microgliosis and microhemorrhages. In summary, prophylactic tau immunization not only prevents tau pathology but also Aβ deposition and related pathologies in a sustained manner, indicating that tau pathology can promote Aβ deposition, and that a short immunization regimen can have a long-lasting beneficial effect.