Faculty Bibliography

Droxidopa, a synthetic norepinephrine precursor, was recently approved to treat symptomatic neurogenic orthostatic hypotension (nOH). The pressor response is variable with some patients responding to doses of 100 mg while others requiring up to 600 mg three times/day. It is not known which factors predict the magnitude of the pressor response to droxidopa. We prospectively evaluated the BP response to increasing doses of droxidopa in patients with nOH in an outpatient setting. BP supine and after 3-min standing was measured before and 1-h after oral administration of 100 mg of droxidopa. Droxidopa was progressively increased until (i) complete relief of symptoms, (ii) supine systolic BP >180 mmHg, (iii) occurrence of side effects, or (iv) the maximum dose of 600 mg was reached. Sixteen subjects with nOH (6 with Parkinson disease, 5 with pure autonomic failure, 3 with autoimmune autonomic ganglionopathy, and 2 with multiple system atrophy) were evaluated. Mean BP was 126 +/- 28/72 +/- 11 mmHg supine, and 89 +/- 19/ 53 +/- 15 mmHg after 3-min standing (fall of 37/18 mmHg). Mean plasma norepinephrine while supine was 192 +/- 216 pg/ml. Maximum droxidopa dose during the titration was 212 +/- 102 mg (range 100-400 mg). Droxidopa increased BP to an average of 148 +/- 53/ 90 +/- 13 mmHg supine and 135 +/- 38/66 +/- 16 mmHg after 3-min standing (p<0.001). Plasma norepinephrine levels were inversely correlated with higher systolic BP after 3-min standing following droxidopa treatment (R2 = 0.42; p = 0.023). Four patients (3 with AAG and 1 with PAF) with very low plasma norepinephrine levels (<90 pg/ml) experienced transient nausea, vomiting, and abdominal pain during titration with dosages of 200 mg. In these patients, treatment with 100 mg/day was effective and well tolerated. Diagnostic categories did not predict response to droxidopa. In patients with nOH, lower plasma norepinephrine levels are associated with a greater pressor response to droxidopa. This response is probably related to the degree of denervation supersensitivity. Supine norepinephrine levels may be useful to predict appropriate dosing of droxidopa in a clinical setting

Congenital insensitivity to pain with anhidrosis (CIPA, also known as hereditary sensory and autonomic neuropathy type IV) is a rare autosomal recessive disorder caused by mutations in the gene encoding for neurotrophic tyrosine kinase receptor type 1, a receptor for nerve growth factor (NTRK1-NGF). We recently described that patients with CIPA have very low or undetectable circulating norepinephrine levels. Since these mutations severely deplete the development of noradrenergic neurons in the periphery, they presumably also affect those in the central nervous system. Patients with CIPA have low IQ and behavioral problems including hyperactivity and reckless impulsivity, likely the result of a central deficiency in norepinephrine. We explored whether treatment with droxidopa, a synthetic norepinephrine precursor, which crosses the blood brain barrier, could improve behavioral features in a patient with CIPA. Our patient was a 29-year-old woman with a classic phenotype and molecular confirmation of a mutation in the NTRK1 gene (c360- 2A >C pathogenic variant). She had symptoms of attention deficit and hyperactivity and scored highly on the adult ADHD self-report scales (Scores Part A: 4/6 and Part B: 9/12). She had high scores in the attentional (17 and 4), motor (21 and 10), and planning (21 and 17) domains of Barratt impulsiveness scale. NICHQ Vanderbilt assessment scale also indicated attention deficits and hyperactivity. After two months treatment with droxidopa (at 400 mg/day), attention and hyperactivity scales scores decreased to the normal range (Scores Part A: 3/6 and Part B: 4/12). Impulsiveness scores assessed by Barratt impulsiveness scales also improved (attentional scores 15 and 11, motor scores 19 and 9 and planning scores 20 and 9). This case report suggests that behavioral deficits might be reversed in patients with CIPA by norepinephrine replenishment therapy. Clinical studies to evaluate the usefulness of droxidopa to treat behavioral problems in CIPA patients are warranted

Background: Pure autonomic failure is a neurodegenerative synucleinopathy largely restricted to the peripheral nervous system. Later in the clinical course of the disease some patients may develop parkinsonism, cerebellar ataxia or cognitive impairment. The purpose of this study is to define the clinical features and biomarkers that predict which patients will retain a pure autonomic failure phenotype, and which will develop clinical deficits indicating spread of the synucleinopathy to the central nervous system.
Method(s): One hundred patients with pure autonomic failure were recruited at 5 medical centers in the US. Participants were followed at 12-months intervals, for 4 years to determine whether they had developed motor/cognitive abnormalities and met the diagnostic criteria of Parkinson disease (PD)/dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). Smell discrimination, occurrence of REM sleep behavior disorder (RBD) and sympathetic and parasympathetic cardiovascular autonomic functions were assessed.
Finding(s): Mean age of onset of autonomic failure was 61 (+/-12) years. Patients had a 10 % per year cumulative risk for developing a CNS synucleinopathy with locomotor dysfunction or dementia. All patients who developed a CNS synucleinopathy had subtle motor impairment and RBD at the time of enrolment. Factors that predicted a future diagnosis of MSA included younger age at onset of autonomic failure, severe bladder/bowel abnormalities, normal olfaction and a >10 bpm cardiac chronotrophic response to tilt. Factors that predicted future diagnosis of PD/DLB were abnormal olfaction, a lesser chronotrophic response to tilt and longer disease duration. Patients that retained a PAF phenotype had very low circulating norepinephrine levels, slow resting heart rate, no RBD or subtle motor deficits and preserved smell discrimination.
Interpretation(s): Pure autonomic failure can be a premotor stage of a central nervous system synucleinopathy or may remain as a restricted peripheral disorder. Patients who developed PD/DLB or MSA have distinct premotor features. Patients who retain a pure autonomic failure phenotype had more severe peripheral sympathetic involvement

The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories. (c) 2016 Wiley Periodicals, Inc.

Physicians who specialize in autonomic disorders think in terms of orthostasis, synapses, catecholamines, ganglionopathies, and baroreflexes. Patients, on the other hand, inhabit a world of streaming, downloads, hashtags, tweets, and blogs. In an increasingly digital era, if we are to communicate effectively with patients, we must understand their language, including that of social media. The cultural revolution of social media opens new opportunities for autonomic medicine. First, social media can direct patients to specialists who have the expertise to evaluate and treat their disorders when such expertise is not available locally. Listing contact information on reputable dysautonomia websites is an effective way to facilitate these connections, as is creating practice websites to showcase unique expertise and resources. Secondly, online platforms can empower the patient population through education. In clinical practice, we see how frequently patients turn to the Internet for medical information. However, search engines alone are inadequate because of the sheer volume of available information, much of which is unmonitored. Patients can quickly be led down a path of misinformation about their particular condition. Dr. Google is frequently wrong. Moreover, it takes on average 2.5 clicks to get from a headache to a brain tumor. As experts in the field, we have an obligation to participate online in the translation and dissemination of accurate medical information. It is important to consider the demographics of the target audience and how best to reach them, be it Facebook, Twitter, Instagram or Snap Chat. By doing this we can assist patients in understanding their autonomic disorders and managing their symptoms. Thirdly, social media can be an important tool for research. Social media platforms can be used to recruit research subjects with rare disorders and as a tool to promote the need for research funding from the public. Social media is undoubtedly an effective way to spread news and can be used to disseminate new knowledge arising from research, which allows patients to keep abreast of current breakthroughs. Lastly, social media can be leveraged to raise public awareness about autonomic disorders and their treatment, build community, share experiences, and engage patient groups in partnership

Autoimmune autonomic ganglionopathy (AAG) is a rare condition characterized by acute-onset generalized autonomic failure. Some of these patients also develop severe sensory and motor deficits. Droxidopa, an oral norepinephrine precursor, has been previously reported as effective treatment of neurogenic orthostatic hypotension (nOH) in one patient with AAG. Here we report our experience using droxidopa to treat symptomatic nOH in 3 patients with suspected AAG. Patient #1 (35-year-old woman) presented with acute-onset recurrent syncope, urinary retention, constipation, dry mouth, and decreased sweating, but no motor or sensory deficits. Patient #2 (11 year-old boy) and patient #3 (43-year-old woman) presented with similar autonomic deficits as well as severe impairment in all sensory modalities, but patient #3 also had severe generalized muscle weakness and had been initially diagnosed with Guillain-Barre syndrome. In all three patients, autonomic testing showed severe nOH confirmed by absent phase IV blood pressure overshoot after release of the Valsalva strain and very low or undetectable plasma norepinephrine levels. Ganglionic acetylcholine receptor antibodies were not detected in any patient. Droxidopa increased blood pressure and improved symptoms in all three patients. After 1 year, patient #1 is still receiving droxidopa 200 mg three times/day with normalization of standing BP, and continued symptomatic improvement. During the initial droxidopa titration, patients #2 and #3 experienced nausea, abdominal pain, and severe hypertension (>180 mmHg) with dosages > 200 mg. Both have now been receiving 100 mg once/day for a year with improvement in orthostatic tolerance and BP, no side effects and no supine hypertension. In conclusion, droxidopa substantially increased blood pressure standing and reduced symptoms of orthostatic hypotension in adult and pediatric patients with suspected acute autonomic ganglionopathy

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.Molecular Psychiatry advance online publication, 24 November 2015; doi:10.1038/mp.2015.172.

PURPOSE: We describe a 2 x 6 channel sodium/proton array for knee MRI at 3T. Multielement coil arrays are desirable because of well-known signal-to-noise ratio advantages over volume and single-element coils. However, low tissue-coil coupling that is characteristic of coils operating at low frequency can make the potential gains from a phased array difficult to realize. METHODS: The issue of low tissue-coil coupling in the developed six-channel sodium receive array was addressed by implementing 1) a mechanically flexible former to minimize the coil-to-tissue distance and reduce the overall diameter of the array and 2) a wideband matching scheme that counteracts preamplifier noise degradation caused by coil coupling and a high-quality factor. The sodium array was complemented with a nested proton array to enable standard MRI. RESULTS: The wideband matching scheme and tight-fitting mechanical design contributed to >30% central signal-to-noise ratio gain on the sodium module over a mononuclear sodium birdcage coil, and the performance of the proton module was sufficient for clinical imaging. CONCLUSION: We expect the strategies presented in this study to be generally relevant in high-density receive arrays, particularly in x-nuclei or small animal applications. Magn Reson Med, 2015. (c) 2015 Wiley Periodicals, Inc.

Objectives: Organizational Skills Training (OST), is a 10-week psychosocial intervention found effective in improving organizational, time management, and planning (OTMP) skills in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Little is known about the feasibility of identifying brain markers for treatment response. Using resting state fMRI (R-fMRI), we aimed to examine neuronal correlates of post-treatment change as a first step toward larger controlled studies of objective predictors of treatment response. Methods: We examined pre- and post-OST R-fMRI data of 15 children (12 males; mean age: 9+/-1 year) with ADHD and significant impairments in OTMP skills indexed by total scores on Children's Organizational Skills Scales-Parent (COSS-P) or Teacher (COSS-T). Our primary outcome measure was the change in COSS-P scores. As secondary summary outcome measure, we used prepost Z-score differences averaged across COSS-T, Homework Problems Checklist, Academic Progress Report and Academic Performance Rating scales. We selected a priori the intrinsic functional connectivity (iFC) of the dorsal anterior cingulate cortex (dACC), based on its role on cognitive control. Multivariate distance matrix regression (MDMR) analysis additionally allowed for whole-brain explorations. Follow-up iFC analyses were conducted on regions with significant within-subject post-OST differences by MDMR analysis. Results: COSS-P decreased significantly (t=7.1, p< 0.0001). In a cluster involving striatum bilaterally, dACC iFC decreased post-OST; these decreases were positively correlated with COSS-P improvements (r=.34, NS) and to improvements in the summary outcome (r=.63; p<0.03). MDMR analyses revealed iFC changes in the right medial and lateral precentral cortex. Followup seed-based iFC analyses of this region showed significant decreases in cortico-striatal iFC post-OST. Conclusions: Results support the feasibility of identifying changes in brain iFC after OST. Two distinct analysis converged on decreased corticosubcortical iFC post-treatment which related to change in clinical measures. As decreases in striato-cortical iFC characterize typical development, results suggest regionally-specific enhanced maturational effects of OST

Objectives: The goals of this study are to describe long-term clinical and functional outcomes in the New York Study of hyperactive children who were followed prospectively for 33 years and identify possible predictors that influence these outcomes. Methods: White hyperactive boys (N = 207 probands) were recruited in childhood and followed in adolescence (mean age 18 years), early adulthood (mean age 25 years), and mid-adulthood (mean age 41 years). In late adolescence, 178 comparison participants were recruited. At the final followup in mid-adulthood, a total of 135 probands and 136 comparison participants (65.2 and 76.4 percent of original cohort, respectively) were assessed. Outcome measures included occupational, economic, and educational attainment and marital history, occupational and social functioning, ongoing and lifetime psychiatric disorders, hospitalizations, obesity, risk-taking behaviors, and criminal behaviors. Results: Compared with peers without ADHD, probands showed greater persistence of ADHD, along with greater prevalence of CD/antisocial personality disorder (APD) and SUD in late adolescence. These dysfunctions continued into early adulthood, even when ADHD remitted for the majority of the sample group, and were associated with deficits in educational and occupational attainment, leading to a relative economic disadvantage. Furthermore, the disproportionally high rate of CD/APD and SUD in probands versus comparison participants translated to significantly higher rates of criminality, risk-taking behavior, and risk-related medical outcomes in adulthood. Probands also showed elevated obesity rates in relation to comparison participants but no differences in mood or anxiety disorders. Conclusions: There is heterogeneity in the clinical and functional outcomes of children with ADHD. This study's findings show that childhood ADHD does not preclude adequate functioning in various life domains. However, it does predispose to maladjustment in adolescence and adulthood in a subset of these children, particularly those who develop CD/APD, an important predictor of long-term outcome