Josh Woolley

The Diagnostic Challenge of Psychiatric Symptoms in Neurodegenerative Disease: Rates of and Risk Factors for Prior Psychiatric Diagnosis in Patients With Early Neurodegenerative Disease

OBJECTIVEnTo identify rates of and risk factors for psychiatric diagnosis preceding the diagnosis of neurodegenerative disease.nnnMETHODnSystematic, retrospective, blinded chart review was performed of 252 patients with a neurodegenerative disease diagnosis seen in our specialty clinic between 1999 and 2008. Neurodegenerative disease diagnoses included behavioral-variant frontotemporal dementia (n = 69), semantic dementia (n = 41), and progressive nonfluent aphasia (n = 17) (all meeting Neary research criteria); Alzheimers disease (n = 65) (National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimers Disease and Related Disorders Association research criteria); corticobasal degeneration (n = 25) (Boxer research criteria); progressive supranuclear palsy (n = 15) (Litvan research criteria); and amyotrophic lateral sclerosis (n = 20) (El Escorial research criteria). Reviewers remained blinded to each patients final neurodegenerative disease diagnosis while reviewing charts. Extensive caregiver interviews were conducted to ensure accurate and reliable diagnostic histories. For each patient, we recorded history of psychiatric diagnosis, family psychiatric and neurologic history, age at symptom onset, and demographic information.nnnRESULTSnA total of 28.2% of patients with a neurodegenerative disease received a prior psychiatric diagnosis. Depression was the most common psychiatric diagnosis in all groups. Behavioral-variant frontotemporal dementia patients received a prior psychiatric diagnosis significantly more often (50.7%; P < .001) than patients with Alzheimers disease (23.1%), semantic dementia (24.4%), or progressive nonfluent aphasia (11.8%) and were more likely to receive diagnoses of bipolar disorder or schizophrenia than were patients with other neurodegenerative diseases (P < .001). Younger age (P < .001), higher education (P < .05), and a family history of psychiatric illness (P < .05) increased the rate of prior psychiatric diagnosis in patients with behavioral-variant frontotemporal dementia. Cognitive, behavioral, and emotional characteristics did not distinguish patients who did or did not receive a prior psychiatric diagnosis.nnnCONCLUSIONSnNeurodegenerative disease is often misclassified as psychiatric disease, with behavioral-variant frontotemporal dementia patients at highest risk. While this study cannot rule out the possibility that psychiatric disease is an independent risk factor for neurodegenerative disease, when patients with neurodegenerative disease are initially classified with psychiatric disease, the patient may receive delayed, inappropriate treatment and be subject to increased distress. Physicians should consider referring mid- to late-life patients with new-onset neuropsychiatric symptoms for neurodegenerative disease evaluation.

Intranasal Oxytocin Selectively Modulates Social Perception, Craving, and Approach Behavior in Subjects With Alcohol Use Disorder.

Objectives:A pharmacotherapy that both improves social abilities and promotes abstinence may be particularly helpful for the treatment of alcohol use disorder. Recent clinical and preclinical evidence suggests that oxytocin has prosocial and antiaddiction effects. We performed a pilot, laboratory-based, preclinical trial of oxytocin in subjects with alcohol abuse (as per Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria) to evaluate therapeutic potential and assess tolerability. Methods:Social perceptual ability, cue-induced craving, and approach bias for alcohol and appetitive imagery were quantified after intranasal oxytocin and placebo administration to 32 nontreatment-seeking individuals with alcohol abuse in a double-blind, crossover study. Because attachment style can moderate the effects of oxytocin, we also explored whether attachment style moderated oxytocins effects on our behavioral measures. Results:Oxytocin significantly improved recognition of easier items on a social perception task, but had no significant group-level effect on cue-induced craving. However, oxytocin effects on craving were moderated by attachment anxiety, with oxytocin reducing craving in more anxiously attached individuals and increasing craving in less anxiously attached individuals. Subjects did not display an approach bias to alcohol images on the placebo day, preventing meaningful analysis of this measure. Subjects did display an approach bias to appetitive images on the placebo day, which was significantly reduced by oxytocin administration. No adverse reactions were observed. Conclusions:Intranasal oxytocin has potential to improve social perception, reduce cue-induced alcohol cravings, and reduce appetitive approach bias in subjects with alcohol abuse, and can be safely tolerated in this population. The effects of oxytocin are complex, however, and require further investigation.

A new biomarker of hedonic eating? A preliminary investigation of cortisol and nausea responses to acute opioid blockade.

Overweight and obese individuals differ in their degree of hedonic eating. This may reflect adaptations in reward-related neural circuits, regulated in part by opioidergic activity. We examined an indirect, functional measure of central opioidergic activity by assessing cortisol and nausea responses to acute opioid blockade using the opioid antagonist naltrexone in overweight/obese women (mean BMI=31.1±4.8) prior to the start of a mindfulness-based intervention to reduce stress eating. In addition, we assessed indices of hedonic-related eating, including eating behaviors (binge eating, emotional eating, external eating, restraint) and intake of sweets/desserts and carbohydrates (Block Food Frequency); interoceptive awareness (which is associated with dysregulated eating behavior); and level of adiposity at baseline. Naltrexone-induced increases in cortisol were associated with greater emotional and restrained eating and lower interoceptive awareness. Naltrexone-induced nausea was associated with binge eating and higher adiposity. Furthermore, in a small exploratory analysis, naltrexone-induced nausea predicted treatment response to the mindfulness intervention, as participants with more severe nausea at baseline maintained weight whereas those with little or no nausea responses tended to gain weight. These preliminary data suggest that naltrexone-induced cortisol release and nausea may help identify individuals who have greater underlying food reward dependence, which leads to an excessive drive to eat. Future research is needed to confirm this finding and to test if these markers of opioidergic tone might help predict success in certain types of weight management programs.

The effects of intranasal oxytocin in opioid-dependent individuals and healthy control subjects: a pilot study

RationaleThere has been an explosion of research on the potential benefits of the social neuropeptide oxytocin for a number of mental disorders including substance use disorders. Recent evidence suggests that intranasal oxytocin has both direct anti-addiction effects and pro-social effects that may facilitate engagement in psychosocial treatment for substance use disorders.ObjectivesWe aimed to assess the tolerability of intranasal oxytocin and its effects on heroin craving, implicit association with heroin and social perceptual ability in opioid-dependent patients receiving opioid replacement therapy (ORT) and healthy control participants.MethodsWe performed a randomized, double-blind, placebo-controlled, within- and between-subjects, crossover, proof-of-concept trial to examine the effects of oxytocin (40 international units) on a cue-induced craving task (ORT patients only), an Implicit Association Task (IAT), and two social perception tasks: the Reading the Mind in the Eyes Task (RMET) and The Awareness of Social Inference Test (TASIT).ResultsOxytocin was well tolerated by patients receiving ORT but had no significant effects on craving or IAT scores. There was a significant reduction in RMET performance after oxytocin administration versus placebo in the patient group only, and a significant reduction in TASIT performance after oxytocin in both the patient and healthy control groups.ConclusionsA single dose of intranasal oxytocin is well tolerated by patients receiving ORT, paving the way for future investigations. Despite no significant improvement in craving or IAT scores after a single dose of oxytocin and some evidence that social perception was worsened, further investigation is required to determine the role oxytocin may play in the treatment of opioid use disorder.Clinical Trial RegistrationMethadone Oxytocin Option. ClinicalTrials.gov identifier: NCT01728909

Schizophrenia or Neurodegenerative Disease Prodrome? Outcome of a First Psychotic Episode in a 35-Year-Old Woman

NIH Public Access Author Manuscript Psychosomatics. Author manuscript; available in PMC 2013 May 22. NIH-PA Author Manuscript Published in final edited form as: Psychosomatics. 2012 May ; 53(3): 280–284. doi:10.1016/j.psym.2011.04.005. Schizophrenia or neurodegenerative disease prodrome? Outcome of a first psychotic episode in a 35-year old woman Baber K. Khan, B.A., University of California San Francisco, Memory and Aging Center, Department of Neurology, 350 Parnassus Avenue, San Francisco, CA 94143. Josh D. Woolley, MD/PhD, University of California San Francisco, Langley Porter, Department of Psychiatry, 401 Parnassus Avenue, Room 159, San Francisco, CA 94143. Steven Chao, MD/PhD, University of California San Francisco, Memory and Aging Center, Department of Neurology, 350 Parnassus Avenue, San Francisco, CA 94143. NIH-PA Author Manuscript Tricia See, ScM, University of California San Francisco, Memory and Aging Center, Department of Neurology, 350 Parnassus Avenue, San Francisco, CA 94143. Anna M. Karydas, B.A., University of California San Francisco, Memory and Aging Center, Department of Neurology, 350 Parnassus Avenue, San Francisco, CA 94143. Bruce L. Miller, MD, and University of California San Francisco, Memory and Aging Center, Department of Neurology, 350 Parnassus Avenue, San Francisco, CA 94143. Katherine P. Rankin, PhD University of California San Francisco, Memory and Aging Center, Department of Neurology, 350 Parnassus Avenue, San Francisco, CA 94143. Abstract NIH-PA Author Manuscript Background—Patients with early onset neurodegenerative disease can present with a clinical syndrome that overlaps with schizophrenia, and it is not uncommon for these patients to undergo long-term care in psychiatric settings rather than receiving more appropriate care by neurologists specializing in their disease. Case report—A 35-year old woman who presented with new-onset delusions, eating abnormalities, disorganized behavior, lack of insight, disinhibition, and stereotypical motor behaviors was diagnosed with schizophrenia and institutionalized. Later she was found to have a

Impaired Recognition and Regulation of Disgust Is Associated with Distinct but Partially Overlapping Patterns of Decreased Gray Matter Volume in the Ventroanterior Insula

BACKGROUNDnThe ventroanterior insula is implicated in the experience, expression, and recognition of disgust; however, whether this brain region is required for recognizing disgust or regulating disgusting behaviors remains unknown.nnnMETHODSnWe examined the brain correlates of the presence of disgusting behavior and impaired recognition of disgust using voxel-based morphometry in a sample of 305 patients with heterogeneous patterns of neurodegeneration. Permutation-based analyses were used to determine regions of decreased gray matter volume at a significance level p <= .05 corrected for family-wise error across the whole brain and within the insula.nnnRESULTSnPatients with behavioral variant frontotemporal dementia and semantic variant primary progressive aphasia were most likely to exhibit disgusting behaviors and were, on average, the most impaired at recognizing disgust in others. Imaging analysis revealed that patients who exhibited disgusting behaviors had significantly less gray matter volume bilaterally in the ventral anterior insula. A region of interest analysis restricted to behavioral variant frontotemporal dementia and semantic variant primary progressive aphasia patients alone confirmed this result. Moreover, impaired recognition of disgust was associated with decreased gray matter volume in the bilateral ventroanterior and ventral middle regions of the insula. There was an area of overlap in the bilateral anterior insula where decreased gray matter volume was associated with both the presence of disgusting behavior and impairments in recognizing disgust.nnnCONCLUSIONSnThese findings suggest that regulating disgusting behaviors and recognizing disgust in others involve two partially overlapping neural systems within the insula. Moreover, the ventral anterior insula is required for both processes.

Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia

Objective: To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study. Methods: Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healthy normal controls [NCs]) were recruited from a tertiary-care dementia clinic. During a standardized breakfast, blood was drawn before, during, and after the breakfast protocol to quantify levels of peripheral satiety-related hormones (ghrelin, cortisol, insulin, leptin, and peptide YY) and glucose. To further explore the role of patients feeding abnormalities on hormone levels, patients were classified into overeating and nonovereating subgroups based on feeding behavior during separate laboratory-based standardized lunch feeding sessions. Results: Irrespective of their feeding behavior in the laboratory, patients with bvFTD, but not patients with Alzheimer disease dementia, have significantly lower levels of ghrelin and cortisol and higher levels of insulin compared with NCs. Furthermore, while laboratory feeding behavior did not predict alterations in levels of ghrelin, cortisol, and insulin, only patients with bvFTD who significantly overate in the laboratory demonstrated significantly higher levels of leptin compared with NCs, suggesting that leptin may be sensitive to particularly severe feeding abnormalities in bvFTD. Conclusions: Despite a tendency to overeat, patients with bvFTD have a hormonal profile that should decrease food intake. Aberrant hormone levels may represent a compensatory response to the behavioral or neuroanatomical abnormalities of bvFTD.

BDNF serum concentrations show no relationship with diagnostic group or medication status in neurodegenerative disease

Brain-derived neurotrophic factor (BDNF) is a growth factor implicated in neuronal survival. Studies have reported altered BDNF serum concentrations in patients with Alzheimers disease (AD). However, these studies have been inconsistent. Few studies have investigated BDNF concentrations across multiple neurodegenerative diseases, and no studies have investigated BDNF concentrations in patients with frontotemporal dementia. To examine BDNF concentrations in different neurodegenerative diseases, we measured serum concentrations of BDNF using enzyme-linked immunoassay in subjects with behavioral-variant frontotemporal dementia (bvFTD, n=20), semantic dementia (SemD, n=16), AD (n=34), and mild cognitive impairment (MCI, n=30), as well as healthy older subjects (HS, n=38). BDNF serum concentrations were compared across diagnoses and correlated with cognitive tests and patterns of brain atrophy using voxelbased morphometry. We found small negative correlations between BDNF serum concentrations and some of the cognitive tests assessing learning, information processing speed and cognitive control in complex situations, however, BDNF did not predict disease group membership despite adequate power. These findings suggest that BDNF serum concentration may not be a reliable diagnostic biomarker to distinguish among neurodegenerative diseases.

Neuromyelitis optica, psychiatric symptoms and primary polydipsia: a case report.

Neuromyelitis optica (NMO) is an aggressive demyelinating disease that typically affects the optic nerves and spinal cord. While it is increasingly recognized that cerebral lesions are common in NMO, there have been no reported cases of NMO presenting with psychiatric symptoms and polydipsia. We describe a patient with classic signs and symptoms of NMO who also demonstrated prominent psychiatric symptoms and polydipsia that were tied to his flares and resolved with treatment of his NMO. This case expands our understanding of possible presentations of NMO.

Intranasal oxytocin increases facial expressivity, but not ratings of trustworthiness, in patients with schizophrenia and healthy controls.

BACKGROUNDnBlunted facial affect is a common negative symptom of schizophrenia. Additionally, assessing the trustworthiness of faces is a social cognitive ability that is impaired in schizophrenia. Currently available pharmacological agents are ineffective at improving either of these symptoms, despite their clinical significance. The hypothalamic neuropeptide oxytocin has multiple prosocial effects when administered intranasally to healthy individuals and shows promise in decreasing negative symptoms and enhancing social cognition in schizophrenia. Although two small studies have investigated oxytocins effects on ratings of facial trustworthiness in schizophrenia, its effects on facial expressivity have not been investigated in any population.nnnMETHODnWe investigated the effects of oxytocin on facial emotional expressivity while participants performed a facial trustworthiness rating task in 33 individuals with schizophrenia and 35 age-matched healthy controls using a double-blind, placebo-controlled, cross-over design. Participants rated the trustworthiness of presented faces interspersed with emotionally evocative photographs while being video-recorded. Participants facial expressivity in these videos was quantified by blind raters using a well-validated manualized approach (i.e. the Facial Expression Coding System; FACES).nnnRESULTSnWhile oxytocin administration did not affect ratings of facial trustworthiness, it significantly increased facial expressivity in individuals with schizophrenia (Zxa0=xa0-2.33, pxa0=xa00.02) and at trend level in healthy controls (Zxa0=xa0-1.87, pxa0=xa00.06).nnnCONCLUSIONSnThese results demonstrate that oxytocin administration can increase facial expressivity in response to emotional stimuli and suggest that oxytocin may have the potential to serve as a treatment for blunted facial affect in schizophrenia.