Neuropsychiatric Changes Research Articles

Neural Correlates of Transient Mal de Debarquement Syndrome: Activation of Prefrontal and Deactivation of Cerebellar Networks Correlate With Neuropsychological Assessment.

Background: Mal de debarquement syndrome (MdDS) is characterized by a subjective perception of self-motion after exposure to passive motion, mostly after sea travel. A transient form of MdDS (t-MdDS) is common in healthy individuals without pathophysiological certainty. In the present cross-sectional study, the possible neuropsychiatric and functional neuroimaging changes in local fishermen with t-MdDS were evaluated.Methods: The present study included 28 fishermen from Buan County in South Korea; 15 (15/28, 53.6%) participants experienced t-MdDS for 1–6 h, and 13 were asymptomatic (13/28, 46.4%). Vestibular function tests were performed using video-oculography, the video head impulse test, and ocular and cervical vestibular-evoked myogenic potentials. Visuospatial function was also assessed by the Corsi block test. Brain imaging comprised structural MRI, resting-state functional MRI, and [18F]FDG PET scans.Results: The results of vestibular function tests did not differ between the fishermen with and those without t-MdDS. However, participants with t-MdDS showed better performance in visuospatial memory function than those without t-MdDS (6.40 vs. 5.31, p-value = 0.016) as determined by the Corsi block test. Structural brain MRIs were normal in both groups. [18F]FDG PET showed a relative hypermetabolism in the bilateral occipital and prefrontal cortices and hypometabolism in the vestibulocerebellum (nodulus and uvula) in participants with t-MdDS compared to those without t-MdDS. Resting-state functional connectivities were significantly decreased between the vestibular regions of the flocculus, superior temporal gyrus, and parietal operculum and the visual association areas of the middle occipital gyrus, fusiform gyrus, and cuneus in participants with t-MdDS. Analysis of functional connectivity of the significant regions in the PET scans revealed decreased connectivity between the prefrontal cortex and visual processing areas in the t-MdDS group.Conclusion: Increased visuospatial memory, altered metabolism in the prefrontal cortex, visual cognition cortices, and the vestibulocerebellum, and decreased functional connectivity between these two functional areas might indicate reductions in the integration of vestibular input and enhancement of visuospatial attention in subjects with t-MdDS. Current functional neuroimaging similarities from transient MdDS via chronic MdDS to functional dizziness and anxiety disorders suggest a shared mechanism of enhanced self-awareness as a kind of continuum or as overlap disorders.

Frontal Behavior Syndromes in Idiopathic Normal Pressure Hydrocephalus as a Function of Alzheimer's Disease Biomarker Status.

Cognitive impairment and apathy are well-documented features of idiopathic normal pressure hydrocephalus (iNPH). However, research examining other neuropsychiatric manifestations of iNPH is scant, and it is unknown whether the neuropsychiatric presentation differs for iNPH patients with comorbid Alzheimer's disease (AD) versus iNPH without AD. This study aims to advance our understanding of neuropsychiatric syndromes associated with iNPH. Fifty patients from Butler Hospital's Normal Pressure Hydrocephalus Clinic met inclusion criteria. Caregiver ratings on the Frontal Systems Behavior Scale (FrSBe) were examined to appraise changes in apathy, executive dysfunction, and disinhibition. Patients also completed cognitive tests of global cognition, psychomotor speed, and executive functioning. AD biomarker status was determined by either amyloid-beta (Aβ) positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) total tau to Aβ-42 ratio. Results revealed clinically significant elevations on the FrSBe's apathy and executive dysfunction scales and modest correlations among these scales and cognitive measures. Of the 44 patients with available neuroimaging or CSF draw data, 14 presented with comorbid AD. Relative to the iNPH-only group, the iNPH + AD group showed a larger increase from pre-illness to current informant ratings on the executive dysfunction scale, but not the apathy or disinhibition scales. These results replicate and extend prior research by identifying apathy and executive dysfunction as prominent neuropsychiatric symptoms of iNPH and suggest comorbid AD exacerbates dysexecutive behaviors. Future research is warranted to examine the effects of comorbid AD pathology in response to shunt surgery for iNPH, neuropsychiatric symptom changes, and resultant caregiver burden.

Neuroimaging Findings in Chronic Hepatitis C Virus Infection: Correlation with Neurocognitive and Neuropsychiatric Manifestations

Chronic hepatitis C virus (HCV) infection is commonly associated with neurocognitive dysfunction, altered neuropsychological performance and neuropsychiatric symptoms. Quantifiable neuropsychological changes in sustained attention, working memory, executive function, verbal learning and recall are the hallmark of HCV-associated neurocognitive disorder (HCV-AND). This constellation is at variance with the neuropsychological complex that is seen in minimal hepatic encephalopathy, which is typified by an array of alterations in psychomotor speed, selective attention and visuo-constructive function. Noncognitive symptoms, including sleep disturbances, depression, anxiety and fatigue, which are less easily quantifiable, are frequently encountered and can dominate the clinical picture and the clinical course of patients with chronic HCV infection. More recently, an increased vulnerability to Parkinson’s disease among HCV-infected patients has also been reported. The degree to which neurocognitive and neuropsychiatric changes are due to HCV replication within brain tissues or HCV-triggered peripheral immune activation remain to be determined. Without absolute evidence that clearly exonerates or indicts HCV, our understanding of the so-called “HCV brain syndrome”, relies primarily on clinical and neuropsychological assessments, although other comorbidities and substance abuse may impact on neurocognitive function, thus confounding an appropriate recognition. In recent years, a number of functional and structural brain imaging studies have been of help in recognizing possible biological markers of HCV-AND, thus providing a rationale for guiding and justifying antiviral therapy in selected cases. Here, we review clinical, neuroradiological, and therapeutic responses to interferon-based and interferon-free regimens in HCV-related cognitive and neuropsychiatric disorder.

Early-Motor Phenotype Relates to Neuropsychiatric and Cognitive Disorders in Huntington's Disease.

To determine the relationships between the motor phenotype and the presence of specific neuropsychiatric and neuropsychological disorders in patients with early motor-manifest Huntington's disease (HD). From the Enroll-HD study, 3,505 individuals with HD who had ≤5 years of motor symptoms were classified based on the predefined parkinsonism/chorea index into chorea-dominant (n = 1125), parkinsonism-dominant (n = 867), and mixed-motor phenotype (n = 1513) groups. An analysis was performed on the results of the short Problem Behaviors Assessment. This test assesses patients for neuropsychiatric disorders such as depression, irritability/aggression, apathy, obsessive-compulsive behaviors, and psychosis as well as cognitive disorders by using neuropsychological tests such as the Stroop Interference test, Trail Making Test Part A and B, letter fluency, Symbol Digit Modality test, and animal fluency test. In these early motor-manifest HD individuals, motor phenotype was associated with neuropsychiatric and cognitive changes. Independent of the age of motor onset, motor duration and severity, CAG repeat expansion, and medication use, the parkinsonism-dominant group had more severe neuropsychiatric disorders (depression, apathy, obsessive-compulsive behaviors, and psychosis) and poorer performance on all cognitive tests than those patients in the mixed-motor phenotype and chorea-dominant groups. The patients in the chorea-dominant group had less apathy and depression than those in the mixed-motor phenotype group. In the early stage of motor-manifest HD, parkinsonism-dominant patients appear to have more severe neuropsychiatric disturbances and more cognitive impairments than those HD patients with chorea-dominant and mixed-motor phenotypes. Future studies should explore the brain mechanisms of these disorders and the possible treatments. © 2020 International Parkinson and Movement Disorder Society.

Neuropsychiatric changes in Parkinson’s disease patients: A prospective observational two years study

Neuropsychiatric changes in Parkinson’s disease patients: A prospective observational two years study

Evaluation of the Cunningham Panel™ in pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS): Changes in antineuronal antibody titers parallel changes in patient symptoms

ObjectiveThis retrospective study examined whether changes in patient pre- and post-treatment symptoms correlated with changes in anti-neuronal autoantibody titers and the neuronal cell stimulation assay in the Cunningham Panel in patients with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection (PANDAS), and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). MethodsIn an analysis of all tests consecutively performed in Moleculera Labs' clinical laboratory from April 22, 2013 to December 31, 2016, we identified 206 patients who were prescribed at least one panel prior to and following treatment, and who met the PANDAS/PANS diagnostic criteria. Patient follow-up was performed to collect symptoms and treatment or medical intervention. Of the 206 patients, 58 met the inclusion criteria of providing informed consent/assent and documented pre- and post-treatment symptoms. Clinician and parent-reported symptoms after treatment or medical intervention were categorized as “Improved/Resolved” (n = 34) or “Not-Improved/Worsened” (n = 24). These were analyzed for any association between changes in clinical status and changes in Cunningham panel test results. Clinical assay performance was also evaluated for reproducibility and reliability. ResultsComparison of pre- and post-treatment status revealed that the Cunningham Panel results correlated with changes in patient's neuropsychiatric symptoms. Based upon the change in the number of positive tests, the overall accuracy was 86%, the sensitivity and specificity were 88% and 83% respectively, and the Area Under the Curve (AUC) was 93.4%. When evaluated by changes in autoantibody levels, we observed an overall accuracy of 90%, a sensitivity of 88%, a specificity of 92% and an AUC of 95.7%. Assay reproducibility for the calcium/calmodulin-dependent protein kinase II (CaMKII) revealed a correlation coefficient of 0.90 (p < 1.67 × 10−6) and the ELISA assays demonstrated test-retest reproducibility comparable with other ELISA assays. ConclusionThis study revealed a strong positive association between changes in neuropsychiatric symptoms and changes in the level of anti-neuronal antibodies and antibody-mediated CaMKII human neuronal cell activation. These results suggest there may be clinical utility in monitoring autoantibody levels and stimulatory activity against these five neuronal antigen targets as an aid in the diagnosis and treatment of infection-triggered autoimmune neuropsychiatric disorders. Future prospective studies should examine the feasibility of predicting antimicrobial and immunotherapy responses with the Cunningham Panel.

Encefalopatía hepática: historia natural de la enfermedad, nueva clasificación e impacto en la calidad de vida

Hepatic Encephalopathy (HE) is a term including a wide range of neuropsychiatric changes, secondary to chronic hepatic damage. In Mexico, there is scarce epidemiological data about cirrhosis; thus, its prevalence is unknown. In 2000, cirrhosis was the fifth cause of death and in 2011 INEGI reported that digestive diseases were the fifth most common cause of mortality: in 2013, cirrhosis was the fourth cause of death. It has been estimated that by 2020 there will be 1,496,000 patients with cirrhosis, and by 2050 the figure will rise to 1,866,000. Therefore, an analysis was carried out in order to propose the new classification as a tool to calculate the epidemiology of hepatic encephalopathy and cirrhosis in Mexico, as well as to evaluate its impact on quality of life. Based on the historical descriptions of the HE, the natural history of the disease was reviewed focusing on the classifications. The results showed that the minimal hepatic encephalopathy requires, like any other subclinical hepatic encephalopathy, a meticulous clinical testing. Regarding the quality of life, several researchers have associated improvement with the treatment for hepatic encephalopathy. The authors conclude that hepatic encephalopathy must be classified according to the underlying etiology, clinical severity, course of time, and triggering factors analyzed in the latest international guidelines.

Autoimmune encephalitis: What has changed during the past 15 years?

AbstractNon‐infectious encephalitis has been a recognized entity for many years; however, its pathophysiology was not fully understood. Patients (usually women) presented with acute behavioral changes and were admitted to mental hospitals, without a correct diagnosis. With the new advances on antibody detection, the non‐infectious encephalitis panorama has been changing. Immune‐mediated diseases of the central nervous system encompass a variety of disorders, including the classic paraneoplastic encephalitis and the more recently discovered autoimmune encephalitis. Recognition of the new syndromes and antigens, in addition to the advances in diagnostic methods, such as antibody detection and imaging, and early implementation of immunotherapy, have changed the field of autoimmune encephalitis significantly over the past two decades. The best recognized form of autoimmune encephalitis is anti‐N‐methyl‐D‐aspartate receptor encephalitis, which usually presents with neuropsychiatric changes, seizures, autonomic dysfunction and usually a decreased level of consciousness. Nevertheless, the panorama for other types of receptors, such as anti‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor, anti‐gamma‐aminobutyric acid and, most recently, anti‐glycine receptor, anti‐metabotropic glutamate receptor 5, dopamine receptor D2 and dipeptidyl‐peptidase‐like protein 6, which can present clinically as encephalitis, is currently changing, meaning that the panorama for diagnosis and treatment is broadening every day.

Pediatric post-operative cerebellar mutism syndrome, cerebellar cognitive affective syndrome, and posterior fossa syndrome: historical review and proposed resolution to guide future study.

Cerebellar mutism (CM), pseudobulbar palsy, posterior fossa syndrome (PFS), and cerebellar cognitive affective syndrome (CCAS) are terms that have been used, sometimes interchangeably, to refer to the complex neurological constellation that occurs following surgical removal of cerebellar and fourth ventricular tumors, mostly in children, but also sometimes in adults. This paper reviews the origins of what is now regarded as pediatric post-operative cerebellar mutism, the cerebellar cognitive affective syndrome, and the neurological manifestations of injury to or disruption of brainstem and cerebellar structures. It examines the specific components of each of these phenomena in the context of the evolving understanding of the role of the cerebellum in nervous system function. Children undergoing surgical management of tumors in the posterior cranial fossa are at risk of experiencing cranial neuropathies, corticospinal damage, cerebellar ataxia and related motor disorders, neuropsychiatric and cognitive changes, and in some patients, mutism. These clinical presentations are differentiated from each other and examined in the context of the relevant anatomical structures and distributed neural circuits. The term posterior fossa syndrome is not sufficiently helpful in distinguishing the different elements of the clinical phenomena from each other, and because of this lack of precision and specificity, there is consensus among investigators in the international Posterior Fossa Society that the designation be retired. Using contemporary brain imaging methods and guided by careful clinical observation and meticulous definition of clinical phenomenology, it is now feasible to perform detailed structure function correlation analyses to achieve two critical goals in the care of children with tumors in the posterior cranial fossa. The first goal is to identify and understand the neural circuits responsible for the different manifestations-arousal, cranial neuropathies, long tract signs, cerebellar motor syndrome, cerebellar vestibular syndrome, cerebellar cognitive affective syndrome including emotional dyscontrol, and mutism. The second goal is to transform this knowledge into practical clinical intervention, preventing the complications inherent in the necessary surgery whenever possible, and develop new approaches to treatment with methods including brain modulation targeting interconnected nodes of the damaged neural circuits.

Clinical and neuroimaging heterogeneity of dementia with Lewy bodies

To study clinical characteristics of dementia with Lewy bodies (DLB) depending on neuropsychological, neuroimaging and concomitant cerebrovascular changes as well as on the character of disease onset. Forty-five patients with DLB (25 men and 20 women, men age 72.9±7.2 years, illness duration 2.9±2.2) were studied. The diagnosis was made according to international criteria (McKeith, et al, 2017). MRI, clinical/neurological examination and psychometric scales were used. Clinical, neuropsychological and neuroimaging results reveal the heterogeneity of DLB, which remains poorly investigated. An analysis of the clinical picture, cognitive profile, neuropsychiatric changes and MRI results identified three subtypes of DLB course: 1) typical; 2) with early psychotic manifestation; 3) atypical (mixed). This approach may improve the diagnosis of DLB, prognosis of disease course and treatment effectiveness.

Structural correlates of cognitive impairment in normal pressure hydrocephalus.

ObjectivesThe pathological bases for the cognitive and neuropsychiatric symptoms in normal pressure hydrocephalus (NPH) have not been elucidated. However, the symptoms may indicate dysfunction of subcortical regions. Previously, volume reductions of subcortical deep grey matter (SDGM) structures have been observed in NPH patients. The present study used automated segmentation methods to investigate whether SDGM structure volumes are associated with cognitive and neuropsychiatric measures.MethodsFourteen NPH patients and eight healthy controls were included in the study. Patients completed neuropsychological tests of general cognition, verbal learning and memory, verbal fluency and measures of apathy and depression pre‐ and postshunt surgery. Additionally, patients underwent 3 Tesla T1‐weighted magnetic resonance imaging at baseline and 6 months postoperatively. Controls were scanned once. SDGM structure volumes were estimated using automated segmentation (FSL FIRST). Since displacement of the caudate nuclei occurred for some patients due to ventriculomegaly, patient caudate volumes were also estimated using manual tracing. Group differences in SDGM structure volumes were investigated, as well as associations between volumes and cognitive and neuropsychiatric measures in patients.ResultsVolumes of the caudate, thalamus, putamen, pallidum, hippocampus and nucleus accumbens (NAcc) were significantly reduced in the NPH patients compared to controls. In the NPH group, smaller caudate and NAcc volumes were associated with poorer performance on neuropsychological tests and increased severity of neuropsychiatric symptoms, while reduced volume of the pallidum was associated with better performance on the MMSE and reduced apathy.ConclusionsStriatal volume loss appears to be associated with cognitive and neuropsychiatric changes in NPH.

Clinical outcomes and hospital costs of hepatic encephalopathy: an analysis of "real life" data from Marche Region.

Hepatic encephalopathy (HE) describes a spectrum of potentially reversible neuropsychiatric changes observed in patients with hepatic dysfunction and/or portosystemic shunt. The aim of this study is to compare data from clinical trials and observational studies with Italian real-world (RW) data as for clinical outcomes; other aim is to evaluate economic burden of hepatic encephalopathy related to hospitalization for overt HE. The work is based on data from the Health Information Systems (SIS) of Marche Region, Italy (about 1.5 million patients) available for the period 2008-2014. 450 subjects were identified (62% men, mean age 68 years) with a first episode of overt HE (OHE) in the three-year period 2010-2012. The mortality in the index hospitalization was equal to 32.2%; the 2-year mortality rate for a specific cause was 24.3% while that for all cases was 33.1%. The proportion of patients discharged alive from the hospitalization index that in the following two years incurs in rehospitalization, correlated with OHE is on average 66.6%. These figures largely exceed those identified in clinical trials or observational studies. Assuming that the incidence of OHE cases observed in the Marche region is representative of the national one we could estimate a charge to the NHS equal to about € 200 million for hospital assistance in the first year from the OHE event.

Presence of Toxoplasma gondii infection in brain as a potential cause of risky behavior: a report of 102 autopsy cases

Toxoplasmosis was linked to impairment in brain function, encompassing a wide range of behavioral and neuropsychiatric changes. Currently, the precise localization of Toxoplasma gondii in the human brain is limited and the parasite DNA was not found in population-based screening of autopsy cases. The aim of proposed study was to identify the presence of parasite DNA within the brain and its association with risky behavior and alcohol consumption in postmortem examination. Preliminarily, 102 cases with certain circumstances of death at time of forensic autopsy was included. Due to high risk of bias, the females were excluded from the analysis and final study group consists 97 cases divided into three groups: risky behavior, inconclusively risky behavior, and control group. The obtained tissue samples for Nested PCR covered four regions of the brain: symmetric left/right and anterior/posterior horns of lateral ventricles comprising lining ependyma and hippocampus. The second type of material comprised blood evaluated for antibodies prevalence using ELISA and alcohol concentration using HS-GC-FID. Analysis demonstrated 16.5% prevalence concerning the parasite DNA presence in examined brain tissue samples without specific distribution and association with age at death or days after death until an autopsy was performed. Results have shown correlation between occurrence of risky behavior leading to death and higher proportions of positive parasite DNA presence within the brain. Correlation was not observed between parasite DNA presence and excessive alcohol consumption. Conducted screening demonstrated correlation between parasite DNA presence in the brain with risky behavior and provided new information on possible effects of latent toxoplasmosis.

Behavioural and trait changes in parkinsonian patients with impulse control disorder after switching from dopamine agonist to levodopa therapy: results of REIN-PD trial

ObjectiveIn this multicentre open-label trial, we compared behavioural and neuropsychiatric symptoms in Parkinson’s disease (PD) patients with impulse control disorders (ICD) treated with dopamine agonists before and 12 weeks after...

Psycho-rheumatic Integration in Systemic Lupus Erythematosus: An Insight into Antibodies Causing Neuropsychiatric Changes.

The main purpose of this paper is to bring together all the antibodies and markers related to neurological and psychiatric manifestations in systemic lupus erythematosus and also the pharmacology that could help treat these symptoms. Existing research data regarding specific antibodies involved in the disease process and drugs that were being studied was collected and analyzed. After reviewing the studies published by various authors, symptoms were shown to be mainly caused by antibodies against N-methyl-D-aspartate receptor (NMDAR) antibodies, anti-endothelial, anti-ribosomal P, antiphospholipid antibodies, cytokines like interferons and chemokines. The monoclonal antibody rituximab has shown to be beneficial in some of the cases. Based on all the articles reviewed, the antibodies and cytokines showed the most effective evidence in causing the different manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE), but studies regarding the drugs being effective against all the symptoms are inconclusive as there are very few studies. Further research to support the drug’s effectiveness in managing the symptoms is needed. More studies are needed regarding early diagnosis of NPSLE using the antibodies as biomarkers as it could help in preventing these manifestations.

Crimean Congo Hemorrhagic Fever (CCHF) Review

Crimean Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by the arbovirus (a spherical enveloped RNA virus having diameter about 100nm). The virus belongs to Nairovirus genus of Bunyaviridae family. CCHF is a tick-borne viral disease of zoonotic importance prevalent in about 30 countries worldwide. Most susceptible species of virus are humans, livestock, mall vertebrates and ostriches. CCHF is also known as Congo fever, Central Asian hemorrhagic fever, Congo virus disease, Hungribta (blood taking), Crimean hemorrhagic fever, Khunymuny (nose bleeding), Karakhalak (black death), and viral tick-borne hemorrhagic fever disease. CCHF virus transmits to humans through tick biting (genus Hyalomma) and/or exposure to blood and/or tissues of infected livestock or direct contact with body fluids and/ or blood of viraemic persons. CCHF has been found fatal in humans but does not show clinical signs in Small vertebrates (excluding birds) and livestock. Most often mortality remains around 30%, however it may range up to 5% to 80%. Viremic person shows dramatic progression characterized by hemorrhages, chilling, sudden onset of high fever, headache, dizziness, gastrointestinal symptoms, severe back, and abdominal pain and myalgia, after 3–7 days of incubation. Other symptoms include diarrhea, vomiting, nausea, cardiovascular, and neuropsychiatric changes. However, in severe infection, hemorrhages ranging from petechiae to large areas of ecchymosis may develop. Early diagnosis using ELISA (enzyme-linked immunoassay) and molecular tools such as RT-PCR (real-time reverse transcription-polymerase chain reaction) is helpful for prevention and therapeutic measures. Although, currently there is no antiviral drug available for CCHF, however, Immunotherapy and Ribavirin have been found to be effective during sporadic outbreaks of disease. Further sound scientific research about basic biology of CCHFV may lead to the better treatment plan in the future.

Alzheimer's disease drug development pipeline: 2018

IntroductionTreatments for Alzheimer's disease (AD) are needed due to the growing number of individuals with preclinical, prodromal, and dementia forms of AD. Drug development for AD therapies can be examined by inspecting the drug development pipeline as represented on clinicaltrials.gov. MethodsClinicaltrials.gov was assessed as of January 30, 2018 to determine AD therapies represented in phase I, phase II, and phase III. ResultsThere are 112 agents in the current AD treatment pipeline. There are 26 agents in 35 trials in phase III, 63 agents in 75 trials in phase II, and 23 agents in 25 trials in phase I. A review of the mechanisms of actions of the agents in the pipeline shows that 63% are disease-modifying therapies, 22% are symptomatic cognitive enhancers, and 12% are symptomatic agents addressing neuropsychiatric and behavioral changes. Trials in phase III are larger and longer than phase II or phase I trials, particularly those involving disease-modifying agents. Comparison with the 2017 pipeline shows that there are four new agents in phase III, 14 in phase II, and eight in phase I. Inspection of the use of biomarkers as revealed on clinicaltrials.gov shows that amyloid biomarkers are used as entry criterion in 14 phase III disease-modifying agent trials and 17 disease-modifying agent trials in phase II. Twenty-one trials of disease-modifying agents in phase II did not require biomarker confirmation for AD at trial entry. DiscussionThe AD drug development pipeline is slightly larger in 2018 than in 2017. Trials increasingly include preclinical and prodromal populations. There is an increase in nonamyloid mechanisms of action for drugs in earlier phases of drug development. Biomarkers are increasingly used in AD drug development but are not used uniformly for AD diagnosis confirmation.

The site of stimulation moderates neuropsychiatric symptoms after subthalamic deep brain stimulation for Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus for Parkinson's disease is an established advanced therapy that addresses motor symptoms and improves quality of life. However, it has also been associated with neuropsychiatric symptoms such as impulsivity and hypomania. When significant, these symptoms can be distressing, necessitating psychiatric intervention. However, a comprehensive analysis of neurocognitive and neuropsychiatric outcomes with reference to the site of subthalamic stimulation has not been undertaken. We examined this matter in a consecutive sample of 64 persons with Parkinson's disease undertaking subthalamic deep brain stimulation. Participants were assessed with a battery of neuropsychiatric instruments at baseline and at repeated postoperative intervals. A psychiatrist identified patients with emergent, clinically-significant symptoms due to stimulation. The site of the active electrode contact and a simulated volume of activated tissue were evaluated with reference to putative limbic, associative and motor subregions of the subthalamic nucleus. We studied anatomical correlates of longitudinal neuropsychiatric change and delineated specific subthalamic regions associated with neuropsychiatric impairment. We tested the ability of these data to predict clinically-significant symptoms. Subthalamic stimulation within the right associative subregion was associated with inhibitory errors on the Excluded Letter Fluency task at 6-weeks (p = 0.023) and 13-weeks postoperatively (p = 0.0017). A cluster of subthalamic voxels associated with inhibitory errors was identified in the right associative and motor subregions. At 6-weeks, clinically-significant neuropsychiatric symptoms were associated with the distance of the active contact to the right associative subregion (p = 0.0026) and stimulation within the right associative subregion (p = 0.0009). At 13-weeks, clinically-significant symptoms were associated with the distance to the right (p = 0.0027) and left (p = 0.0084) associative subregions and stimulation within the right associative subregion (p = 0.0026). Discrete clusters of subthalamic voxels associated with high and low likelihood of postoperative neuropsychiatric symptoms were identified in ventromedial and dorsolateral zones, respectively. When a classifier was trained on these data, clinically-significant symptoms were predicted with an accuracy of 79%. These data underscore the importance of accurate electrode targeting, contact selection and device programming to reduce postoperative neuropsychiatric impairment. The ability to predict neuropsychiatric symptoms based on subthalamic data may permit anticipation and prevention of these occurrences, improving safety and tolerability.

Deployed Sailor With an Acute Presentation of WIlson Disease

A 23 year old previously healthy US Sailor was evacuated from Bahrain after presenting to a local hospital with dyspnea on exertion, abdominal swelling, jaundice, cognitive decline, and months of fatigue. Patient had no past medical or surgical history and was an infrequent drinker. Family history was notable for an uncle with schizophrenia who died of cirrhosis presumed to be from alcohol in his early 40s. Examination demonstrated hypomimia, bradyphrenia, bradykinesia, Kayser-Fleischer rings, jaundice, new ascites, but no asterixis. Labs were notable for pancytopenia with platelets of 37K, an absolute neutrophil count (ANC) 111, and a coombs negative hemolytic anemia. Alkaline phosphatase was 133, Aspartate aminotransferase was 81, Alanine aminotransferase was 57, and total bilirubin was 1.9. Presentation INR was 2.8, with a calculated MELD sodium of 26. A contrast MRI showed multiple basal ganglia signal abnormalities. On arrival in Germany, ceruloplasmin was low at 8 mg/dL. 24 hour urine copper collection was performed and treatment was subsequently initiated with oral zinc based on a presumptive diagnosis of Wilson disease. Subsequent transjugular liver biopsy was performed with an elevated HVPG of 12 confirming portal hypertension. Small esophageal varices were noted on EGD. Wilson disease is a rare autosomal recessive disease with a worldwide incidence approaching 1 in 30,000 that results from copper accumulation and injury to affected tissues. Defects in the ATP7B gene, which encodes transmembrane transport of copper within hepatocytes, play a role in the disease. Key clinical features include liver disease, neuropsychiatric changes, Kayser-Fleischer rings, and coombs negative hemolytic anemia. However, given significant variability in disease presentation, both the European Association for the Study of Liver Disease (EASL) and the American Association for the Surgery of Liver Disease (AASLD) have proposed criteria to aid in diagnosis. Using the EASL criteria, the diagnosis was made approximately 8 days earlier, although ultimately the patient met the requirements from both societies. This atypical presentation of jaundice and constitutional symptoms in a deployed sailor highlights the potential advantages of the EASL criteria which do not require 24 hour urine copper which is not readily accessible in a deployed setting.

The Neuropsychology of Huntington's Disease.

Huntington's disease is an inherited, degenerative brain disease, characterized by involuntary movements, cognitive disorder and neuropsychiatric change. Men and women are affected equally. Symptoms emerge at around 40 years, although there is wide variation. A rare juvenile form has onset in childhood or adolescence. The evolution of disease is insidious and structural and functional brain changes may be present more than a decade before symptoms and signs become manifest. The earliest site of pathology is the striatum and neuroimaging measures of striatal change correlate with neurological and cognitive markers of disease. Chorea and other aspects of the movement disorder are the most visible aspect of the disease. However, non-motor features have greatest affect on functional independence and quality of life, so require recognition and management. The evidence-base for non-pharmacological treatments in Huntington's disease is currently limited, but recent intervention studies are encouraging.