Early Behavioral Changes Research Articles

Pearls and Oy-sters: Typical Atypical Creutzfeld-Jakob Disease: A Case Presenting as a Rapidly Progressive Corticobasal Syndrome Without Dementia.

Creutzfeld-Jakob Disease (CJD) is a rare disease but a common cause of rapidly progressive neurodegeneration. Although the "classic" presentation involves early dementia or behavioral changes, there are well-described atypical variants with less prominent cognitive symptoms at onset. One such variant is Corticobasal Syndrome (CBS), which may be seen with other underlying neurodegenerative processes, but when due to prion disease pathology involves much more rapid progression and certain characteristic imaging findings. This report presents a case presenting as CBS without cognitive or behavioral changes at onset, which rapidly progressed and was determined ultimately to be due to underlying CJD. This case illustrates the need for a high index of suspicion for CJD in order to drive appropriate diagnostic testing and careful review of imaging and EEG findings, which may be subtle in early disease.

Editors' Note: Phenotypic Variability in ALS-FTD and Effect on Survival

Dr. Ahmed et al. examined initial presentations and cognitive and behavioral profiles in 59 patients with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) and 39 patients with behavioral variant frontotemporal dementia (bvFTD) and compared their MRI brain atrophy patterns and survival trajectories. They found that initial motor presentation in ALS-FTD was associated with shorter survival than those with a cognitive presentation, despite similar overall cognitive deficits. Patients with ALS-FTD also showed reduced emotional processing as well as greater motor cortex and dorsal lateral prefrontal cortex atrophy than those with bvFTD, with motor cortex atrophy, in turn, associated with a 1.5-fold reduction in survival. In response, Dr. Abe cites a case report of a patient with ALS and dementia who presented with disturbances in emotion processing and behavior, with such early behavioral changes also noted in other studies of ALS-FTD. Dr. Abe suggests that functional neuroimaging studies may help further elucidate pathophysiologic processes in these cases, citing a case of a patient with ALS-FTD and prominent bulbar palsy and memory loss but preserved personality who had hypoperfusion in the central and prefrontal cortex, but not in the dorsolateral prefrontal cortex. Responding to these comments, the authors agree that ALS-FTD can present with cognitive and behavioral changes. They note that their study results suggest that survival in ALS-FTD may be mediated by motor function and other critical physiologic aspects. They also note that patients with ALS-FTD and an initial cognitive presentation had more prominent language changes, but contrary to the conventional perception of bvFTD as having more deficits in emotional processing, patients with ALS-FTD had greater deficits in this domain in their study. They agree that functional neuroimaging, in combination with clinical, structural, and pathologic evaluation, can help improve our understanding of these diseases. This exchange demonstrates how modern phenotypic studies are challenging previous assumptions about distinctions between different subtypes of FTD and ALS-FTD and elucidating new discoveries about these conditions. Dr. Ahmed et al. examined initial presentations and cognitive and behavioral profiles in 59 patients with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) and 39 patients with behavioral variant frontotemporal dementia (bvFTD) and compared their MRI brain atrophy patterns and survival trajectories. They found that initial motor presentation in ALS-FTD was associated with shorter survival than those with a cognitive presentation, despite similar overall cognitive deficits. Patients with ALS-FTD also showed reduced emotional processing as well as greater motor cortex and dorsal lateral prefrontal cortex atrophy than those with bvFTD, with motor cortex atrophy, in turn, associated with a 1.5-fold reduction in survival. In response, Dr. Abe cites a case report of a patient with ALS and dementia who presented with disturbances in emotion processing and behavior, with such early behavioral changes also noted in other studies of ALS-FTD. Dr. Abe suggests that functional neuroimaging studies may help further elucidate pathophysiologic processes in these cases, citing a case of a patient with ALS-FTD and prominent bulbar palsy and memory loss but preserved personality who had hypoperfusion in the central and prefrontal cortex, but not in the dorsolateral prefrontal cortex. Responding to these comments, the authors agree that ALS-FTD can present with cognitive and behavioral changes. They note that their study results suggest that survival in ALS-FTD may be mediated by motor function and other critical physiologic aspects. They also note that patients with ALS-FTD and an initial cognitive presentation had more prominent language changes, but contrary to the conventional perception of bvFTD as having more deficits in emotional processing, patients with ALS-FTD had greater deficits in this domain in their study. They agree that functional neuroimaging, in combination with clinical, structural, and pathologic evaluation, can help improve our understanding of these diseases. This exchange demonstrates how modern phenotypic studies are challenging previous assumptions about distinctions between different subtypes of FTD and ALS-FTD and elucidating new discoveries about these conditions.

Влияние афобазола на изменения в раннем постнатальном периоде у мышей линии BALB/c с фетальным вальпроатным синдромом

Введение. Воздействие вальпроевой кислотой во время беременности у грызунов широко используется для моделирования расстройств аутистического спектра (РАС). Цель исследования - изучение ранних поведенческих изменений у мышей BALB/c, пренатально подвергшихся однократному воздействию натриевой соли вальпроевой кислоты (400 мг/кг), и возможности их коррекции афобазолом. Методика. Объект исследования - мыши линии BALB/c с фетальным вальпроат-синдромом (ФВС), которым с 7-х по 14-е сут постнатального развития перорально ежедневно вводили афобазол (10 мг/кг) или 0,9% раствор хлорида натрия. Контрольная группа получала 0,9% раствор хлорида натрия в эквивалентном объеме (0,1 мл на 10 г массы). Состояние мышат изучали с 6-х по 14-е сут постнатального развития, оценивали их физическое развитие, скорость созревания сенсорно-двигательных рефлексов, эмоционально-двигательное поведение и точную координацию движений при помощи батареи «развитийных» тестов. Результаты. Введение самкам мышей на 13-й день беременности вальпроевой кислоты приводило к отставанию созревания у потомства сенсорно-двигательных рефлексов, нарушению эмоционально-двигательного поведения и координации движений в гнездовом периоде. Афобазол, при введении 10 мг/кг перорально ежедневно, начиная с 7-х сут постнатального развития мышам с ФВС, корригировал отмеченные нарушения в тестах, отражающих нарушения развития нервной системы. Заключение. Установлены корригирующие свойства афобазола в отношении нарушений, вызванных пренатальным введением ВПК, что определяет целесообразность дальнейшего изучения афобазола на моделях РАС. Introduction. Exposure of rodents to valproic acid during pregnancy is associated with increased incidence of autism spectrum disorders, and has been extensively used as an appropriate model of autism. Aim. To study early behavioral changes in BALB/c mice prenatally exposed to a single dose of valproic acid sodium salt (400 mg/kg) and a possibility of correcting these changes with afobazole. Methods. The study was performed on BALB/c mice with fetal valproate syndrome (FVS). The mice were daily injected orally afobazole 10 mg/kg or 0.9% sodium chloride from day 7 to day 14 of the postnatal development. The control group was injected with an equivalent volume (0.1 ml per 10 g body weight) of 0.9% sodium chloride. The condition of mice was studied from day 6 to day 14 of the postnatal development with evaluation of their physical development, maturation rate of sensory-motor reflexes, emotional-motor behavior, and precise coordination using a battery of «developmental» tests. Results. Administration of valproic acid to female mice on the 13th day of pregnancy led to delayed maturation of the offspring’s sensory-motor reflexes, impaired emotional-motor behavior and coordination of movements during the nesting period. Afobazole administered to mice with fetal valproate syndrome from day 7 to day 14 of the postnatal development at a dose of 10 mg/kg (daily, orally), corrected the disorders in the tests used for assessing retardation or disruption of nervous system development.

Experimental study on relationship between early invasive behavior and structural changes of extracellular matrix using cancer spheroids

Experimental study on relationship between early invasive behavior and structural changes of extracellular matrix using cancer spheroids

Depressive symptoms are associated with hippocampal neurodegeneration in preclinical autosomal dominant Alzheimer’s disease

AbstractBackgroundIncreasing evidence suggests that depressive symptoms may be among early behavioral changes in Alzheimer’s Disease (AD). However, the neurobiology of these symptoms in the preclinical stages of AD remains unclear, particularly in relation to markers of neurodegeneration. Studying depression in individuals who carry mutations for autosomal dominant AD (ADAD) is a compelling way to characterize depressive symptoms in preclinical AD, as virtually all ADAD mutation carriers develop dementia and have a well‐characterized trajectory from pre‐symptomatic to clinical disease stages.MethodWe evaluated cross‐sectional associations between the 15‐item Geriatric Depression Scale (GDS) and neurodegeneration of the hippocampus, one of the most vulnerable brain regions in ADAD and depression, in 27 cognitively unimpaired PSEN1 E280A mutation carriers and 26 matched non‐carrier family members of a Colombian kindred with ADAD. Global cognition was measured by the Mini‐Mental State Examination (MMSE); hippocampal volume was assessed by structural MRI. A general linear model with dependent variable GDS, predictor hippocampal volume, and covariates, age, sex, MMSE, and intracranial volume (ICV), was employed.Result PSEN1 E280A carriers and non‐carriers did not differ in GDS (carriers:2.2±2.6, non‐carriers:2.9±3.5; p=0.64), sex (carriers:70% females, non‐carriers:88% females; p=0.24), age (carriers:35.9±8.2 years, non‐carriers:37.0±6.5; p=0.56), ICV (carriers:1.4 x106 ±1.1 x 105 mm3, non‐carriers:1.4 x 106 ±1.3 x 105 mm3; p=0.16), or hippocampal volume (carriers: 3867±569 mm3, non‐carriers: 4090±371 mm3; p=0.20). Compared to non‐carriers, carriers had lower MMSE scores (carriers: 28.3±2.9, non‐carriers: 29.7±0.5; p=0.03). In carriers, GDS was negatively associated with hippocampal volume (β= ‐0.71, t= ‐2.6, p=0.02), but not with age, sex, MMSE, or ICV. This association between GDS and hippocampal volume was not observed in non‐carriers (β= ‐0.26, t= ‐1.2, p=0.25).ConclusionDepressive symptoms in cognitively‐unimpaired carriers of an ADAD mutation are significantly associated with early hippocampal neurodegeneration, years before the estimated onset of dementia. This provides some of the first evidence of a region‐specific neurodegenerative basis of depressive symptoms in preclinical ADAD. Future longitudinal investigation is needed to characterize the temporal sequence of depressive symptoms in relation to markers of brain pathology and cognitive decline in AD. Findings may have implications for early interventions to reduce depressive symptoms in individuals who have AD risk factors.

Longitudinal increase in depressive symptoms in relation to neurodegeneration in clinically normal older adults: Findings from the Harvard Aging Brain Study

AbstractBackgroundEvidence suggests that depressive symptoms may be early behavioral changes preceding the development of Alzheimer’s Disease (AD). However, the neurobiological trajectory of depressive symptoms in reference to neurodegeneration of the hippocampus—a structure implicated in both mood and memory regulation—remains poorly understood in preclinical AD. In the current study, we examined the impact of baseline hippocampal volume (HV) both independently, and interactively with amyloid‐ß, on longitudinal change in depressive symptoms in clinically normal (CN) older adults.Method270 Harvard Aging Brain Study participants (age:73.5 ±6.1; 58% females) completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=4.28 annual visits). All participants were cognitively unimpaired without clinically significant depression at study entry (mean GDS=3.09±2.86; range: (0‐12)). All underwent structural MRI scans and amyloid‐ß (11C‐Pittsburgh Compound B) PET at study year 1. In the primary linear mixed model, the association between dependent variable GDS (for each annual study visit) and HV was examined, with a random intercept and slope for each participant, covariates: age, sex, and education; and the interaction of predictors with time. In a secondary model, HV X cortical amyloid, X time was additionally included as a predictor.ResultIn the primary model, lower baseline HV (ß=‐0.0006; t=‐1.909; 95 % CI (‐1.2 x 10‐3, 1.7 x10‐5); p=0.057), but not its interaction with time (HV X time:(ß =‐0.000; t=‐1.12; 95% CI (‐7x10‐5, 6x10‐5); p=0.903) was marginally associated with higher GDS. In the secondary model, baseline HV and cortical amyloid were not interactive predictors of longitudinal GDS (HV X cortical amyloid X time: (ß =‐0.0001; t=‐0.90; 95% CI (‐4x10‐4, 0.0002); p=0.364).ConclusionLower baseline hippocampal volume is marginally associated with greater depressive symptoms; however, it did not independently, or in synergy with cortical amyloid, predict worsening depressive symptoms over time. These preliminary findings suggest that hippocampal atrophy may not be a predominant indicator of accelerating depression in CN older adults. Of note, our sample was non‐depressed at baseline. Future work in samples with non‐restricted behavioral symptoms and incorporating longitudinal AD biomarkers is needed to better understand neurobiological trajectory and identify targets for treatment at the earliest stages of AD.

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI—which is commonly used to assess RSFC in humans—have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.

A single episode of early-life status epilepticus impacts neonatal ultrasonic vocalization behavior in the Fmr1 knockout mouse

Fragile X syndrome (FXS) is a genetic disorder caused by a trinucleotide (CGG) expansion mutation in the Fmr1 gene located on the X chromosome. It is characterized by hyperactivity, increased anxiety, repetitive-stereotyped behaviors, and impaired language development. Many children diagnosed with FXS also experience seizures during their lifetime. However, the underlying etiology of the relationship between FXS and epilepsy is not fully understood. Ultrasonic vocalizations (UVs) are one tool that may be used to measure early behavioral changes in mouse pups. In the present study, neonatal UVs were analyzed as a measure of communicative behavior in a mouse model of FXS, both with and without early-life seizures (ELSs). On postnatal day (PD) 10, status epilepticus (SE) was induced via intraperitoneal injections of 0.5% kainic acid (2.0 mg/kg) in male Fmr1 knockout (KO) and wild-type (WT) mice. On PD 12, all pups were temporarily isolated from their dam and UVs were recorded. Significant alterations were found in both spectral and temporal measures across genotype and seizure groups. Early-life seizure experience resulted in a significant increase in the quantity of UVs only in WT animals (p < 0.05). We also found that while there was no difference between genotypes in the total number of vocalizations made, calls produced by Fmr1 KO mice were significantly shorter and had a higher peak frequency compared with WT mice. Overall, these findings support the use of vocalization behavior as an early phenotypic marker and highlight the importance of utilizing double-hit models to better understand comorbid disorders.

Perinatal exposure to omega-3 fatty acid imbalance leads to early behavioral alterations in rat pups

Polyunsaturated long-chain omega-3 fatty acids (n3-PUFAs) are crucially involved in brain development and function. Inadequate n3-PUFA intake in rats during the perinatal period leads to behavioral deficits in adulthood, but early behavioral changes have not yet been investigated. The present study aimed to investigate potential behavioral alterations in neonatal rats exposed to a perinatal n3-PUFA imbalance. Female Sprague Dawley rats were fed an n3-PUFA–enriched or an n3-PUFA–deficient diet throughout mating, pregnancy, and lactation. Controls were fed an n6/n3-PUFA–balanced diet. We observed maternal behavior from postnatal day (PND) 2 to PND 13 and tested pups in the isolation-induced ultrasonic vocalization (USV) emission task at PNDs 3, 5, 9 and 13 to evaluate the impact of perinatal n3-PUFA on early emotional traits. Both the n3-PUFA–enriched and n3-PUFA–deficient diets profoundly decreased maternal behavior. At PNDs 3 and PND 5, pups of the n3-PUFA–deficient or –enriched diet groups emitted significantly fewer USVs compared with control pups. Further, the sonographic pattern of the USVs was altered in the test pups compared with the control pups at PND 9 and PND 13. The present findings indicate that both n3-PUFA deficiency and supplementation induce alterations in mother-infant interaction and early behavioral disturbances in the offspring.

Community Vs. hospital HIV testing sites in Jerusalem, Israel - who\u2019s tested and who\u2019s at risk?

BackgroundAfter decades of constant increase in HIV diagnoses among men who have sex with men (MSM), a gradual decrease has been reported in recent years. Timely detection of HIV leads to early treatment and behavioral changes which decrease further transmissions. This cross-sectional study aimed to assess demographic and behavioral characteristics of individuals who were tested for HIV in Jerusalem, Israel.MethodsThis study compared individuals who were tested at Hadassah AIDS Center (HAC) with those tested at the Jerusalem Open House (JOH) - an LGBTQ community center. Participants completed anonymous questionnaires regarding their demographic, HIV-testing history, and sexual behaviors. High-risk sexual behavior (HRSB) was defined as a diagnosis of sexually transmitted disease or condomless anal/vaginal sex during the last year.ResultsAmong 863 participants, 104 (12.1%) were tested in HAC and 759 (87.9%) in JOH. Of those, 19 (18.3%) and 227 (29.9%) were HRSB, respectively. Two MSM were tested positive in JOH. JOH received more MSM, HRSB and individuals who were previously tested for HIV, while HAC received more migrants and health-care workers. HRSB-participants were more commonly younger, males, non-Jewish, with lower income, previously tested for HIV, reported more sexual partners, payed for sex or used drugs.ConclusionsMSM and HRSB-individuals were more likely to be tested in JOH, while migrants and health-care workers in HAC, possibly due to the geographic location, reputation and specific atmosphere. In order to encourage HIV-tests among HRSB and non-Jews, additional interventions should be employed, including outreach activities, extending opening hours and reducing testing costs should be employed.

Impairment to Cognitive Functions in Wistar Rats in a Model of the Preclinical Stage of Parkinson’s Disease

The preclinical stage of Parkinson’s disease (PD), when most dopaminergic neurons in the nigrostriatal system of the brain are still intact and compensatory mechanisms have not yet been overwhelmed, is the most effective “therapeutic window.” Much attention in recent years has therefore been focused on seeking early markers for the neurodegenerative process and developing experimental models. The present study addressed the task of analyzing early behavioral changes reflecting impairments in the cognitive and affective domains on modeling the premotor stage of PD in rats, with identification of the most informative tests. A model developed in our laboratory is based on a prolonged (21 days) preclinical stage of PD in rats by increasing suppression of the ubiquitin-proteasome system of the brain induced by two intranasal doses of the specific proteasome inhibitor lactacystin. Cognitive impairments were assessed using the novel object recognition and Y maze tests and the what–where–when paradigm. Anxiety was assessed in the elevated plus maze and open field tests. Administration of lactacystin was found to degrade spatial memory, episodic memory, and recognition of novel objects in rats on the background of a transient increase in the level of anxiety. These data suggest that impairments in the cognitive and affective domains may be early signs of the development of neurodegeneration in the brain.

Comparison between Tail Suspension Swing Test and Standard Rotation Test in Revealing Early Motor Behavioral Changes and Neurodegeneration in 6-OHDA Hemiparkinsonian Rats

The unilateral 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD) is one of the most commonly used in rodents. The anatomical, metabolic, and behavioral changes that occur after severe and stable 6-OHDA lesions have been extensively studied. Here, we investigated whether early motor behavioral deficits can be observed in the first week after the injection of 6-OHDA into the right substantia nigra pars compacta (SNc), and if they were indicative of the severity of the dopaminergic (DAergic) lesion in the SNc and the striatum at different time-points (day 1, 3, 5, 7, 14, 21). With this aim, we used our newly modified tail suspension swing test (TSST), the standard rotation test (RT), and immunohistochemical staining for tyrosine hydroxylase (TH). The TSST, but not the standard RT, revealed a spontaneous motor bias for the 6-OHDA-lesioned rats from the day 1 post-surgery. Both tests detected the motor asymmetry induced by (single and repeated) apomorphine (APO) challenges that correlated, in the first week, with the DAergic neuronal degeneration. The described TSST is fast and easy to perform, and in the drug-free condition is useful for the functional assessment of early motor asymmetry appearing after the 6-OHDA-lesion in the SNc, without the confounding effect of APO challenges.

Are We #StayingHome to Flatten the Curve?

The recent spread of COVID-19 across the U.S. led to concerted efforts by states to flatten the curve through the adoption of stay-at-home mandates that encourage individuals to reduce travel and maintain social distance. Combining data on changes in travel activity with COVID-19 health outcomes and state policy adoption timing, we characterize nationwide changes in mobility patterns and isolate the portion attributable to statewide mandates. We find evidence of dramatic nationwide declines in mobility prior to adoption of any statewide mandates. Once states adopt a mandate, we estimate further mandate-induced declines between 2.1 and 7.0 percentage points across methods that account for states' differences in travel behavior prior to policy adoption. In addition, we investigate the effects of stay-at-home mandates on changes in COVID-19 health outcomes while controlling for pre-trends and observed pre-treatment mobility patterns. We estimate mandate-induced declines between 0.13 and 0.17 in deaths (5.6 to 6.0 in hospitalizations) per 100 thousand across methods. Across 43 adopting states, this represents 23,366-30,144 fewer deaths (and roughly one million averted hospitalizations) for the months of March and April - which indicates that death rates could have been 42-54% higher had states not adopted statewide policies. We further find evidence that changes in mobility patterns prior to adoption of statewide policies also played a role in reducing COVID-19 mortality and morbidity. Adding in averted deaths due to pre-mandate social distancing behavior, we estimate a total of 48-71,000 averted deaths from COVID-19 for the two-month period. Given that the actual COVID-19 death toll for March and April was 55,922, our estimates suggest that deaths would have been 1.86-2.27 times what they were absent any stay-at-home mandates during this period. These estimates represent a lower bound on the health impacts of stay-at-home policies, as they do not account for spillovers or undercounting of COVID-19 mortality. Our findings indicate that early behavior changes and later statewide policies reduced death rates and helped attenuate the negative consequences of COVID-19. Further, our findings of substantial reductions in mobility prior to state-level policies convey important policy implications for re-opening.

Pilot Site Deployment of an IoT Solution for Older Adults' Early Behavior Change Detection.

The world demography is continuously changing. During the last decade, we noticed a regular variation in the world demography leading to a nearly balanced society share between the young and aging population. This increasing older adult population is facing many problems. In fact, the transition to the aging period is associated with physical, psychological, cognitive, and societal changes. Negative behavior changes are considered as indicators of older adults’ frailty. This is why it is important to detect such behavior changes early in order to prevent isolation, sedentary lifestyle, and even diseases, and therefore delay the frailty period. This paper exhibits a proof-of-concept pilot site deployment of an Internet of Thing (IoT) solution for the continuous monitoring and detection of older adults’ behavior changes. The objective is to help geriatricians detect sedentary lifestyle and health-related problems at an early stage.

Thiamine Deficiency Modulates p38MAPK and Heme Oxygenase-1 in Mouse Brain: Association with Early Tissue and Behavioral Changes.

Thiamine deficiency (TD) produces severe neurodegenerative lesions. Studies have suggested that primary neurodegenerative events are associated with both oxidative stress and inflammation. Very little is known about the downstream effects on intracellular signaling pathways involved in neuronal death. The primary aim of this work was to evaluate the modulation of p38MAPK and the expression of heme oxygenase 1 (HO-1) in the central nervous system (CNS). Behavioral, metabolic, and morphological parameters were assessed. Mice were separated into six groups: control (Cont), TD with pyrithiamine (Ptd), TD with pyrithiamine and Trolox (Ptd + Tr), TD with pyrithiamine and dimethyl sulfoxide (Ptd + Dmso), Trolox (Tr) and DMSO (Dmso) control groups and treated for 9 days. Control groups received standard feed (AIN-93M), while TD groups received thiamine deficient feed (AIN-93DT). All the groups were subjected to behavioral tests, and CNS samples were collected for cell viability, histopathology and western blot analyses. The Ptd group showed a reduction in weight gain and feed intake, as well as a reduction in locomotor, grooming, and motor coordination activities. Also, Ptd group showed a robust increase in p38MAPK phosphorylation and mild HO-1 expression in the cerebral cortex and thalamus. The Ptd group showed a decreased cell viability, hemorrhage, spongiosis, and astrocytic swelling in the thalamus. Groups treated with Trolox and DMSO displayed diminished p38MAPK phosphorylation in both the structures, as well as attenuated thalamic lesions and behavioral activities. These data suggest that p38MAPK and HO-1 are involved in the TD-induced neurodegeneration in vivo, possibly modulated by oxidative stress and neuroinflammation.

Locomotion and eating behavior changes in Yucatan minipigs after unilateral radio-induced ablation of the caudate nucleus

The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.

C-35 Clinical Diagnosis of Behavioral Variant Frontotemporal Dementia with Underlying Primary Age-Related Tauopathy

Abstract Objective Primary age-related tauopathy (PART) is a neuropathologic entity characterized by neurofibrillary tangles in medial temporal regions comparable to Alzheimer’s disease (AD), but with few or no amyloid plaques. A definitive clinical phenotype for PART has not been determined. Some studies report milder deficits and a longer course compared with AD. In the National Alzheimer’s Coordinating Center database, the most common clinical diagnosis of PART cases classified as dementia is AD, though primary progressive aphasia/behavioral-variant frontotemporal dementia (bvFTD) is also common. We describe 3 patients diagnosed with bvFTD later found to have PART to further describe possible PART phenotypes. Method Charts of 3 autopsy-proven PART cases clinically diagnosed as bvFTD by consensus conference were reviewed. All patients (A, B, C) were male and presented with behavioral changes. Only B was APOE4+. Neuroimaging was mostly unremarkable (ventriculomegaly in patient C). Results All subjects presented with anosognosia, fatigue, and behavioral changes, 1 (A) with pronounced apathy and 2 (B, C) with disinhibition, impulsivity, and mood swings. Onset was early 70’s for A &amp; C, and 50’s for B. Patients B &amp; C had gradual onset/course (~20 years) with initial subtle executive (EF) dysfunction and intact memory. Patient A had a 6-year course and initial deficits in EF and memory. Conclusion This review underscores the varied presentation and clinical course of PART, including presence of early behavioral changes. Slower progression as previously reported was seen in 2 of 3 patients. Future research is warranted to better characterize the entire spectrum of clinical presentations in subjects with PART neuropathology.

Aeromonas hydrophila infection in silver catfish causes hyperlocomotion related to stress

Aeromonosis is a fish disease that leads to haemorrhagic septicaemia and high mortality. The detection of early behavioural changes associated to this disease could be helpful in anticipating the initiation of treatment, increasing the probability of success. The influence of this disease on the hypothalamic-pituitary-interrenal (HPI) axis and on the brain expression of heat shock proteins (HSP) is little known. Therefore, the aim of this study was to evaluate the effect of Aeromonas hydrophila infection on individual behaviour and brain expression of genes related to stress (slc6a2, hsp90, hspa12a, hsd20b, hsd11b2, crh) in silver catfish (Rhamdia quelen). Thirty fish were divided into healthy and infected groups. The fish of the infected group were inoculated intramuscularly with 50 μL of bacterial suspension (6.4 × 108 CFU/mL), while control animals received 50 μL of saline. On day five post-infection, animals were submitted to the novel tank test, euthanized, and the brain was collected for molecular analysis. Infected fish swam more in the unknown aquarium and presented an increase in brain expression of genes related to HSP (hspa12a) and the route of cortisol synthesis (crh) when compared to uninfected fish. Therefore, this disease causes hyperlocomotion related to stress.

Is stage of change enough? Confidence as a predictor of outcome in inpatient treatment for eating disorders.

While stage of change has been shown to be a robust predictor of eating disorder treatment outcome, little attention has been paid to the role of confidence. This study sought to better understand the role of confidence and the possible interaction it may have with stage of change in promoting eating disorder symptom change. Participants were adult women in inpatient treatment for eating disorders. They completed measures of motivation for change, which assessed precontemplation, action, confidence and internality (changing for oneself vs. others) and eating disorder symptom severity at pretreatment (N = 159) and posttreatment (n = 59). Only treatment completer analyses were used. Precontemplation and confidence had significant effects on pretreatment and posttreatment symptom severity, while action only had a significant effect on pretreatment symptoms. Confidence was shown to moderate relations between both measures of stage of change (i.e., precontemplation and action) and symptoms posttreatment. Follow-up analyses indicated that high precontemplation was associated with poor outcome, irrespective of confidence, however, low precontemplation was associated with better outcome at high levels of confidence. The interaction between confidence and action was also significant at very high levels of confidence. That is, among individuals who had high action at baseline, those with low confidence had significantly poorer outcomes relative to those with high confidence. Findings indicate that stage of change and confidence are both important prognostic factors and suggest that early behavior change in the absence of confidence may not guarantee best outcomes in inpatient eating disorder treatment.

Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease.

Catching primal functional changes in early, 'very far from disease onset' (VFDO) stages of Huntington's disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca2+ imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington's disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington's disease pathogenesis long before the onset of clinical symptoms.