Neuropsychiatric Disturbances Research Articles

Far-Infrared Therapy Based on Graphene Ameliorates High-Fat Diet-Induced Anxiety-Like Behavior in Obese Mice via Alleviating Intestinal Barrier Damage and Neuroinflammation.

The consumption of a high-fat diet (HFD) has been implicated in the etiology of obesity and various neuropsychiatric disturbances, including anxiety and depression. Compelling evidence suggests that far-infrared ray (FIR) possesses beneficial effects on emotional disorders. However, the efficacy of FIR therapy in addressing HFD-induced anxiety and the underlying mechanisms remain to be elucidated. Here, we postulate that FIR emitted from a graphene-based therapeutic device may mitigate HFD-induced anxiety behaviors. The graphene-FIR modify the gut microbiota in HFD-mice, particularly by an enriched abundance of beneficial bacteria Clostridiaceae and Erysipelotrichaceae, coupled with a diminution of harmful bacteria Lachnospiraceae, Anaerovoracaceae, Holdemania and Marvinbryantia. Graphene-FIR also improved intestinal barrier function, as evidenced by the augmented expression of the tight junction protein occludin and G protein-coupled receptor 43 (GPR43). In serum level, we observed the decreased free fatty acids (FFA), lipopolysaccharides (LPS), diamine oxidase (DAO) and D-lactate, and increased the glucagon-like peptide-2 (GLP-2) levels in graphene-FIR mice. Simultaneously, inflammatory cytokines IL-6, IL-1β, and TNF-α manifested a decrease subsequent to graphene-FIR treatment in both peripheral and central system. Notably, graphene-FIR inhibited over expression of astrocytes and microglia. We further noticed that the elevated the BDNF and decreased TLR4 and NF-κB expression in graphene-FIR group. Overall, our study reveals that graphene-FIR rescued HFD-induced anxiety via improving the intestine permeability and the integrity of blood-brain barrier, and reduced inflammatory response by down regulating TLR4/NF-κB inflammatory pathway.

Transcriptomic dynamics governing serotonergic dysregulation in the dorsal raphe nucleus following mild traumatic brain injury

Mild traumatic brain injury (mTBI) is a leading cause of disability in the United States, with neuropsychiatric disturbances such as depression, anxiety, PTSD, and social disturbances being common comorbidities following injury. The molecular mechanisms driving neuropsychiatric complications following neurotrauma are not well understood and current FDA-approved pharmacotherapies employed to ameliorate these comorbidities lack desired efficacy. Concerted efforts to understand the molecular mechanisms of and identify novel drug candidates for treating neurotrauma-elicited neuropsychiatric sequelae are clearly needed. Serotonin (5-HT) is linked to the etiology of neuropsychiatric disorders, however our understanding of how various forms of TBI directly affect 5-HT neurotransmission is limited. 5-HT neurons originate in the raphe nucleus (RN) of the midbrain and project throughout the brain to regulate diverse behavioral phenotypes. We hypothesize that the characterization of the dynamics governing 5-HT neurotransmission after injury will drive the discovery of novel drug targets and lead to a greater understanding of the mechanisms associated with neuropsychiatric disturbances following mild TBI (mTBI). Herein, we provide evidence that closed-head mTBI alters total DRN 5-HT levels, with RNA sequencing of the DRN revealing injury-derived alterations in transcripts required for the development, identity, and functional stability of 5-HT neurons. Further, using gene ontology analyses combined with immunohistological analyses, we have identified a novel mechanism of transcriptomic control within 5-HT neurons that may directly influence 5-HT neuron identity/function post-injury. These studies provide molecular evidence of injury-elicited 5-HT neuron dysregulation, data which may expedite the identification of novel therapeutic targets to attenuate TBI-elicited neuropsychiatric sequelae.

Susceptibility to acute cognitive dysfunction in aged mice is underpinned by reduced white matter integrity and microgliosis

Age is a significant but heterogeneous risk factor for acute neuropsychiatric disturbances such as delirium. Neuroinflammation increases with aging but the determinants of underlying risk for acute dysfunction upon systemic inflammation are not clear. We hypothesised that, with advancing age, mice would become progressively more vulnerable to acute cognitive dysfunction and that neuroinflammation and neuronal integrity might predict heterogeneity in such vulnerability. Here we show region-dependent differential expression of microglial transcripts, but a ubiquitously observed primed signature: chronic Clec7a expression and exaggerated Il1b responses to systemic bacterial LPS. Cognitive frailty (vulnerability to acute disruption under acute stressors LPS and double stranded RNA; poly I:C) was increased in aged animals but showed heterogeneity and was significantly correlated with reduced myelin density, synaptic loss and severity of white matter microgliosis. The data indicate that white matter disruption and neuroinflammation may be key substrates of the progressive but heterogeneous risk for delirium in aged individuals.

Exploring Panchakarma therapy in the management of Wilson disease: An observation

Wilson disease is not just a disease of children and young adults but may present at any age. The key features of Wilson disease are liver disease and cirrhosis, neuropsychiatric disturbances, Kayser–Fleischer rings, and acute episodes of hemolysis, often in association with acute liver failure. The diagnosis of Wilson disease is not always straightforward as clinical presentation of the disease can vary widely. In Ayurveda, it can be correlated with Vatavyadhi (~disorders due to vitiated Vata). Furthermore, increased copper levels in the body are also to be considered while planning the management. A 30-year-old patient visited the outpatient department with slurred speech, repetition and slowness of physical activity, muscle stiffness all over the body, loss of physical coordination, difficulty and change in handwriting, mood swings, dropping of saliva, loss of appetite, belching, and nausea. The patient was examined, assessed, and treated with Udvartana karma (~therapeutic powder massage), Abhyanga (~therapeutic massage), Swedana (~sudation therapy), and Basti karma (~therapeutic enema) along with internal administration of suitable Ayurveda medicines. All the symptoms were subsided by the end of the management along with a reduction in the urine copper levels from 915 µg/24 h to 37.5 µg/24 h. This single observation inferred that a patient with Wilson disease can have an improved quality of life when rationally managed with internal Ayurveda medication along with suitable Panchakarma (~five internal bio-cleansing therapies) procedures.

Neuroimaging of neuropsychological disturbances following ischaemic stroke (CONNECT): a prospective cohort study protocol

IntroductionNeuropsychiatric distubance is a common clinical manifestation in acute ischemic stroke. However, it is frequently overlooked by clinicians. This study aimed to explore the possible aetiology and pathogenesis of neuropsychiatric...

Functional and structural analysis of a novel splice site HMBS variant in a Chinese AIP patient.

Background: Acute intermittent porphyria (AIP) is a rare metabolic disorder that results from mutations in the gene encoding hydroxymethylbilane synthase (HMBS), an enzyme involved in heme biosynthesis. AIP follows an autosomal dominant inheritance pattern, but most carriers are asymptomatic. The clinical manifestations of AIP include acute attacks of abdominal pain and neuropsychiatric disturbances. The pathogenicity of novel HMBS variants identified in Chinese patients has not been well established. Objective: The article aims to identify the pathogenic mutation in an AIP patient and prove its pathogenicity through in vitro experiments. Methods: A 22-year-old female diagnosed with AIP participated in the study. Variant screening of her HMBS gene was carried out through Sanger sequencing. To ascertain the consequences of the newly discovered variant, we conducted in vitro experimentation targeting HMBS gene expression and enzymatic function. Additionally, protein structure analysis was performed. Cycloheximide treatment and UPF1-specific siRNA knockdown were employed to assess the impact of the mutation on the mechanism of non-sense-mediated mRNA decay (NMD). Results: A novel splice site variant in the HMBS gene (c.648_651+1delCCAGG) was detected in the patient, which caused aberrant mRNA splicing. In vitro experiments demonstrated that this variant significantly decreased the expression of HMBS. Further investigation confirmed that this decrease was due to NMD. Additionally, structural analysis indicated that this variant would destabilize the HMBS protein and impair its catalytic activity. To gain a comprehensive understanding of HMBS mutations in the context of AIP, we conducted a literature search on PubMed using the keywords 'HMBS' and 'Acute intermittent porphyria' from 2013 to 2023. This search yielded 19 clinical case reports written in English, which collectively described 220 HMBS gene mutations worldwide. Conclusion: The study identified and proved the pathogenicity of a novel splice site HMBS variant for the first time. Our results elucidated the pathological mechanism by which this mutation causes AIP through reducing HMBS expression and activity. These findings provide theoretical guidance for the diagnosis, treatment and genetic counseling of AIP patients.

Tiger nut/coconut dietary intervention as antidotal nutritional remediation strategy against neurobehavioural deficits following organophosphate-induced gut-brain axis dysregulation in mice

Organophosphate poisoning remains a global health crisis without efficacious treatments to prevent neurotoxicity. We examined whether antidotal tiger nut and coconut dietary intervention could ameliorate neurobehavioral deficits from organophosphate dichlorvos-induced gut-brain axis dysregulation in a mouse model. Mice were divided into groups given control diet, dichlorvos-contaminated diets, or dichlorvos plus nut-enriched diets. They were exposed to a DDVP-contaminated diet for 4 weeks before exposure to the treatment diets for another 8 weeks. This was followed by behavioural assessments for cognitive, motor, anxiety-, and depressive-like behaviours. Faecal samples (pre- and post-treatment), as well as blood, brain, and gut tissues, were collected for biochemical assessments following euthanasia. Dichlorvos-exposed mice displayed impairments in cognition, motor function, and mood along with disrupted inflammatory and antioxidant responses, neurotrophic factor levels, and acetylcholinesterase activity in brain and intestinal tissues. Weight loss and altered short-chain fatty acid levels additionally indicated gut dysfunction. However, intervention with tiger nut and/or coconut- enriched diet after dichlorvos exposure attenuated these neurobehavioral, and biochemical alterations. Our findings demonstrate organophosphate-induced communication disruptions between the gut and brain pathways that manifest in neuropsychiatric disturbances. Overall, incorporating fibre-rich nuts may represent an antidotal dietary strategy to reduce neurotoxicity and prevent brain disorders associated with organophosphate poisoning.

Central nervous system and neuropsychiatric disturbances in people living with HIV

Central nervous system and neuropsychiatric disturbances in people living with HIV

Differences in Dementia Caregiver Distress Based on Caregiver Gender and Care Recipient Neuropsychiatric Symptoms

AbstractBackgroundOur healthcare system relies on unpaid family caregivers (e.g., spouses) for care of individuals with Alzheimer’s disease and related dementias (ADRD). Several caregiver and care recipient characteristics are known to be associated with caregiver burden and psychological outcomes in dementia caregivers. Research suggests that caregiver emotional distress is higher among women versus men, and that it increases with elevated care recipient neuropsychiatric symptoms (NPS). However, it is unclear whether gender differences in caregiver distress are independent of care recipient characteristics.MethodCaregivers completed the Neuropsychiatric Inventory‐ Questionnaire (NPI‐Q). Presence of NPS in care recipients was summed across 12 NPI‐Q domains. Using one‐way analyses of covariance (ANCOVAs), we assessed how caregiver gender (woman/man) and care recipient NPS are associated with caregiver burden (Zarit Burden Interview), anxiety (Geriatric Anxiety Index), quality of life (WHO‐5 Well‐Being Index), preparedness for caregiving (Preparedness for Caregiving Scale), and self‐efficacy (General Self‐Efficacy Scale) in a sample of 112 unpaid family caregivers. Covariates included caregiver age and co‐living status. Bonferroni corrections were used to adjust for multiple comparisons. The sample was comprised of 73.2% women with a mean age of 64.6 ± 12.2 years. Caregivers were primarily spouses (68.5%) and daughters (20.7%) of care recipients.ResultRelative to men caregivers, women caregivers reported higher levels of burden (F(1,103) = 24.4, p<.005) and anxiety (F(1,103) = 8.60, p<.005) and lower quality of life (F(1,103) = 9.85, p <.005). Caregivers who rated their care recipients as having more NPS also reported greater burden (F(1,103) = 27.2, p<.005), higher anxiety (F(1,103) = 26.0, p<.005), and lower quality of life (F(1,103) = 34.9, p <.005). There were no significant interactions between gender and NPS. Gender and presence of NPS were not associated with caregivers’ preparedness for caregiving or general self‐efficacy.ConclusionWhile women and men caregivers in this sample reported similar levels of preparedness and self‐efficacy, women endorsed greater levels of emotional distress in the form of caregiver burden, anxiety, and decreased quality of life. Across caregiver gender, age, and co‐living status, NPS in care recipients predicted poor psychosocial outcomes in our sample. Our data suggest the need for interventions to support women caregivers, and mitigate the burden associated with neuropsychiatric disturbances.

Deep Brain Stimulation for Parkinson's Disease‐the Developing World's Perspective

AbstractBackgroundDeep brain stimulation (DBS) is the most widely used device‐assisted therapy in patients with moderately advanced stages of Parkinson's disease (PD) experiencing motor complications. Only a minority of eligible patients get the opportunity to undergo DBS in the developing world.ObjectivesTo examine the proportion and characteristics of patients with motor complications of PD who are willing for DBS and who undergo surgery.MethodsPatients with motor complications of PD eligible for DBS over a five‐year study period (2016–2020) were included. The demographic, clinical and socio‐economic characteristics and information on their status in 2021 were collected and analyzed.ResultsAmong 1017 patients, 223 had motor symptoms qualifying for DBS and follow‐up information available. Only 78 (35%) opted for surgery. The willing patients had higher socioeconomic status, were older and had longer duration of PD and motor complications, more freezing of gait, cognitive symptoms, and neuropsychiatric disturbances. 37 of them were found unfit during pre‐operative work‐up; only 41 (18%) with motor complications were finally taken up for DBS. Age, duration or severity of motor symptoms did not differ between patients who were finally selected for surgery and those who were not.ConclusionsLess than one‐fifth of our patients with motor complications of PD finally underwent DBS. The patients appeared to wait till the late stages of PD, before making a decision on availing surgical treatment. The delay resulted in nearly half of them being found unfit in pre‐operative work‐up. Our findings may enable clinicians to counsel eligible patients more efficiently.

The association between depression and efavirenz-based antiretroviral treatment in people living with human immune-deficiency virus: a systematic review

The neuropsychiatric disturbance such as depression in people living with (PLHIV) requires serious attention as this affects their health outcome. Efavirenz (EFV)-based treatment has been associated with neuropsychiatric adverse events, but its mechanism still unknown. The purpose of this systematic review is to dissect recent studies regarding EFV and depression, in the hope to discover reasonings behind this association. PRISMA flow chart was used to search for the related literatures in the last five years (2018-2023). Targeted population was PLHIV on EFV-based ART only and/or compared with non-EFV-based ART. Relevant keywords used to search were HIV, efavirenz and depression. Five eligible articles were selected which included a total of 3272 PLHIV. Overall, three studies agreed that EFV-based ART was related to depression, while the other two studies did not. It was shown that EFV-based ART did cause neuropsychiatric adverse effects in the first few weeks of treatment, but subsided after several months. However, longer-term research is needed to determine its long-term effects. Variation of results in different studies must be influenced by the possible genetic factors, baseline depression, different social and psychological circumstances throughout the treatment and different assessment tools for depression. Depression on EFV-based treatment in PLHIV may manifest in the initial few weeks of treatment, and additional research is still needed to determine its effects throughout longer treatment durations. Early diagnosis of depression in PLHIV is essential to decide the best choice of ARV for better outcome.

Locomotor Behavior and Memory Dysfunction Induced by 3-Nitropropionic Acid in Adult Zebrafish: Modulation of Dopaminergic Signaling.

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by neuropsychiatric disturbance, cognitive impairment, and locomotor dysfunction. In the early stage (chorea) of HD, expression of dopamine D2 receptors (D2R) is reduced, whereas dopamine (DA) levels are increased. Contrary, in the late stage (bradykinesia), DA levels and the expression of D2R and dopamine D1 receptors (D1R) are reduced. 3-Nitropropionic acid (3-NPA) is a toxin that may replicate HD behavioral phenotypes and biochemical aspects. This study assessed the neurotransmitter levels, dopamine receptor gene expression, and the effect of acute exposure to quinpirole (D2R agonist) and eticlopride (D2R antagonist) in an HD model induced by 3-NPA in adult zebrafish. Quinpirole and eticlopride were acutely applied by i.p. injection in adult zebrafish after chronic treatment of 3-NPA (60mg/kg). 3-NPA treatment caused a reduction in DA, glutamate, and serotonin levels. Quinpirole reversed the bradykinesia and memory loss induced by 3-NPA. Together, these data showed that 3-NPA acts on the dopaminergic system and causes biochemical alterations similar to late-stage HD. These data reinforce the hypothesis that DA levels are linked with locomotor and memory deficits. Thus, these findings may suggest that the use of DA agonists could be a pharmacological strategy to improve the bradykinesia and memory deficits in the late-stage HD.

Comorbid amyloid with cerebrovascular disease in domain-specific cognitive and neuropsychiatric disturbances: a cross-sectional memory clinic study

Dementia is a multifactorial disorder that is likely influenced by both Alzheimer’s disease (AD) and vascular pathologies. We evaluated domain-specific cognitive and neuropsychiatric dysfunction using a two-neuroimaging biomarker construct (beta-amyloid [Aβ] and cerebrovascular disease [CeVD]). We analyzed data from 216 memory clinic participants (mean age = 75.9 ± 6.9; 56.5% female) with neuropsychological and neuropsychiatric assessments, 3T-MRI, and Aβ-PET imaging. Structural equation modeling showed that the largest Aβ (A+) effect was on memory (B = −1.50) and apathy (B = 0.26), whereas CeVD effects were largest on language (B = −1.62) and hyperactivity (B = 0.32). Group comparisons showed that the A+C+ group had greater memory impairment (B = −1.55), hyperactivity (B = 0.79), and apathy (B = 0.74) compared to A−C+; and greater language impairment (B = −1.26) compared to A+C−. These potentially additive effects of Aβ and CeVD burden underline the importance of early detection and treatment of Aβ alongside optimal control of vascular risk factors as a potential strategy in preventing cognitive and neurobehavioral impairment.

Let Us Talk Money: Subjectively Reported Financial Performance of People Living with Neurodegenerative Diseases-A Systematic Review.

Neurodegenerative diseases (NDDs) form a heterogeneous, widespread group of disorders, generally characterized by progressive cognitive decline and neuropsychiatric disturbances. One of the abilities that seems particularly vulnerable to the impairments in neurodegenerative diseases is the capability to manage one's personal finances. Indeed, people living with neurodegenerative diseases were shown to consistently present with more problems on performance-based financial tasks than healthy individuals. While objective, performance-based tasks provide insight into the financial competence of people living with neurodegenerative diseases in a controlled, standardized setting; relatively little can be said, based on these tasks, about their degree of success in dealing with the financial demands, issues, or questions of everyday life (i.e., financial performance). The aim of this systematic review is to provide an overview of the literature examining self and informant reports of financial performance in people living with neurodegenerative diseases. In total, 22 studies were included that compared the financial performance of people living with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis to a (cognitively) normal control group. Overall, the results indicate that people living with neurodegenerative diseases are more vulnerable to impairments in financial performance than cognitively normal individuals and that the degree of reported problems seems to be related to the severity of cognitive decline. As the majority of studies however focused on MCI or AD and made use of limited assessment methods, future research should aim to develop and adopt more comprehensive assessments to study strengths and weaknesses in financial performance of people living with different neurodegenerative diseases.

Cognition and Functionality Were Not Affected Due to the COVID-19 Pandemic in People with Mild Cognitive Impairment and AD Dementia Attending Digital Non-Pharmacologic Interventions.

The majority of previous studies showed that older adults with mild cognitive impairment (MCI) as well as Alzheimer's disease dementia (ADD) had impaired cognition and mood status, as well as increased behavioral disturbances after the first wave of the COVID-19 pandemic. However, there are still controversial data as regards the multifactorial impact of the restrictive measures on cognition, mood and daily function in older adults with MCI and ADD. In the current study, the scope is to identify possible deterioration by means of cognitive and functional level due to mood and behavioral alterations during the second quarantine imposed in Greece between November 2020 and May 2021, as well as one year after the second quarantine, in May 2022. Participants were recruited from the two day centers of the Greek Association of Alzheimer Disease and Related Disorders (GAADRD). They underwent three yearly follow up assessments from May 2020 to May 2022 and participated in cognitive training interventions (through digital online means) during the aforementioned period. Mixed measures analyses of variance as well as path models were used for the study's purposes. The study sample comprised 210 participants (175 people with MCI and 35 people with ADD). The mean age was 71.59 and 77.94 for people with MCI and mild ADD, respectively, whereas the average number of years of education was 12.65 for those with MCI and 9.83 for people with mild ADD. The results show that participants' deterioration rate (D), calculated by means of their performance in neuropsychological and functional assessments between 2020 and 2021 (D1) and 2021 and 2022 (D2), did not change significantly, except for the Rey Auditory Verbal Learning Test (RAVLT), since both groups displayed a larger D2 across the test conditions (immediate recall, fifth trial and delayed recall). Trail Making Test-B (TMT-B) performance, applied only in the MCI group, decreased more in relation to the deterioration rate D2. Additionally, two path models were applied to measure the direct relationships between diagnosis, performance in tests measuring mood and neuropsychiatric disturbances (NPI) and cognition, as measured by the RAVLT, in the 2020-2022 assessments. TMT-B was administered only in the MCI population, and therefore was not included in path models. The results show that participants' scores in RAVLT conditions were related to diagnosis and NPI performance, which was positively affected by diagnosis. No other relationships between RAVLT with mood tests were observed. Our results show that after the second lockdown period, the neuropsychological performance of people with MCI and ADD, calculated by means of their D2, did not change, except from their verbal memory, as well as visual scanning and information processing, measured using the TMT-B. Therefore, it can be assumed that those who were enrolled in digital non-pharmacological interventions during the COVID-19 pandemic home restrictions did not experience increased cognitive and functional deterioration due to mood and behavioral alterations after the pandemic.

MR Imaging Findings in a Large Population of Autoimmune Encephalitis.

Autoimmune encephalitis is a rare condition in which autoantibodies attack neuronal tissue, causing neuropsychiatric disturbances. This study sought to evaluate MR imaging findings associated with subtypes and categories of autoimmune encephalitis. Cases of autoimmune encephalitis with specific autoantibodies were identified from the medical record (2009-2019). Cases were excluded if no MR imaging of the brain was available, antibodies were associated with demyelinating disease, or >1 concurrent antibody was present. Demographics, CSF profile, antibody subtype and group (group 1 intracellular antigen or group 2 extracellular antigen), and MR imaging features at symptom onset were reviewed. Imaging and clinical features were compared across antibody groups using χ2 and Wilcoxon rank-sum tests. Eighty-five cases of autoimmune encephalitis constituting 16 distinct antibodies were reviewed. The most common antibodies were anti-N-methyl-D-aspartate (n = 41), anti-glutamic acid decarboxylase (n = 7), and anti-voltage-gated potassium channel (n = 6). Eighteen of 85 (21%) were group 1; and 67/85 (79%) were group 2. The median time between MR imaging and antibody diagnosis was 14 days (interquartile range, 4-26 days). MR imaging had normal findings in 33/85 (39%), and 20/33 (61%) patients with normal MRIs had anti-N-methyl-D-aspartate receptor antibodies. Signal abnormality was most common in the limbic system (28/85, 33%); 1/68 (1.5%) had susceptibility artifacts. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2. Sixty-one percent of patients with autoimmune encephalitis had abnormal brain MR imaging findings at symptom onset, most commonly involving the limbic system. Susceptibility artifact is rare and makes autoimmune encephalitis less likely as a diagnosis. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.

Brain free‐water increases in mild behavioral impairment

AbstractBackgroundMild behavioural impairment (MBI) is proposed as a diagnostic construct to identify dementia‐free individuals with sustained neuropsychiatric symptoms as an early manifestation of dementia. Our previous study has demonstrated that MBI predicts faster cognitive decline and progression to dementia. Other studies have shown that MBI was associated with Alzheimer’s disease biomarkers for Aβ and tau. However, cerebrovascular disease (CeVD), which is another critical pathology in dementia, has not been investigated in MBI. Here, we sought to test brain free‐water (FW) alterations, a marker for CeVD, in MBI compared with non‐MBI participants and their associations with longitudinal changes in cognition, function, and neuropsychiatric symptoms.MethodLongitudinal global cognitive scores, clinical dementia rating sum‐of‐boxes (CDR‐SoB), neuropsychiatric inventory (NPI) scores, over 5 years were reported in 281 dementia‐free participants (40 MBI and 241 non‐MBI). MBI was diagnosed using established criteria. All participants underwent T1‐weighted structural and diffusion MRI at baseline. FW imaging method was applied to derive individual‐level white matter (WM) and grey matter (GM) FW maps from diffusion MRI. We compared baseline GM‐FW and WM‐FW between non‐MBI and MBI subjects. We then tested the associations of MBI‐related FW increase with baseline and longitudinal changes in global cognition, CDR‐SB, and NPI scores using linear regression models.ResultMBI had greater GM‐FW in executive control (prefrontal), motor sensory (precentral), attention (insula) and memory (left temporal and right cingulate and cuneus) networks and widespread higher WM‐FW compared with non‐MBI (Fig‐1). Both higher GM‐FW and WM‐FW were associated with lower global cognition, higher CDR‐SB, and higher NPI scores across all participants at baseline (Table‐1). There was no interaction effect of MBI status on such association. Moreover, higher baseline GM‐FW and WM‐FW were associated with longitudinal worsening in global cognition, CDR‐SB, and NPI scores (Table‐2). Interestingly, such associations were greater in MBI than in non‐MBI (Fig‐2).ConclusionThis study demonstrated that MBI was associated with increased brain FW, which may have contributed to the relationship between persistent neuropsychiatric disturbances and clinical and cognitive outcomes. Early detection of cerebrovascular‐related FW alteration may allow for timely management of MBI individuals before development of dementia.

Mitochondrial Dysfunction Links to Impaired Hippocampal Serotonin Release in a Mouse Model of Alzheimer's Disease.

Deprivation of extracellular serotonin has been linked to cognitive decline and neuropsychiatric disturbances in Alzheimer's disease (AD). However, despite degeneration of serotonin-producing neurons, whether serotonin release is affected in AD-sensitive brain regions is unknown. This study investigated the impact of mitochondrial dysfunction in decreased hippocampal serotonin release in AD amyloidosis mouse model 5xFAD mice. Electrochemical assays were applied to examine hippocampal serotonin release. We also employed multidisciplinary techniques to determine the role of oligomeric amyloid-β (Aβ) in hippocampal mitochondrial deficits and serotonin release deficiency. 5xFAD mice exhibited serotonin release decrease and relatively moderate downregulation of serotonergic fiber density as well as serotonin content in the hippocampal region. Further experiments showed an inhibitory effect of oligomeric amyloid-β (Aβ) on hippocampal serotonin release without affecting the density of serotonergic fibers. Pharmaceutical uncoupling of mitochondrial oxidative phosphorylation (OXPHOS) disrupted hippocampal serotonin release in an ex vivo setting. This echoes the mitochondrial defects in serotonergic fibers in 5xFAD mice and oligomeric Aβ-challenged primary serotonergic neuron cultures and implicates a link between mitochondrial dysfunction and serotonin transmission defects in AD-relevant pathological settings. The most parsimonious interpretation of our findings is that mitochondrial dysfunction is a phenotypic change of serotonergic neurons, which potentially plays a role in the development of serotonergic failure in AD-related conditions.

Abstract #1406181: Complications in the Management of Hypercalcemia in a Patient with Systemic Lupus Erythematous and Lupus Nephritis During Pregnancy

Hypercalcemia can present with a multitude of symptoms including anorexia, nausea and vomiting, constipation and neuropsychiatric disturbances. There is an overlap in these symptoms with those experienced during both pregnancy and in systemic lupus erythematosus. This case report highlights the difficulties in the diagnostic evaluation and management of hypercalcemia during pregnancy. A 26-year-old female with history of Systemic lupus erythematosus (SLE) complicated by Class V lupus nephritis and antiphospholipid syndrome presented August 2022 with symptomatic hypercalcemia at 8-weeks gestation. The patient reported fatigue, nausea and vomiting and new onset severe constipation, polydipsia and polyuria. Lab work was notable for hypercalcemia with calcium 13.2 mg/dl (corrected 13.7 mg/dl for Albumin 3.4g/dl) and parathyroid hormone (PTH) 153pg/ml. No parathyroid nodules were seen on ultrasound and 1st trimester ultrasound demonstrated a single live intra-uterine pregnancy. The patient was diagnosed with primary hyperparathyroidism and started on 0.9% normal saline intravenous fluid at 200cc/hr and Furosemide 20mg/Q6H IV to promote diuresis. Despite this, calcium could not be lowered to less than 12.4 mg/dl (13.0 mg/dl albumin corrected). The patient was discharged with instructions to drink 3-4L water per day and take Furosemide 20mg daily. On follow up at 14 weeks, Calcium was still elevated at 11.9 mg/dl and reported intermittent vomiting and constipation. ENT was consulted to consider parathyroidectomy however opted for conservative management of hypercalcemia prior to delivery due to inability to localize an adenoma and exclude ectopic parathyroid on imaging. The patient was followed closely for the remainder of her pregnancy with improvement in her symptoms, however continued to have persistent hypercalcemia posing risk of materno-fetal complications. Treatment for hypercalcemia is based upon the severity and symptoms, but it is important to consider gestational age. Exceeding the upper normal limit of calcium during pregnancy of 9.5 mg/dL increases the risk of fetal complications including spontaneous abortion, still birth and neonatal tetany. There is added difficulty in determining true symptomatic hypercalcemia given the overlap in symptomatology with pregnancy. In pregnant patients undergoing parathyroid surgery, localization can be done with ultrasound rather than Sestamibi but risks missing ectopic parathyroid glands. If surgery is not recommended, there are limited therapeutic options during pregnancy for hypercalcemia. Notably, IV fluids and diuretics provide modest temporary benefit. Total serum calcium is reported to decline across gestation, likely due to plasma volume expansion, and this may temporize the harmful effects of hypercalcemia to defer surgery until after birth. There is inadequate data on the safe use of Cinacalcet during pregnancy with no known risk of teratogenicity reported in case reports. There is however an increased risk of neonatal hypocalcemia due to gestational suppression of the fetal parathyroid glands.

Psycho-Cognitive Profile and NGF and BDNF Levels in Tears and Serum: A Pilot Study in Patients with Graves’ Disease

Nerve Growth Factor (NGF) and Brain derived Neurotrophic Factor (BDNF) mature/precursor imbalance in tears and serum is suggested as a risk factor and symptomatology aggravation in ophthalmology and neuropsychiatric disturbances. Cognitive and mood alterations are reported by patients with Graves' Orbitopathy (GO), indicating neurotrophin alterations might be involved. To address this question, the expression levels of NGF and BDNF and their precursors in serum and tears of GO patients were analyzed and correlated with the ophthalmological and psycho-cognitive symptoms. Hamilton Rating Scale for Anxiety (HAM-A) and Depression (HAM-D), Temperament and Character Inventory (TCI), and Cambridge Neuropsychological Test Automated Battery (CANTAB) test were used as a score. NGF and BDNF levels were measured using ELISA and Western Blot and statistically analyzed for psychiatric/ocular variable trend association. GO patients show memorization time and level of distraction increase, together with high irritability and impulsiveness. HAM-A and CANTAB variables association, and some TCI dimensions are also found. NGF and BDNF expression correlates with ophthalmological symptoms only in tears, while mature/precursor NGF and BDNF correlate with the specific psycho-cognitive variables both in tears and serum. Our study is the first to show that changes in NGF and BDNF processing in tears and serum might profile ocular and cognitive alterations in patients.