Multiple Neuropsychiatric Symptoms Research Articles

Neuropsychiatric symptoms in Systemic Lupus Erythematosus: mixed methods analysis of patient-derived attributional evidence in the international INSPIRE project.

Attribution of neuropsychiatric symptoms in systemic lupus erythematosus (SLE) relies heavily on clinician assessment. Limited clinic time, variable knowledge, and symptom under-reporting contributes to discordance between clinician assessments and patient symptoms. We obtained attributional data directly from patients and clinicians in order to estimate and compare potential levels of direct attribution to SLE of multiple neuropsychiatric symptoms using different patient-derived measures. Quantitative and qualitative data analysed included: prevalence and frequency of neuropsychiatric symptoms, response to corticosteroids, and concurrence of neuropsychiatric symptoms with non-neuropsychiatric SLE disease activity. SLE patients were also compared with controls and inflammatory arthritis (IA) patients to explore attributability of neuropsychiatric symptoms to the direct disease effects on the brain/nervous system. We recruited 2,817 participants, including 400 clinicians. SLE patients (n = 609) reported significantly higher prevalences of neuropsychiatric symptoms than controls (n = 463) and IA patients (n = 489). SLE and IA patients' quantitative data demonstrated multiple neuropsychiatric symptoms relapsing/remitting with other disease symptoms such as joint pain. Over 45% of SLE patients reported resolution/improvement of fatigue, positive sensory symptoms, severe headache, and cognitive dysfunction with corticosteroids. Evidence of direct attributability in SLE was highest for hallucinations and severe headache. SLE patients had greater reported improvement from corticosteroids (p= 0.008), and greater relapsing-remitting with disease activity (p< 0.001) in the comparisons with IA patients for severe headache. Clinician and patients reported insufficient time to discuss patient-reported attributional evidence. Symptoms viewed as indirectly related/non-attributable were often less prioritised for discussion and treatment. We found evidence indicating varying levels of direct attributability of both common and previously unexplored neuropsychiatric symptoms in SLE patients, with hallucinations and severe headache assessed as the most directly attributable. There may also be-currently under-estimated-direct effects on the nervous system in IA and other systemic rheumatological diseases.

The simultaneous presence of demoralization, apathy, and depression has a detrimental impact on both cognitive function and motor symptoms in Parkinson's disease patients.

Parkinson's disease (PD) is marked not only by motor symptoms but also by neuropsychiatric manifestations, including demoralization, apathy, and depression. Understanding the clinical distribution and characteristics of these co-occurring symptoms is crucial for improving quality of life of PD patients. This study enrolled 195 Chinese PD patients from Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine. The study involved analyzing the clinical characteristics related to the simultaneous presence of demoralization, apathy, and depression in PD patients. Linear regression was employed to elucidate the linear trend between the quantity of negative neuropsychiatric symptoms and cognitive function, as well as motor symptoms and motor complications. SPSS mediation models were utilized to investigate whether the severity of cognitive function mediated the connection between multiple negative neuropsychiatric symptoms and motor symptoms. Among PD patients, a notable 57.5% experience the presence of multiple concurrent negative neuropsychiatric symptoms. Our investigation unveiled a correlation where patients with more negative neuropsychiatric symptoms displayed heightened cognitive impairment (P=0.048) and more severe motor symptoms (P=0.024), following a linear trend with increasing symptom numbers. Additionally, cognitive impairment played a partial mediating role in the impact of multiple negative neuropsychiatric symptoms on motor symptoms (β=0.747; 95% bootstrap confidence interval: 0.195 to 1.532). The co-occurrence of these negative neuropsychiatric symptoms has the potential to worsen cognitive function and motor symptoms in PD patients. Moreover, cognitive impairment was identified as playing a partial mediating role in the relationship between multiple negative neuropsychiatric symptoms and motor symptoms.

A case report on Creutzfeldt-Jacob Disease: Early diagnosis through multidisciplinary lens

Background: Creutzfeldt Jacob disease is a rapidly progressive neurodegenerative disorder, which is invariably fatal and results in death within 1 year of onset. Patient presents with a variety of non-specific neuropsychiatric symptoms, like myoclonus, cerebellar symptoms, visual impairment, and behavioural abnormalities. The symptoms are rapidly progressive and cause early functional impairment in the patient. Case presentation: In this report, we discussed a case of 49 years old male presented with multiple neuropsychiatric symptoms. After a series of extensive diagnostic examinations and follow-up, the patient was diagnosed as probable sporadic Creutzfeldt-Jakob disease based on 2018 Centres for Disease Control and Prevention (CDC) criteria, with key findings of myoclonus, behavioural and cerebellar problems, visual abnormalities, abnormal hyperintensity signals on diffusion-weighted MRI and characteristic EEG waves. CSF 14-3-3 protein was significantly high. Conclusion: Sporadic CJD is a rare and fatal rapidly progressive neurodegenerative disorder, which claims prompt and precise diagnosis to help the clinicians in distinguishing it from potentially treatable neuropsychiatric disorders. This aspect elevates the significance of our report, as it aids not only the medical professionals but also the affected families. Early diagnosis enables family to prepare for disease course and appropriate management strategies.

Target-capture full-length double-stranded cDNA long-read sequencing through Nanopore revealed novel intron retention in patient with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a relatively common autosomal dominant disorder characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms caused by loss-of-function mutation of either TSC1 or TSC2. The genetic diagnosis of inherited diseases, including TSC, in the clinical field is widespread using next-generation sequencing. The mutations in protein-coding exon tend to be verified because mutations directly cause abnormal protein. However, it is relatively difficult to verify mutations in the intron region because it is required to investigate whether the intron mutations affect the abnormal splicing of transcripts. In this study, we developed a target-capture full-length double-stranded cDNA sequencing method using Nanopore long-read sequencer (Nanopore long-read target sequencing). This method revealed the occurrence of intron mutation in the TSC2 gene and found that the intron mutation produces novel intron retention splicing transcripts that generate truncated proteins. The protein-coding transcripts were decreased due to the expression of the novel intron retention transcripts, which caused TSC in patients with the intron mutation. Our results indicate that Nanopore long-read target sequencing is useful for the detection of mutations and confers information on the full-length alternative splicing of transcripts for genetic diagnosis.

Exploring the relationship between patient-relevant outcomes and Alzheimer's disease progression assessed using the clinical dementia rating scale: a systematic literature review.

People with Alzheimer's disease (AD) have difficulties in performing activities of daily living (ADLs) as the disease progresses, commonly experience neuropsychiatric symptoms (NPS), and often have comorbidities such as cardiovascular disease. These factors all contribute to a requirement for care and considerable healthcare costs in AD. The Clinical Dementia Rating (CDR) scale is a widely used measure of dementia staging, but the correlations between scores on this scale and patient-/care partner-relevant outcomes have not been characterized fully. We conducted a systematic literature review to address this evidence gap. Embase, MEDLINE, and the Cochrane Library were searched September 13, 2022, to identify published studies (no restriction by date or country) in populations with mild cognitive impairment due to AD or AD dementia. Studies of interest reported data on the relationships between CDR Global or CDR-Sum of Boxes (CDR-SB) scores and outcomes including NPS, comorbidities, ADLs, nursing home placement, healthcare costs, and resource use. Overall, 58 studies met the inclusion criteria (42 focusing on comorbidities, 14 on ADLs or dependence, five on nursing home placement, and six on economic outcomes). CDR/CDR-SB scores were correlated with the frequency of multiple NPS and with total scores on the Neuropsychiatric Inventory. For cardiovascular comorbidities, no single risk factor was consistently linked to AD progression. Increasing CDR/CDR-SB scores were correlated with decline in multiple different measures of ADLs and were also associated with nursing home placement and increasing costs of care. NPS, ADLs, and costs of care are clearly linked to AD progression, as measured using CDR Global or CDR-SB scores, from the earliest stages of disease. This indicates that scores derived from the CDR are a meaningful way to describe the severity and burden of AD for patients and care partners across disease stages.

A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder (P11-9.004)

<h3>Objective:</h3> To investigate the full neurologic, psychiatric, and developmental phenotypic spectrum of individuals with <i>CACNA1C</i>-related disorder. <h3>Background:</h3> <i>CACNA1C</i> encodes the voltage gated L-type Ca_V1.2 calcium channel. A specific gain of function pathogenic variant in <i>CACNA1C</i> causes Timothy syndrome type 1 (TS1) with multi-system involvement including cardiac long QT syndrome, syndactyly, and neuropsychiatric symptoms. We found that the TS1 variant alters neuronal activity-dependent signaling and interneuron migration. The broader spectrum of <i>CACNA1C</i>-related disorder (CRD) includes isolated cardiac disease, isolated neurologic deficits, and TS, but it is unknown how the clinical presentation of CRD variants other than TS relate to neural defects. We surveyed individuals with CRD to define the neuropsychiatric and developmental phenotype to guide future research into the role of calcium channels in neural development. <h3>Design/Methods:</h3> Caregivers of and individuals with CRD completed an online survey of pre- and perinatal events, cardiac events, developmental milestones, neuropsychiatric symptoms, and neuropsychiatric diagnoses. Multiple Mann-Whitney tests were used for comparison of categorical values and Fisher’s exact test for comparison of categorical variables between participants with and without LQTS. <h3>Results:</h3> Twenty-four participants with germline <i>CACNA1C</i> variants completed the survey. The most common neuropsychiatric symptoms and/or diagnoses were developmental delay in 92%, incoordination in 71%, hypotonia in 67%, autism spectrum disorder in 50% (autistic features in 92%), seizures in 37.5%, and attention deficit hyperactivity disorder in 21% of participants. There were no significant differences in symptoms between participants with and without LQTS. <h3>Conclusions:</h3> In our CRD cohort there was an increased prevalence of multiple neuropsychiatric symptoms compared with the general population. These findings indicate the key role of Ca_V1.2 in brain development and the clinical importance of screening and treating neuropsychiatric symptoms in all individuals with CRD. Future directions include deep phenotyping of neuropsychiatric symptoms and efforts to relate these symptoms to specific cellular defects. <b>Disclosure:</b> Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Tome. Mrs. Timothy has nothing to disclose. Dr. Underwood has received personal compensation for serving as an employee of Akrivia Health. Dr. Underwood has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for HM Courts and Tribunal Service. The institution of Dr. Underwood has received research support from the Wellcome Trust. Prof. Hall has stock in meomics. The institution of Prof. Hall has received research support from takeda. Dr. Bernstein has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CHANGE HEALTHCARE. The institution of Dr. Bernstein has received research support from NIH. Prof. Pasca has received intellectual property interests from a discovery or technology relating to health care.

A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder

BackgroundCACNA1C encodes the voltage-gated L-type calcium channel CaV1.2. A specific gain-of-function pathogenic variant in CACNA1C causes Timothy syndrome type 1 (TS1) with cardiac long QT syndrome, syndactyly, and neuropsychiatric symptoms. Our previous work found that the TS1 mutation alters neuronal activity-dependent signaling and interneuron migration. Recent case series highlighted a broader spectrum of CACNA1C-related disorder (CRD) that includes isolated cardiac disease, isolated neurologic deficits, and TS, but it is unknown how the clinical presentation of other CRD variants relates to neural defects. We surveyed individuals with CRD to define the neuropsychiatric and developmental phenotype in an effort to guide future research into the role of calcium channels in neural development. MethodsCaregivers of and individuals with CRD completed an online survey of pre- and perinatal events, cardiac events, developmental milestones, neuropsychiatric symptoms, and neuropsychiatric diagnoses. Multiple Mann-Whitney tests were used for comparison of categorical values and Fisher exact test for comparison of categorical variables between participants with and without cardiac arrhythmia. ResultsTwenty-four participants with germline CACNA1C variants including TS1 completed the survey. The most common neuropsychiatric symptoms and/or diagnoses were developmental delay in 92%, incoordination in 71%, hypotonia in 67%, autism spectrum disorder in 50% (autistic features in 92%), seizures in 37.5%, and attention-deficit/hyperactivity disorder in 21% of participants. There were no significant differences in symptoms between participants with and without arrhythmia. ConclusionsIn our CRD cohort, there was an increased prevalence of multiple neuropsychiatric symptoms compared with the general population. These findings indicate the key role of CaV1.2 in brain development and the clinical importance of screening and therapeutically addressing neuropsychiatric symptoms in all individuals with CRD. Future directions include deep phenotyping of neuropsychiatric symptoms and efforts to relate these symptoms to cellular defects.

Genotype and Phenotype Landscape of 283 Japanese Patients with Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms, caused by loss of function mutations in either TSC1 or TSC2. Genotype and phenotype analyses are conducted worldwide, but there have been few large-scale studies on Japanese patients, and there are still many unclear points. This study analyzed 283 Japanese patients with TSC (225 definite, 53 possible, and 5 genetic diagnoses). A total of 200 mutations (64 TSC1, 136 TSC2) were identified, of which 17 were mosaic mutations, 11 were large intragenic deletions, and four were splicing abnormalities due to deep intronic mutations. Several lesions and symptoms differed in prevalence and severity between TSC1 and TSC2 patients and were generally more severe in TSC2 patients. Moreover, TSC2 missense and in-frame mutations may attenuate skin and renal symptoms compared to other TSC2 mutations. Genetic testing revealed that approximately 20% of parents of a proband had mild TSC, which could have been missed. The patient demographics presented in this study revealed a high frequency of TSC1 patients and a low prevalence of epilepsy compared to global statistics. More patients with mild neuropsychiatric phenotypes were diagnosed in Japan, seemingly due to a higher utilization of brain imaging, and suggesting the possibility that a significant amount of mild TSC patients may not be correctly diagnosed worldwide.

Association of Cerebral Small Vessel Disease Burden with Neuropsychiatric Symptoms in Non-Demented Elderly: A Longitudinal Study.

The links between cerebral small vessel disease (CSVD) burden and neuropsychiatric symptoms (NPS) have not been fully studied. We aimed to explore the associations of the CSVD burden with Neuropsychiatric Inventory (NPI) total scores and its subsyndromes in the elderly without dementia. We investigated 630 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative. All of them had NPI assessments and 3 Tesla MRI scans at baseline and 616 had longitudinal NPI assessments during the follow-up. Linear mixed-effects models were used to investigate the cross-sectional and longitudinal associations of CSVD burden with NPI total scores and its subsyndromes. Higher CSVD burden longitudinally predicted more serious neuropsychiatric symptoms, including NPS (p &amp;lt; 0.0001), hyperactivity (p = 0.0006), affective symptoms (p = 0.0091), and apathy (p &amp;lt; 0.0001) in the total participants. Lacunar infarcts (LIs), white matter hyperactivities (WMHs), and cerebral microbleeds (CMBs) might play important roles in the occurrence of NPS, since they were longitudinally associated with specific neuropsychiatric subsyndromes. LIs contributed to hyperactivity (p = 0.0092), psychosis (p = 0.0402), affective symptoms (p = 0.0156), and apathy (p &amp;lt; 0.0001). WMHs were associated with hyperactivity (p = 0.0377) and apathy (p = 0.0343). However, CMBs were only related to apathy (p = 0.0141). CSVD burden was associated with multiple neuropsychiatric symptoms, suggesting the importance of monitoring and controlling vascular risk factors. Different markers of CSVD were associated with specific subsyndromes of NPS, suggesting that different markers tended to occur in different encephalic regions.

Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice

Tuberous sclerosis complex (TSC) is a genetic disorder involving a variety of physical manifestations, and is associated with epilepsy and multiple serious neuropsychiatric symptoms. These symptoms are collectively known as TSC-associated neuropsychiatric disorders (TAND), which is a severe burden for patients and their families. Overactivation of the mechanistic target of rapamycin complex 1 (mTORC1) by mutations in TSC1 or TSC2 is thought to cause TSC, and mTORC1 inhibitors such as sirolimus and everolimus are reported to be effective against various tumor types of TSC. However, there are various reports on the effect of mTORC1 inhibitor therapy on TAND in patients with TSC, which may or may not be effective. In our previous investigations, we generated TSC2 conditional knockout mice (Mitf-Cre, Tsc2 KO; Tsc2 cKO). These mice developed spontaneous epileptic activity. In the current study, we further analyzed the detailed behaviors of Tsc2 cKO mice and confirmed that they exhibited phenotypes of TAND as well as epileptic seizures, indicating that Tsc2 cKO mice are a useful model for TAND. Furthermore, the olfactory bulb and piriform cortex caused epilepsy and TAND in Tsc2 cKO mice, and neurodegeneration was observed. Immunohistology and immunophenotypic analysis of cells, and quantitative RT-PCR suggested that changes in microglial polarity were involved in the onset of TSC epilepsy and neuropsychiatric symptoms. Although the effect of mTORC1 inhibitors on TAND has not been established, the results of this study might help elucidate the mechanism of TAND pathogenesis and suggest that sirolimus may be a valuable therapeutic tool for TAND.

Epigenetic prediction of 17β-estradiol and relationship to trauma-related outcomes in women

17β-estradiol (E2) levels in women correlate with multiple neuropsychiatric symptoms, including those that are stress-related. Furthermore, prior work from our group has demonstrated that E2 status influences DNA methylation (DNAm) across the genome. We developed and validated a DNAm-based predictor of E2 (one of four naturally occurring estrogens) using a training set of 183 females and a test set of 79 females from the same traumatized cohort. We showed that predicted E2 levels were highly correlated with measured E2 concentrations in our testing set (r ​= ​0.75, p ​= ​1.8e-15). We further demonstrated that predicted E2 concentrations, in combination with measured values, negatively correlated with current post-traumatic stress disorder (PTSD) (β ​= ​−0.38, p ​= ​0.01) and major depressive disorder (MDD) diagnoses (β ​= ​−0.45, p ​= ​0.02), as well as a continuous measure of PTSD symptom severity (β ​= ​−2.3, p ​= ​0.007) in females. Finally, we tested our predictor in an independent data set (n ​= ​85) also comprised of recently traumatized female subjects to determine if the predictor would generalize to a different population than the one on which it was developed. We found that the correlation between predicted and actual E2 concentrations in the external validation data set was also high (r ​= ​0.48, p ​= ​3.0e-6). While further validation is warranted, a DNAm predictor of E2 concentrations will advance our understanding of hormone-epigenetic interactions. Furthermore, such a DNAm predictor may serve as an epigenetic proxy for E2 concentrations and thus provide an important biomarker to better evaluate the contribution of E2 to current and potentially future psychiatric symptoms in samples for which E2 is not measured.

Impaired neurite development and mitochondrial dysfunction associated with calcium accumulation in dopaminergic neurons differentiated from the dental pulp stem cells of a patient with metatropic dysplasia

Transient receptor potential vanilloid member 4 (TRPV4) is a Ca2+ permeable nonselective cation channel, and mutations in the TRPV4 gene cause congenital skeletal dysplasias and peripheral neuropathies. Although TRPV4 is widely expressed in the brain, few studies have assessed the pathogenesis of TRPV4 mutations in the brain. We aimed to elucidate the pathological associations between a specific TRPV4 mutation and neurodevelopmental defects using dopaminergic neurons (DNs) differentiated from dental pulp stem cells (DPSCs). DPSCs were isolated from a patient with metatropic dysplasia and multiple neuropsychiatric symptoms caused by a gain-of-function TRPV4 mutation, c.1855C>T (p.L619F). The mutation was corrected by CRISPR/Cas9 to obtain isogenic control DPSCs. Mutant DPSCs differentiated into DNs without undergoing apoptosis; however, neurite development was significantly impaired in mutant vs. control DNs. Mutant DNs also showed accumulation of mitochondrial Ca2+ and reactive oxygen species, low adenosine triphosphate levels despite a high mitochondrial membrane potential, and lower peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial content. These results suggested that the persistent Ca2+ entry through the constitutively activated TRPV4 might perturb the adaptive coordination of multiple mitochondrial functions, including oxidative phosphorylation, redox control, and biogenesis, required for dopaminergic circuit development in the brain. Thus, certain mutations in TRPV4 that are associated with skeletal dysplasia might have pathogenic effects on brain development, and mitochondria might be a potential therapeutic target to alleviate the neuropsychiatric symptoms of TRPV4-related diseases.

Neuropsychiatric Symptoms and Caregiver's Burden in Parkinson's Disease Patients in a Tertiary Care Teaching Hospital in South India: A Cross-Sectional Study

In patients with Parkinson's disease (PD), the occurrence of motor and non-motor symptoms increases with disease progression. The range of neuropsychiatric symptoms (NPS) vary among individuals and can be burdensome for caregivers. Only a few studies have identified the contributing factors of NPS and caregiver burden in India. We aimed to study the clinical profile, disability, and predictive factors of NPS in PD patients and associated caregiver's burden. This was a cross-sectional observational study carried out in PD patients and their respective caregivers attending a movement disorder clinic in a tertiary care teaching hospital in Kerala. A total of 104 patients diagnosed with idiopathic PD receiving levodopa therapy and who had a primary caregiver were enrolled in the study. Structured questionnaires were administered to both patients and caregivers to collect data. Data analysis was done using an independent t-test, linear, and multiple regression analysis. Among 104 patients recruited for the study, 61.5% of patients had shown at least one NPS and 40.44% showed multiple NPS. Results from the study showed that depression is the primary NPS occurring in IPD patients (55.8%) followed by irritability, anxiety, and apathy. On linear regression models, the prime determinant of NPS was the Everyday Abilities Scale for India (EASI). For caregiver burden, the main determinants were the presence of NPS, duration of caregiving, EASI, and RBDSQ score. NPS in PD are highly associated with and are determinants of caregiver burden. Detailed assessment and specific interventions aimed at NPS could alleviate caregiver burden.

Focal Cortical Dysplasia: Relevant for Seizures in Phelan-McDermid Syndrome?

Phelan-McDermid syndrome (PMS) is a neurogenetic disorder characterized by global developmental delay, intellectual disability, absent or severely impaired language, and hypotonia, combined with a broad spectrum of other clinical symptoms and variable dysmorphic features. Apart from various organ-associated conditions like renal or heart anomalies, multiple neuropsychiatric symptoms like sleep disturbances, impaired coordination, symptoms of autism spectrum, and epileptic seizures can emerge during the patients’ life span.

δ scores predict multiple neuropsychiatric symptoms.

Dementia severity is strongly related to Spearman's general intelligence factor "g", via the latent dementia phenotype "δ" and is distinct from domain-specific cognitive impairments arising from disease-specific regional pathologies. It is an empiric question whether behavioral and psychological symptoms of dementia (BPSD) are associated with δ or with domain-specific constructs. A recently developed δ homolog ("dDx") was tested as a predictor of 1 year prospective BPSD in n = 723 Mexican-American and non-Hispanic White participants in the Texas Alzheimer's Research and Care Consortium (TARCC). The informant-rated frequencies of 12 BPSD were rated by the neuropsychiatric inventory (NPI-Q). Baseline BPSD, demographic features, selected biomarkers, and treatment exposure to acetylcholinesterase inhibitors were used as covariates. Composite scores derived from orthogonal latent measures of domain-specific memory (MEM) and executive function (EF) were also tested as predictors. "Functionally salient cognitive impairment (FSCI)" that is, categorical "dementia" as diagnosed by dDx was associated with increased prospective frequency of 11/12 BPSD, independently of baseline behavior and covariates. Age, depressive symptoms, and EF were associated with individual BPSD. MEM was not associated with any. Dementia severity, as measured by dDx, was also associated with a prospective increase in total NPI-Q scores. δ is associated non-specifically with multiple BPSD. This suggests the existence of a dementia-specific behavioral profile, arising from insults to general intelligence, and unrelated to disease-specific regional pathology(ies).

ADDRESSING DEPRESSION WITH AND WITHOUT COEXISTING ANXIETY IN COMMUNITY-DWELLING PERSONS WITH DEMENTIA

Introduction Depression and anxiety are common in persons with dementia (PWD) and are associated with a myriad of poor outcomes, which include poorer quality of life, greater impairment in activities of daily living, worsened cognitive impairment, and higher rates of institutionalization. Guidelines for treating depression in PWD are heterogeneous. Multiple international guidelines suggest repeated screening and evaluation over time for depression and other neuropsychiatric symptoms with appropriate treatment if symptoms are present. While mild to moderate depression should primarily be managed with psychosocial or environmental interventions when available, severe, persistent depression often requires pharmacological management. In contrast to depression, formal guidelines for treating depression with coexisting anxiety in PWD are lacking. Few studies have investigated the impact of coexisting depression and anxiety in this population. This study's goals were to increase knowledge about depression with and without coexisting anxiety in PWD living in the community. It explores prevalence, pharmacologic management, and mental health service use in PWD with depression with and without coexisting anxiety. Methods The sample for this cross-sectional study comprised 160 community-dwelling PWD enrolled in a randomized, controlled trial of a behavioral intervention aimed to prevent the development of aggression in PWD by addressing the management of pain, depression and communication with their caregivers. Baseline data on depression, anxiety, psychotropic medications and mental health service use were examined. Outcome variables included proportions of participants receiving antidepressant, anxiolytic, antipsychotic and sleep medications; total number of psychotropic medications per participant; and frequency of mental health services visits. The first analysis used one-way ANOVA and chi-square tests to compare participants with dementia alone to participants with dementia and depression and participants with dementia and depression with co-existing anxiety. The second analysis used chi-square and Fisher exact tests to compare participants with mild to moderate depression to participants with severe depression based on total score on the Geriatric Depression Scale (GDS). Presence of clinically significant depression and anxiety symptoms were defined by previously validated score cut-points of the GDS and the Geriatric Anxiety Inventory (GAI), respectively. Results The sample's mean GDS score was 11.22 (SD = 6.16) and median GAI score was 1 (IQR = 0-3). Forty-one percent of participants had dementia alone, 28% had dementia with depression, 27% had dementia and depression with coexisting anxiety, and 4% had dementia with anxiety. Fifty-five percent of participants reported clinically significant depression. Clinically significant anxiety was present in 49% of participants with depression and in 27% of the total sample. The proportion of participants with severe depression symptoms was significantly larger in participants with depression and anxiety compared to those participants with depression alone (Fisher exact p Conclusions This study adds to the literature on the prevalence, pharmacologic management and mental health service use in PWD with depression with and without coexisting anxiety living in the community. Additional studies need to explore the relationship between dementia with depression with coexisting anxiety and short- and long-term patient outcomes, as the literature is lacking in this area. Depression with and without anxiety is very common in PWD, but there is variable adherence to treatment guidelines. Absence of pharmacological and nonpharmacological treatment in a significant minority of participants with severe depression in this study may reflect a lack of detection or lack of treatment. The considerable number of patients with dementia alone prescribed antidepressants may be explained by several factors. These include the fact that antidepressants are used in the treatment of multiple neuropsychiatric symptoms in PWD, participants in this group may have had partial or full response to an antidepressant trial and were being continued on maintenance treatment to prevent relapse, or the possibility that antidepressant medications are being used improperly and without indication in this sample. Mental health service use is low and there is a need for patient, provider, and system-level interventions to facilitate access to mental health providers This research was funded by: National Institute of Nursing Research

The functional roles of IGF-1 variants in the susceptibility and clinical outcomes of mild traumatic brain injury

BackgroundInsulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. This study attempted to elucidate the effects of IGF-1 variants on the risk and neuropsychiatric outcomes of mTBI.MethodsBased on 176 recruited mTBI patients and 1517 control subjects from the Taiwan Biobank project, we first compared the genotypic distributions of IGF-1 variants between the two groups. Then, we analyzed associations of IGF-1 variants with neuropsychiatric symptoms after mTBI, including anxiety, depression, dizziness, and sleep disturbances. Functional annotation of IGF-1 variants was also performed through bioinformatics databases.ResultsThe minor allele of rs7136446 was over-represented in mTBI patients compared to community-based control subjects. Patients carrying minor alleles of rs7136446 and rs972936 showed more dizziness and multiple neuropsychiatric symptoms after brain injury.ConclusionsIGF-1 variants were associated with the risk and neuropsychiatric symptoms of mTBI. The findings highlight the important role of IGF-1 in the susceptibility and clinical outcomes of mTBI.

Outcome of neuropsychiatric symptoms and daily functioning of patients with dementia treated on an acute psychogeriatric ward

Background: Dementia is associated with progressive deterioration in multiple cognitive domains, functional impairment and neuropsychiatric symptoms (NPS).Aims: The aim of this study was to explore the factors associated with the outcome of NPS and daily functioning in patients with dementia during acute psychogeriatric hospitalization.Materials and method: The data (n = 175) were collected between 2009 and 2013 in naturalistic settings on one acute psychogeriatric ward at one university hospital in Finland. Behavioural symptoms were assessed using the Neuropsychiatric Inventory (NPI) and activities of daily living using the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL).Results: During the hospital stay (45 days ±30.4) NPI total score decreased from 33.9 to 18.2 (p < .001). Daily functioning score decreased from 31.7 to 20.9 (p < .001). The number of patients taking antipsychotics (96–130, p = .004) and anxiolytics (54–102, p < .001) increased from admission to discharge. Overall mean dosage (mg/day) of antipsychotics (from 40.2 to 72.0 in chlorpromazine equivalents, p < .00) and anxiolytics (from 3.43 to 7.47 in diazepam equivalents, p < .001) also increased. Higher antipsychotic dosage at discharge was a significant predictor for large NPI score change (p = .002) indicating better symptom reduction. Neither higher antipsychotic dosage or anxiolytic dosage at discharge were significant predictors for ADL score change.Conclusions: Neuropsychiatric symptoms improved while deterioration was found in daily functioning from admission to discharge. Higher antipsychotic dosage at discharge was a predictor for larger NPI score change indicating better symptom reduction. Preventing threatening ADL decline during hospital stay is especially important.

Identify a shared neural circuit linking multiple neuropsychiatric symptoms with Alzheimer's pathology.

Neuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD)-associated neurodegeneration. However, NPS lack a consistent relationship with AD pathology. It is unknown whether any common neural circuits can link these clinically disparate while mechanistically similar features with AD pathology. Here, we explored the neural circuits of NPS in AD-associated neurodegeneration using multivariate pattern analysis (MVPA) of resting-state functional MRI data. Data from 98 subjects (70 amnestic mild cognitive impairment and 28AD subjects) were obtained. The top 10 regions differentiating symptom presence across NPS were identified, which were mostly the fronto-limbic regions (medial prefrontal cortex, caudate, etc.). These 10 regions' functional connectivity classified symptomatic subjects across individual NPS at 69.46-81.27%, and predicted multiple NPS (indexed by Neuropsychiatric Symptom Questionnaire-Inventory) and AD pathology (indexed by baseline and change of beta-amyloid/pTau ratio) all above 70%. Our findings suggest a fronto-limbic dominated neural circuit that links multiple NPS and AD pathology. With further examination of the structural and pathological changes within the circuit, the circuit may shed light on linking behavioral disturbances with AD-associated neurodegeneration.

Cortical brain volume abnormalities associated with few or multiple neuropsychiatric symptoms in Alzheimer's disease.

New research on assessing neuropsychiatric manifestations of Alzheimer´s Disease (AD) involves grouping neuropsychiatric symptoms into syndromes. Yet this approach is limited by high inter-subject variability in neuropsychiatric symptoms and a relatively low degree of concordance across studies attempting to cluster neuropsychiatric symptoms into syndromes. An alternative strategy that involves dichotomizing AD subjects into those with few versus multiple neuropsychiatric symptoms is both consonant with real-world clinical practice and can contribute to understanding neurobiological underpinnings of neuropsychiatric symptoms in AD patients. The aim of this study was to address whether the number of neuropsychiatric symptoms (i.e., presence of few [≤2] versus multiple [≥3] symptoms) in AD would be associated with degree of significant gray matter (GM) volume loss. Of particular interest was volume loss in brain regions involved in memory, emotional processing and salience brain networks, including the prefrontal, lateral temporal and parietal cortices, anterior cingulate gyrus, temporo-limbic structures and insula. We recruited 19 AD patients and 13 healthy controls, which underwent an MRI and neuropsychiatric assessment. Regional brain volumes were determined using voxel-based morphometry and other advanced imaging processing methods. Our results indicated the presence of different patterns of GM atrophy in the two AD subgroups relative to healthy controls. AD patients with multiple neuropsychiatric manifestations showed more evident GM atrophy in the left superior temporal gyrus and insula as compared with healthy controls. In contrast, AD subjects with few neuropsychiatric symptoms displayed more GM atrophy in prefrontal regions, as well as in the dorsal anterior cingulate ad post-central gyri, as compared with healthy controls. Our findings suggest that the presence of multiple neuropsychiatric symptoms is more related to the degree of atrophy in specific brain networks rather than dependent on the global severity of widespread neurodegenerative brain changes.