Niemann-Pick Type C (NPC) is a genetic neurodegenerative lysosomal storage disorder commonly associated with psychiatric symptoms and delays to accurate diagnosis and treatment. This study investigated biomarker levels and diagnostic utility of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in NPC compared to healthy controls.

Patients with NPC were recruited from a specialist assessment and management service. Data was available from an age and sex-matched healthy control group. NfL and GFAP were measured on Quanterix Simoa HD-X analysers and groups compared using generalised linear models. NfL levels were compared to, and percentiles derived from, recently developed NfL reference ranges.

Plasma NfL was significantly elevated in 11 patients with NPC compared to 25 controls (mean 17.1 vs. 7.4 pg/ml, p < 0.001), and reference ranges (all >98th percentile). NfL distinguished NPC from controls with high accuracy. GFAP levels were not elevated in NPC (66.6 vs. 75.1 pg/ml).

The study adds important evidence on the potential diagnostic utility of plasma NfL in NPC, extends the literature of NfL as a diagnostic tool to differentiate neurodegenerative from primary psychiatric disorders, and adds support to the pathology in NPC primarily involving neuronal, particularly axonal, degeneration.

Neuropsychological criteria for mild cognitive impairment (MCI) more accurately predict progression to Alzheimer’s disease (AD) and are more strongly associated with AD biomarkers and neuroimaging profiles than ADNI criteria. However, research to date has been conducted in relatively healthy samples with few comorbidities. Given that history of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are risk factors for AD and common in Veterans, we compared neuropsychological, typical (Petersen/Winblad), and ADNI criteria for MCI in Vietnam-era Veterans with histories of TBI or PTSD.

267 Veterans (mean age = 69.8) from the DOD-ADNI study were evaluated for MCI using neuropsychological, typical, and ADNI criteria. Linear regressions adjusting for age and education assessed associations between MCI status and AD biomarker levels (cerebrospinal fluid [CSF] p-tau181, t-tau, and Aβ42) by diagnostic criteria. Logistic regressions adjusting for age and education assessed the effects of TBI severity and PTSD symptom severity simultaneously on MCI classification by each criteria.

Agreement between criteria was poor. Neuropsychological criteria identified more Veterans with MCI than typical or ADNI criteria, and were associated with higher CSF p-tau181 and t-tau. Typical and ADNI criteria were not associated with CSF biomarkers. PTSD symptom severity predicted MCI diagnosis by neuropsychological and ADNI criteria. History of moderate/severe TBI predicted MCI by typical and ADNI criteria.

MCI diagnosis using sensitive neuropsychological criteria is more strongly associated with AD biomarkers than conventional diagnostic methods. MCI diagnostics in Veterans would benefit from incorporation of comprehensive neuropsychological methods and consideration of the impact of PTSD.

Many Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans have sustained a mild traumatic brain injury (mTBI) during their military service and a substantial “miserable minority” frequently report significant cognitive complaints long after injury. Although existing studies have shown associations between genetic factors (e.g., apolipoprotein E [APOE] and brain-derived neurotrophic factor [BDNF]) and cognitive performance in this vulnerable population, the TBI-genetics literature has generally been varied and inconsistent. Although past findings suggest that individuals who possess APOE £4 and BDNF Met alleles have worse cognitive outcomes after mTBI, this has not been consistently reported. Additionally, the influence of any gene-by-gene interactions on cognition has not been sufficiently explored and therefore remains a critical area of interest. Thus, we examined relationships between APOE and BDNF genotypes on neuropsychological function in a well-characterized sample of younger Veterans with mTBI histories.

Participants included Veterans with a history of mTBI who adequately completed performance validity testing. In total, 78 Veterans (84.6% male; age: M=32.95, SD=7.00; race/ethnicity: 51.3% White, 28.2% Hispanic/Latino, and 20.5% Another Race/Ethnicity) completed a structured clinical interview to collect detailed information on TBI history and underwent a comprehensive neuropsychological exam. A buccal swab was also collected to determine APOE and BDNF allele status for each participant. Three cognitive composite scores were computed reflecting memory (8 items), attention/processing speed (7 items), and executive functioning (10 items). Two-way analyses of covariance (ANCOVAs) adjusting for age, sex, and race/ethnicity were used to assess the effects of APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) on cognitive functioning (ε4+/Met-: n=12, ε4+/Met+: n=8, £4-/Met-: n=35, and ε4-/Met+: n=23).

ANCOVAs revealed no significant main effects for APOE or BDNF genotypes on cognitive functioning; however, there was a significant APOE x BDNF genotype interaction for all three cognitive composites (memory: p=.026, np2=.068; attention/processing speed: p=.045, np2=.055; and executive functioning: p=.031, np2=.064). Specifically, the interaction was such that Veterans in the ε4+/Met+ group demonstrated the poorest cognitive functioning relative to all other allele group combinations (ε4+/Met-, ε4-/Met+, ε4-/Met-).

The results of this preliminary study demonstrate that, compared to the other genetic subgroups in the TBI sample, Veterans with APOE £4 and BDNF Met alleles demonstrated the poorest cognitive functioning across several domains known to be negatively affected in the context of head injury (i.e., memory, attention/processing speed, and executive functioning). These findings are the first to show an APOE x BDNF interaction in Veterans with histories of mTBI. Further

research is necessary to replicate and extend this study in larger samples. Moreover, future work should incorporate neuroimaging variables to better interrogate structural and functional correlates of these observed genetic polymorphism associations in Veterans with mTBI histories.

Veterans with a history of mild traumatic brain injury (mTBI) often endorse enduring postconcussive symptoms (PCS) including cognitive and neuropsychiatric complaints. However, although several studies have shown associations between these complaints and brain structure and cerebrovascular function, few studies have examined relationships between structural and functional brain alterations and PCS in the context of remote mTBI. We therefore examined whether PCS were associated with cortical thickness and cerebral blood flow (CBF) in a well-characterized sample of Veterans with a history of mTBI.

116 Veterans underwent structural neuroimaging and a clinical interview to obtain detailed TBI history and injury-related information. Participants also completed the following self-report measures: the Neurobehavioral Symptom Inventory (NSI) for ratings of cognitive, emotional, somatic-sensory, and vestibular symptoms, and the Posttraumatic Stress Disorder (PTSD) Checklist for PTSD symptom severity. Regional brain thickness was indexed using FreeSurfer-derived cortical parcellations of frontal and temporal regions of interest (ROIs) including the superior frontal gyrus (SFG), middle frontal gyrus (MFG), inferior frontal gyrus (IFG), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), medial temporal lobe (MTL), and lateral temporal lobe (LTL). A subset of Veterans (n=50) also underwent multi-phase pseudo-continuous arterial spin labeling (MPPCASL) to obtain resting CBF. T1-weighted structural and MPPCASL scans were co-registered and CBF estimates were extracted from the 7 bilateral parcellations of ROIs. To assess the relationship between NSI total and subscale scores and ROI thickness and CBF, multiple regression analyses were conducted adjusting for age, sex, and PTSD symptom severity. False Discovery Rate was used to correct for multiple comparisons.

NSI total and subscale scores were not associated with cortical thickness of any ROI. However, higher NSI scores were associated with increased ROI CBF of the SFG (q=.014) and MFG CBF (q=.014). With respect to symptom subscales, higher affective subscale scores were associated with increased SFG (q=.001), MFG (q=.001), IFG (q=.039), ACC (q=.026), and LTL CBF (q=.026); higher cognitive subscale scores were associated with increased SFG (q=.014) and MFG CBF (q=.032); and higher vestibular subscale scores were associated with increased ACC CBF (q=.021). NSI somatic-sensory subscale scores were not associated with ROI CBF.

Results demonstrate that in TBI-susceptible anterior ROIs, alterations in CBF but not cortical thickness are associated with postconcussive symptomatology in Veterans with a history of mTBI. Specifically, postconcussive total symptoms as well as affective, cognitive, and vestibular subscale symptoms were strongly linked primarily to CBF of frontal regions. Remarkably, these results indicate that enduring symptoms in generally younger samples of Veterans with head injury histories may be closely tied to cerebrovascular function rather than brain structure changes. These findings may provide a neurological basis for negative clinical outcomes (e.g., enduring PCS and poor quality of life) that is frequently reported by many individuals following mTBI. Future work is needed to examine unique effects of blast exposure as well as associations with repeated injury on brain-behavior relationships.

People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown.

We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other.

Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone.

CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

Exploration of the themes and content of psychotic symptoms in young-onset dementia (YOD) is limited to case analysis. The primary objective of this study was to determine the themes of psychotic symptoms in individuals diagnosed with YOD.

Comprehensive retrospective file review of discharge summaries.

Neuropsychiatry, a specialist mental health service located at the Royal Melbourne Hospital, Australia.

Inpatients at Neuropsychiatry admitted between 2018 and 2020 (inclusive).

Data extracted included descriptions and prevalence of psychotic symptoms as well as general demographic and clinical data. Data analysis was conducted using a thematic approach.

Twenty-three inpatients had a diagnosis of YOD with psychotic symptoms. Themes were identified in the domains of delusions (six themes), auditory hallucinations (five themes), and visual hallucinations (two themes). Strong recurring themes across the modalities of hallucinations and delusions were beliefs and experiences relating to paranoia, suspicion, harm, and abuse. Themes did not clearly intersect across the modalities of hallucinations and delusions. A degree of thematic heterogeneity existed within individuals, and individuals experienced delusions or hallucinations of multiple themes. The themes of the psychotic symptoms did not clearly relate to diagnostic category, nor to time from diagnosis.

This study is the first thematic analysis of psychotic symptoms in YOD and provides further understanding of patient phenomenology and experiences of psychosis in YOD.

Dyfunctions of prefrontal neuronal circuits contribute to the pathophysiology of depression. Previous studies showed increased functional MRI and EEG connectivity in patients with depression. In this study we investigated a large sample of patients with major depression (n=228) and healthy subjects (n=215).

Spectrotemporal dynamics during resting state with closed eyes were analyzed in sensor and source space to examine functional EEG connectivity (fcEEG) alterations between groups. Quantitative measures of delta, theta, alpha, beta and gamma power, hemispheric asymmetry, coherence, phase and current source density (CSD, eLORETA) analyses were calculated from artifact-free EEG recordings.

EEG theta power was increased in all brain regions in the group of patients with a focus in frontal regions and increased frontal theta and alpha power. Excessive coherence differences were detected in the delta, theta and alpha-bands in frontal, frontal-temporal and frontal-parietal regions. There were changes in phase differences in the delta, theta, alpha-bands between patients and healthy subjects. Differences in CSD were found for the delta, theta, alpha-band in the (rostral and subgenual) anterior cingulate cortex (ACC) with increased CSD in the patients.

The main finding of the present study was an increase in cortical slow-wave activity in sensor and source space in patients with depression revealing marked differences in prefrontal cortical networks. Functional delta, theta and alpha connectivity (coherence and phase) were altered with a predominance in the left hemisphere. Dysfunctions of the ACC, together with alterations in fcEEG may contribute to the pathophysiology of major depression.

A large body of literature has demonstrated that people affected by psychotic disorders show deficits in working memory, in Emotion Recognition (ER) and in data-gathering to reach a decision (Jumping To Conclusions – JTC).

To investigate a possible correlation between working memory, JTC and ER in FEP.

41 patients and 89 healthy controls completed assessments of working memory using WAIS shortened version, JTC using the 60:40 Beads Task and ER using Degraded Facial Affect Recognition Task.

According to the literature, cases had poorer performance in working memory tasks (Digit Span: μ7,72 [ds=2,98] vs μ10,14 [ds=3,10], U=865,00, p=0,00; Digit Symbol: μ5,36 [ds=2,43] vs μ10,05 [ds=3,10], U=455,50, p=0,00; Arithmetic: μ5,46 [ds=2,76] vs μ8,74 [ds=3,24], U=865,50, p=0,00; Block Design: μ4,82 [ds=2,72] vs μ7,60 [ds=3,18], U=912,00, p=0,00), in Beads Task (81,6% vs 51,1%, χ2=10,27, p=0,001, μ2,53 [ds=3,57] vs μ4,23 [ds=4,77], U=1171,00, p=0,006) and in DFAR (total errors: μ21,62 [ds=7,43] vs μ16,58 [ds=8,69], U=554,50, p=0,002). Furthermore working memory tasks in cases group correlated significantly with JTC (Digit Span: r_rho=0,276, p=0,003; Digit Symbol: r_rho=0,275, p=0,002; Arithmetic: r_rho=0,265, p=0,003; Block Design: r_rho=0,292, p=0,001), but only Digit Span with ER (r_rho=-0,239; p=0,021). In addition, we found that JTC and ER were significantly associated (r_rho=-0,281; p=0,004).

Data show that working memory impairments, JTC style and dysfunctions in the facial emotions recognition are phenomena strongly correlated in the group of patients. Preliminary results suggest the importance of early rehabilitation as the impairments detected may lead to difficulties in social and relational adaptation in psychotic patients.

Of the 13 US vancomycin-resistant Staphylococcus aureus (VRSA) cases, 8 were identified in southeastern Michigan, primarily in patients with chronic lower-extremity wounds. VRSA infections develop when the vanA gene from vancomycin-resistant enterococcus (VRE) transfers to S. aureus. Incl8-like plasmids in VRE and pSK41-like plasmids in S. aureus appear to be important precursors to this transfer.

Identify the prevalence of VRSA precursor organisms.

Prospective cohort with embedded case-control study.

Southeastern Michigan adults with chronic lower-extremity wounds.

Adults presenting to 3 southeastern Michigan medical centers during the period February 15 through March 4, 2011, with chronic lower-extremity wounds had wound, nares, and perirectal swab specimens cultured for S. aureus and VRE, which were tested for pSK41-like and Incl8-like plasmids by polymerase chain reaction. We interviewed participants and reviewed clinical records. Risk factors for pSK41-positive S. aureus were assessed among all study participants (cohort analysis) and among only S. aureus-colonized participants (case-control analysis).

Of 179 participants with wound cultures, 26% were colonized with methicillin-susceptible S. aureus, 27% were colonized with methicillin-resistant S. aureus, and 4% were colonized with VRE, although only 17% consented to perirectal culture. Six participants (3%) had pSK41-positive S. aureus, and none had Incl8-positive VRE. Having chronic wounds for over 2 years was associated with pSK41-positive S. aureus colonization in both analyses.

Colonization with VRSA precursor organisms was rare. Having long-standing chronic wounds was a risk factor for pSK41-positive S. aureus colonization. Additional investigation into the prevalence of VRSA precursors among a larger cohort of patients is warranted.