Chronic traumatic encephalopathy neuropathologic change in former Australian rugby players.

AIMS: We applied the 2021 consensus criteria for both chronic traumatic encephalopathy neuropathological change and traumatic encephalopathy syndrome in a small case series of six former elite-level Australian rugby code players. METHODS: Neuropathological assessment of these cases was carried out at the Sydney and Victorian Brain Banks. Clinical data were collected via clinical interviews and health questionnaires completed by the participants and/or their next of kin, and neuropsychological testing was conducted with participants who were capable of completing this testing. RESULTS: All cases exhibited progressive cognitive impairment during life. Chronic traumatic encephalopathy neuropathological change was identified in four out of the six cases. However, coexisting neuropathologies were common, with limbic-predominant age-related TDP-43 encephalopathy and ageing-related tau astrogliopathy seen in all cases, intermediate or high Alzheimer's disease neuropathological change seen in four cases and hippocampal sclerosis seen in two of the six cases. CONCLUSION: The presence of multiple neuropathologies in these cases complicates clinical diagnostic efforts for traumatic encephalopathy syndrome. It will be important for further clinicopathological studies on larger groups to report all neuropathological comorbidities found in cases diagnosed with either chronic traumatic encephalopathy neuropathological change and/or traumatic encephalopathy syndrome.

Heterogeneity of cortical pTDP-43 inclusion morphologies in amyotrophic lateral sclerosis.

BACKGROUND: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with amyotrophic lateral sclerosis (ALS), pathological subclassification is routinely performed in the minority of patients with concomitant frontotemporal dementia (FTD). OBJECTIVE: In order to improve current understanding of the presence and relevance of pathological pTDP-43 subtypes in ALS, the present study examined the pattern of cortical pTDP-43 aggregates in 61 ALS cases without FTD. RESULTS: Based on the presence, morphology and composition of pTDP-43 pathology, three distinct ALS-TDP subtypes were delineated: (1) A predominant pattern of pTDP-43 granulofilamentous neuronal inclusions (GFNIs) and grains that were immuno-negative for p62 was identified in 18% of cases designated ALS-TDP type E; (2) neuronal cytoplasmic inclusions (NCIs) that were immuno-positive for both pTDP-43 and p62 were observed in 67% of cases assigned ALS-TDP type B; and (3) scarce cortical pTDP-43 and p62 aggregates were identified in 15% of cases coined ALS-TDP type SC (scarce cortical). Quantitative analyses revealed a significantly greater burden of pTDP-43 GFNI and grains in ALS-TDP type E. Principal component analysis demonstrated significant relationships between GFNIs, grains and ALS-TDP subtypes to support the distinction of subtypes E and B. No significant difference in age at death or disease duration was found between ALS-TDP subgroups to suggest that these subtypes represent earlier or later stages of the same disease process. Instead, a significantly higher ALS-TDP stage, indicating greater topographical spread of pTDP-43, was identified in ALS-TDP type E. Alzheimer's disease neuropathological change (ABC score ≥ intermediate) and Lewy body disease (Braak stage ≥ IV) was more prevalent in the ALS-TDP type SC cohort, which also demonstrated a significantly lower overall cognitive score. CONCLUSION: In summary, the present study demonstrates that ALS-TDP does not represent a single homogenous neuropathology. We propose the subclassification of ALS-TDP into three distinct subtypes using standard immuno-stains for pTDP-43 and p62 in the motor cortex, which is routinely sampled and evaluated for diagnostic neuropathological characterisation of ALS. We propose that future studies specify both clinicopathological group and pTDP-43 subtype to advance current understanding of the pathogenesis of clinical phenotypes in pTDP-43 proteinopathies, which will have significant relevance to the development of targeted therapies for this heterogeneous disorder.

Poly-GA immunohistochemistry is a reliable tool for detecting C9orf72 hexanucleotide repeat expansions.

Poly-GA immunohistochemistry (A) on formalin fixed paraffin embedded cerebellum sections shows a similar distribution to p62 antibody (B) and reliably identifies neuronal cytoplasmic inclusions and neurites in cases with known C9orf72 repeat expansion. This is useful in the research setting where genetic testing has not been performed in life or suitable tissue is not avilable post-mortem.

Treatment with the copper compound CuATSM has no significant effect on motor neuronal pathology in patients with ALS.

AIMS: Although the orally available brain-penetrant copper compound CuATSM has demonstrated promising effects in SOD1-linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown. METHODS: The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [N = 6 cases composed of ALS-TDP (n = 5) and ALS-SOD1 (n = 1)] versus riluzole only [N = 6 cases composed of ALS-TDP (n = 4) and ALS-SOD1 (n = 2)]. RESULTS: Our results revealed no significant difference in neuron density or TDP-43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not. In patients that had received CuATSM, p62-immunoreactive astrocytes were observed in the motor cortex and reduced Iba1 density was found in the spinal cord. However, no significant difference in measures of astrocytic activity and SOD1 immunoreactivity was found with CuATSM treatment. DISCUSSION: These findings, in this first postmortem investigation of patients with ALS in CuATSM trials, demonstrate that in contrast to that seen in preclinical models of disease, CuATSM does not significantly alleviate neuronal pathology or astrogliosis in patients with ALS.

Prevalence of chronic traumatic encephalopathy in the Sydney Brain Bank.

Chronic traumatic encephalopathy neuropathologic change can only be definitively diagnosed post-mortem. It has been associated with repetitive mild neurotrauma sustained in amateur and professional contact, collision and combat sports, although it has also been documented in people with a single severe traumatic brain injury and in some people with no known history of brain injury. The characteristic neuropathology is an accumulation of perivascular neuronal and astrocytic phosphorylated tau in the depths of the cortical sulci. The tau-immunopositive neurons and astrocytes that are considered pathognomonic for chronic traumatic encephalopathy are morphologically indistinguishable from Alzheimer-related neurofibrillary tangles and ageing-related tau astrogliopathy, respectively, although they are found in different spatial distributions throughout the cortex. The Sydney Brain Bank collection consists of neurodegenerative diseases and neurologically normal controls. We screened 636 of these cases for chronic traumatic encephalopathy neuropathologic change. A subset of 109 cases had a known history of traumatic brain injury. Three cortical regions were screened for the presence of neuronal and astrocytic phosphorylated tau according to the current 2021 National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus criteria for chronic traumatic encephalopathy. Five cases (0.79%) showed pathological evidence of chronic traumatic encephalopathy and three of these had a history of traumatic brain injury. Three cases had coexisting Alzheimer's and/or Lewy body disease pathology meeting criteria for neurodegenerative disease. Another eight cases almost met criteria for chronic traumatic encephalopathy neuropathological change except for an absence of neuronal tau or a strict perivascular arrangement. Ageing-related tau astrogliopathy was found in all eight cases as a coexisting neuropathology. Traumatic brain injury was associated with increased odds ratio [1.79, confidence interval 1.18-2.72] of having a higher neurofibrillary tangle stage and phosphorylated TAR DNA binding protein 43 (OR 2.48, confidence interval 1.35-4.54). Our study shows a very low rate of chronic traumatic encephalopathy neuropathological change in brains with or without neurodegenerative disease from the Sydney Brain Bank. Our evidence suggests that isolated traumatic brain injury in the general population is unlikely to cause chronic traumatic encephalopathy neuropathologic change but may be associated with increased brain ageing.

Child Welfare Policies and Practices Regarding Children with Prenatal Exposure to Alcohol and Other Drugs: An Exploratory Study.

Research indicates that there are more children with prenatal alcohol and other drug exposures in child welfare than in the general population. Using multiple forms of data from staff and caregivers from one urban agency, this exploratory study demonstrated opportunities to inform polices, practice, and data elements regarding this vulnerable group. Findings are discussed within the context of ensuring family preservation, equity and avoiding disproportional race/ethnicity within child welfare when identifying and caring for children with prenatal exposures.

Aging-Related Tau Astrogliopathy in Aging and Neurodegeneration.

Astrocytes are of vital importance to neuronal function and the health of the central nervous system (CNS), and astrocytic dysfunction as a primary or secondary event may predispose to neurodegeneration. Until recently, the main astrocytic tauopathies were the frontotemporal lobar degeneration with tau (FTLD-tau) group of disorders; however, aging-related tau astrogliopathy (ARTAG) has now been defined. This condition is a self-describing neuropathology mainly found in individuals over 60 years of age. Astrocytic tau accumulates with a thorny or granular/fuzzy morphology and is commonly found in normal aging as well as coexisting with diverse neurodegenerative disorders. However, there are still many unknown factors associated with ARTAG, including the cause/s, the progression, and the nature of any clinical associations. In addition to FTLD-tau, ARTAG has recently been associated with chronic traumatic encephalopathy (CTE), where it has been proposed as a potential precursor to these conditions, with the different ARTAG morphological subtypes perhaps having separate etiologies. This is an emerging area of exciting research that encompasses complex neurobiological and clinicopathological investigation.

Coexisting Lewy body disease and clinical parkinsonism in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is associated with a range of clinical phenotypes and shows progressive degeneration of upper and/or lower motor neurons, and phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43) inclusions in motor and non-motor pathways. Parkinsonian features have been reported in up to 30% of ALS patients, and Lewy bodies, normally associated with Lewy body disease (LBD), have been reported in a small number of ALS cases, with unknown clinical relevance. This study investigates the prevalence of clinically relevant LBD in a prospectively studied ALS cohort to determine whether concomitant pathology contributes to the clinical heterogeneity. METHODS: All ALS cases held by the New South Wales Brain Bank (n = 97) were screened for coexisting LBD consistent with clinical disease (Braak ≥ stage IV). Relevant clinical and genetic associations were determined. RESULTS: Six cases had coexisting LBD Braak ≥ stage IV pathology. The age at symptom onset (69 ± 7 years) and disease duration (4 ± 3 years) in ALS cases with coexisting LBD did not differ from ALS cases. Three patients had lower limb onset and two patients had bulbar onset. Two patients developed the clinical features of Parkinson's disease, with one receiving a dual diagnosis. All cases had no known relevant family history or genetic abnormalities. CONCLUSION: The prevalence of clinically relevant LBD pathology in ALS is higher than in the general population, and has implications for clinical and neuropathological diagnoses and the identification of biomarkers.

Sexual Health Services in Schools: A Successful Community Collaborative.

School-based health centers (SBHCs) are an essential part of a comprehensive approach to address the health needs of youth. SBHCs that provide sexual health services (SHS) show promising results in improving reproductive health outcomes among youth. Despite the positive impact SBHCs can have, few school districts have SBHCs, and even fewer provide SHS. This article describes a successful 5-year project to provide SHS through SBHCs in a large county in the southeast United States. A community collaborative, including the schools, health department, community agencies and a local university, was created to address the project goals and objectives. Various steps were taken to plan for the SBHCs, including documenting community support for SHS offered through SBHCs, identifying school sites for SBHCs, and the process for offering pregnancy, STD (sexually transmitted disease), and HIV testing, treatment, and referrals. Protocols for clinic flow, testing, staffing, training, and student recruitment were developed. The staff at the SBHCs were successful in recruiting students to attend educational sessions and to receive testing and treatment. Student feedback was overwhelmingly positive. Lessons learned about the importance of the partnership's collaboration, using recommended clinic protocol, ensuring clear communication with school staff, and employing youth friendly recruitment and clinic practices are shared.

A Practical Approach to Differentiate the Frontotemporal Tauopathy Subtypes.

This study proposes a practical approach, using the minimum number of brain regions and stains, to consolidate previously published neuropathological criteria into one operationalized schema to differentiate subtypes of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau). This approach uses the superior frontal and precentral cortices and hippocampus stained for phosphorylated-tau, p62 and modified Bielschowsky silver, and the midbrain stained only for modified Bielschowsky silver. Accuracy of interrater reliability was determined by 10 raters in 24 FTLD-tau cases (Pick disease = 4, corticobasal degeneration = 9, progressive supranuclear palsy = 5, globular glial tauopathy = 6) including 4 with a mutation in MAPT collected with consent by Sydney Brain Bank. All brain regions and stains assessed proved informative for accurate pathological subtyping, and many neuropathological features were identified as common across the FTLD-tau subtypes. By identifying subtype-specific neuropathological features in the sections selected, 10 independent observers assigned the cases to a FTLD-tau subtype with almost perfect agreement between raters, emphasizing the requirement for the assessment of subtype-specific features for the accurate subtyping of FTLD-tau. This study consolidates current consensus diagnostic criteria for classifying FTLD-tau subtypes with an efficient, simple and accurate approach that can be implemented in future clinicopathological studies.

Children prenatally exposed to alcohol and other drugs: what the literature tells us about child welfare information sources, policies, and practices to identify and care for children.

Many parents who interact with the child welfare system present with substance use issues, which means their children are at risk for prenatal exposure to alcohol and other drugs. Because child welfare agencies play an important role in identifying and providing services to mitigate negative impacts of prenatal exposures, we conducted a search for literature addressing child welfare information sources, policies, and practices related to this population. The search yielded 16 research/evaluation and 16 policy/practice papers, with most addressing exposures to both alcohol and other drugs. The literature most commonly reports that children identified as exposed are referred to child protection agencies during the newborn period. This practice may lead to underidentification, especially of children with prenatal exposure to alcohol. Research suggests that this population is at risk for poorer child welfare outcomes and that there are specific service needs for these children. This review indicates that there is an overall lack of research literature regarding identification of prenatally exposed children involved in the child welfare system that could best inform child welfare policies and practices. Studies investigating how the child welfare system identifies and cares for children with prenatal exposures are needed.

Von Economo Neurons in Behavioral Variant Frontotemporal Dementia with Underlying Alzheimer's Disease.

The selective loss of von Economo neurons has been linked to the behavioral deficits in behavioral variant frontotemporal dementia (bvFTD) but whether these neurons are affected in bvFTD patients with underlying Alzheimer's disease (AD) has yet to be established. The present study assesses the von Economo neurons in pathological AD cases clinically diagnosed with either AD or bvFTD. Our results demonstrate no significant loss of von Economo neurons in all pathological AD cases, irrespective of clinical diagnosis or co-existing Lewy body pathology. These results suggest that the behavioral deficits in patients with clinical bvFTD and underlying pathological AD are not driven by the loss of von Economo neurons.

Coexisting Lewy body disease and clinical parkinsonism in frontotemporal lobar degeneration.

OBJECTIVE: To investigate the prevalence of clinically relevant multiple system atrophy (MSA) and Lewy body disease (LBD) pathologies in a large frontotemporal lobar degeneration (FTLD) cohort to determine if concomitant pathologies underlie the heterogeneity of clinical features. METHODS: All prospectively followed FTLD-tau and FTLD-TDP cases held by the Sydney Brain Bank (n = 126) were screened for coexisting MSA and LBD (Braak ≥ stage IV) pathology. Relevant clinical (including family history) and genetic associations were determined. RESULTS: MSA pathology was not identified in this series. Of the FTLD cohort, 9 cases had coexisting LBD ≥ Braak stage IV and were associated with different FTLD subtypes including Pick disease (n = 2), corticobasal degeneration (n = 2), progressive supranuclear palsy (n = 2), and TDP type A (n = 3). All FTLD-TDP cases with coexisting LBD had mutations in progranulin (n = 2) or an abnormal repeat expansion in C9orf72 (n = 1). All FTLD-tau cases with coexisting LBD were sporadic. The H1H1 MAPT haplotype was found in all cases that could be genotyped (n = 6 of 9). Seven cases presented with a predominant dementia disorder, 3 of which developed parkinsonism. Two cases presented with a movement disorder and developed dementia in their disease course. The age at symptom onset (62 ± 11 years) and disease duration (8 ± 5 years) in FTLD cases with coexisting LBD did not differ from pure FTLD or pure LBD cases in the brain bank. CONCLUSION: Coexisting LBD in FTLD comprises a small proportion of cases but has implications for clinical and neuropathologic diagnoses and the identification of biomarkers.

Heritability in frontotemporal tauopathies.

INTRODUCTION: Exploring the degree of heritability in a large cohort of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau) and determining if different FTLD-tau subtypes are associated with stronger heritability will provide important insight into disease pathogenesis. METHODS: Using modified Goldman pedigree classifications, heritability was examined in pathologically proven FTLD-tau cases with dementia at any time (n = 124) from the Sydney-Cambridge collection. RESULTS: Thirteen percent of the FTLD-tau cohort have a suggested autosomal dominant pattern of inheritance, 25% have some family history, and 62% apparently sporadic. MAPT mutations were found in 9% of cases. Globular glial tauopathy was associated with the strongest heritability with 40% having a suggested autosomal dominant pattern of inheritance followed by corticobasal degeneration (19%), Pick's disease (8%), and progressive supranuclear palsy (6%). DISCUSSION: Similar to clinical frontotemporal dementia syndromes, heritability varies between pathological subtypes. Further identification of a genetic link in cases with strong heritability await discovery.

Adolescent Screening, Brief Intervention, and Referral to Treatment for Substance Use: An Application for School Social Workers.

Alcohol, tobacco, marijuana, and other substance use by adolescents can have a serious impact on their health and well-being according to the American Academy of Pediatrics (AAP, 2016). School social workers (SSW) are trained to conduct assessments and interventions with adolescents and families to improve their functioning and academic performance (National Association of Social Workers [NASW], 2003). Also, substance abuse prevention, identification, brief intervention, and referral to treatment are supported by the profession's standards for working with adolescents (NASW, 2003). For SSW interested in incorporating these services into their work, this practice highlights column describes the importance and principles of conducting adolescent screening, brief intervention, and referral to treatment (SBIRT) for substance use. Highlights are drawn from Substance Use Screening and Intervention Implementation Guide: No Amount of Substance Use Is Safe for Adolescents (hereinafter, AAP Guide), a guide developed through a cooperative agreement between AAP and Centers for Disease Control and Prevention (CDC) (AAP, 2016).

TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia.

The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study. Of these 29 cases, 41% (n=12) had a dual diagnosis of bvFTD-ALS at presentation, all 100% (n=12) of which demonstrated hypoglossal TDP-43 pathology. Of the 59% (n=17) cohort that presented with pure bvFTD, 35% (n=6) were identified with hypoglossal TDP-43 pathology. Review of the case files of all pure bvFTD cases revealed evidence of possible or probable ALS in 5 of the 6 hypoglossal-positive cases (83%) towards the end of disease, and this was absent from all cases without such pathology. In conclusion, the present study validates grading the presence of TDP-43 in the hypoglossal nucleus for the pathological identification of bvFTD cases with clinical ALS, and extends this to include the identification of cases with possible ALS at end-stage.

Neuropathology of α-synuclein propagation and braak hypothesis.

Parkinson's disease is a progressive neurodegenerative disorder with multiple factors contributing to increasing severity of pathology in specific brain regions. The Braak hypothesis of Lewy pathology progression in Parkinson's disease proposes a systematic spread of α-synuclein that can be staged, with the later stages correlating with clinical aspects of the disease. The spread of pathology through the different stages suggests progression, a theory that has proven correct from evidence of pathology in healthy neurons grafted into the brains of patients with Parkinson's disease. Progression of pathology occurs on a number of levels, within a cell, between nearby cells, and then over longer distances throughout the brain, and evidence using prion proteins suggests two dissociable mechanisms-intracellular toxicity versus a nontoxic infectious mechanism for propagation. In Parkinson's disease, intracellular changes associated with mitochondria and lysosome dysfunction appear important for α-synuclein propagation, with high stress conditions favoring mitochondrial cell death mechanisms. Functional neurons appear necessary for propagation. Unconventional exocytosis releases α-synuclein under stress conditions, and endocytic uptake occurs in nearby cells. This cell-to-cell transmission of α-synuclein has been recapitulated in both cell culture and animal models, but the timeframe of transmission is considerably shorter than that observed in transplanted neurons. The time course of Lewy pathology formation in patients is consistent with the long time course observed in grafted neurons, and the restricted neuronal loss in Parkinson's disease is potentially important for the propagation of α-synuclein through relatively intact circuits.