Chronic Traumatic Encephalopathy in the Brains of Military Personnel.

BACKGROUND: Persistent neuropsychiatric sequelae may develop in military personnel who are exposed to combat; such sequelae have been attributed in some cases to chronic traumatic encephalopathy (CTE). Only limited data regarding CTE in the brains of military service members are available. METHODS: We performed neuropathological examinations for the presence of CTE in 225 consecutive brains from a brain bank dedicated to the study of deceased service members. In addition, we reviewed information obtained retrospectively regarding the decedents' histories of blast exposure, contact sports, other types of traumatic brain injury (TBI), and neuropsychiatric disorders. RESULTS: Neuropathological findings of CTE were present in 10 of the 225 brains (4.4%) we examined; half the CTE cases had only a single pathognomonic lesion. Of the 45 brains from decedents who had a history of blast exposure, 3 had CTE, as compared with 7 of 180 brains from those without a history of blast exposure (relative risk, 1.71; 95% confidence interval [CI], 0.46 to 6.37); 3 of 21 brains from decedents with TBI from an injury during military service caused by the head striking a physical object without associated blast exposure (military impact TBI) had CTE, as compared with 7 of 204 without this exposure (relative risk, 4.16; 95% CI, 1.16 to 14.91). All brains with CTE were from decedents who had participated in contact sports; 10 of 60 contact-sports participants had CTE, as compared with 0 of 165 who had not participated in contact sports (point estimate of relative risk not computable; 95% CI, 6.16 to infinity). CTE was present in 8 of 44 brains from decedents with non-sports-related TBI in civilian life, as compared with 2 of 181 brains from those without such exposure in civilian life (relative risk, 16.45; 95% CI, 3.62 to 74.79). CONCLUSIONS: Evidence of CTE was infrequently found in a series of brains from military personnel and was usually reflected by minimal neuropathologic changes. Risk ratios for CTE were numerically higher among decedents who had contact-sports exposure and other exposures to TBI in civilian life than among those who had blast exposure or other military TBI, but the small number of CTE cases and wide confidence intervals preclude causal conclusions. (Funded by the Department of Defense-Uniformed Services University Brain Tissue Repository and Neuropathology Program and the Henry M. Jackson Foundation for the Advancement of Military Medicine.).

Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Advances in Deep Neuropathological Phenotyping of Alzheimer Disease: Past, Present, and Future.

Alzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the presence of neurofibrillary tangles and amyloid beta (Aß) plaques in the brain. The disease was first described in 1906 by Alois Alzheimer, and since then, there have been many advancements in technologies that have aided in unlocking the secrets of this devastating disease. Such advancements include improving microscopy and staining techniques, refining diagnostic criteria for the disease, and increased appreciation for disease heterogeneity both in neuroanatomic location of abnormalities as well as overlap with other brain diseases; for example, Lewy body disease and vascular dementia. Despite numerous advancements, there is still much to achieve as there is not a cure for AD and postmortem histological analyses is still the gold standard for appreciating AD neuropathologic changes. Recent technological advances such as in-vivo biomarkers and machine learning algorithms permit great strides in disease understanding, and pave the way for potential new therapies and precision medicine approaches. Here, we review the history of human AD neuropathology research to include the notable advancements in understanding common co-pathologies in the setting of AD, and microscopy and staining methods. We also discuss future approaches with a specific focus on deep phenotyping using machine learning.

Milk fat globule membrane attenuates high fat diet-induced neuropathological changes in obese Ldlr-/-.Leiden mice.

BACKGROUND: Milk-fat globule membrane (MFGM) is a complex structure secreted by the mammary gland and present in mammalian milk. MFGM contains lipids and glycoproteins as well as gangliosides, which may be involved in myelination processes. Notably, myelination and thereby white matter integrity are often altered in obesity. Furthermore, MFGM interventions showed beneficial effects in obesity by affecting inflammatory processes and the microbiome. In this study, we investigated the impact of a dietary MFGM intervention on fat storage, neuroinflammatory processes and myelination in a rodent model of high fat diet (HFD)-induced obesity. METHODS: 12-week-old male low density lipoprotein receptor-deficient Leiden mice were exposed to a HFD, a HFD enriched with 3% whey protein lipid concentrate (WPC) high in MFGM components, or a low fat diet. The impact of MFGM supplementation during 24-weeks of HFD-feeding was examined over time by analyzing body weight and fat storage, assessing cognitive tasks and MRI scanning, analyzing myelinization with polarized light imaging and examining neuroinflammation using immunohistochemistry. RESULTS: We found in this study that 24 weeks of HFD-feeding induced excessive fat storage, increased systolic blood pressure, altered white matter integrity, decreased functional connectivity, induced neuroinflammation and impaired spatial memory. Notably, supplementation with 3% WPC high in MFGM components restored HFD-induced neuroinflammation and attenuated the reduction in hippocampal-dependent spatial memory and hippocampal functional connectivity. CONCLUSIONS: We showed that supplementation with WPC high in MFGM components beneficially contributed to hippocampal-dependent spatial memory, functional connectivity in the hippocampus and anti-inflammatory processes in HFD-induced obesity in rodents. Current knowledge regarding exact biological mechanisms underlying these effects should be addressed in future studies.

ASNTR's Venture into a Hybrid Conference: Lessons Learned During the COVID-19 Pandemic.

The 28th American Society for Neural Therapy and Repair (ASNTR) returned to the Sheraton Sand Key in Clearwater Beach, Florida after an 18 month hiatus. Like nearly all conferences during the pandemic, the ASNTR conference was held in person while offering a virtual option to the event. These formats are advantageous for those under travel restrictions or personal constraints, but they lack the spontaneity of in-person connections. Highlights from the meeting included the return of the Bernard Sanberg Memorial Award and the Roy Bakay Memorial lecture. The presidential lecture was given by Gabriel de Erausquin, who discussed the possibility of long-term CNS effects resulting from SARS-CoV2 infection. With both virtual and in-person events, including oral and poster presentations, the ASNTR managed to maintain the unique essence of this small important meeting.

Neural Injury and Repair in a Novel Neonatal Mouse Model of Listeria Monocytogenes Meningoencephalitis.

To improve the therapy of neonatal central nervous system infections, well-characterized animal models are urgently needed. The present study analyzes neuropathological alterations with particular focus on neural injury and repair in brains of neonatal mice with Listeria monocytogenes (LM) meningitis/meningoencephalitis using a novel nasal infection model. The hippocampal formation and frontal cortex of 14 neonatal mice with LM meningitis/meningoencephalitis and 14 uninfected controls were analyzed by histology, immunohistochemistry, and in situ tailing for morphological alterations. In the dentate gyrus of the hippocampal formation of mice with LM meningitis/meningoencephalitis, an increased density of apoptotic neurons visualized by in situ tailing (p = 0.04) and in situ tailing plus immunohistochemistry for activated Caspase-3 (p < 0.0001) was found. A decreased density of dividing cells stained with an anti-PCNA-antibody (p < 0.0001) and less neurogenesis visualized by anti-calretinin (p < 0.0001) and anti-calbindin (p = 0.01) antibodies were detected compared to uninfected controls. The density of microglia was higher in LM meningitis (p < 0.0001), while the density of astrocytes remained unchanged. Infiltrating monocytes and neutrophilic granulocytes likely contributed to tissue damage. In conclusion, in the brains of LM-infected mice a strong immune response was observed which led to neuronal apoptosis and an impaired neural regeneration. This model appears very suitable to study therapies against long-term sequelae of neonatal LM meningitis.

The Neuropathology of 1p36 Deletion Syndrome: An Autopsy Case Series.

1p36 deletion syndrome is the most common terminal deletion syndrome, manifesting clinically as abnormal facies and developmental delay with frequent cardiac, skeletal, urogenital, and renal abnormalities. Limited autopsy case reports describe the neuropathology of 1p36 deletion syndrome. The most extensive single case report described a spectrum of abnormalities, mostly related to abnormal neuronal migration. We report the largest published series of 1p36 autopsy cases, with an emphasis on neuropathologic findings. Our series consists of 3 patients: 2 infants (5-hours old and 23-days old) and 1 older child (11 years). Our patients showed abnormal cortical gyration together with a spectrum of neuronal migration abnormalities, including heterotopias and hippocampal abnormalities, as well as cerebellar hypoplasia. Our findings thus support the role of neuronal migration defects in the pathogenesis of cognitive defects in 1p36 deletion syndrome and broaden the reported neuropathologic spectrum of this common syndrome.

What Every Neuropathologist Needs to Know: Practical Aspects and Pitfalls in Molecular Diagnosis of Brain Tumors.

Molecular testing has become part of the routine diagnostic workup of brain tumors after the implementation of integrated histomolecular diagnoses in the 2016 WHO classification update. It is important for every neuropathologist to be aware of practical preanalytical, analytical, and postanalytical factors that impact the performance and interpretation of molecular tests. Prior to testing, optimizing tumor purity and tumor amount increases the ability of the molecular test to detect the genetic alteration of interest. Recognizing basic molecular testing platform analytical characteristics allows selection of the optimal platform for each clinicopathological scenario. Finally, postanalytical considerations to properly interpret molecular test results include understanding the clinical significance of the detected genetic alteration, recognizing that detected clinically significant genetic alterations are occasionally germline constitutional rather than somatic tumor-specific, and being cognizant that recommended and commonly used genetic nomenclature may differ. Potential pitfalls in brain tumor molecular diagnosis are also discussed.

Fetal and Perinatal Brain Autopsy: Useful Macroscopic Techniques Including Agar In-situ and Pre-Embedding Methods.

Fragile perinatal and fetal brains are the rule rather than the exception for developmental neuropathologists. Retrieving the fresh brain from the skull and examining early fetal, macerated or severely hydrocephalic brains after fixation can be a challenge. Textbooks on neurodevelopmental pathology mention these challenges to macroscopic examination of the developing central nervous system only in passing, but many perinatal pathologists recognize this diagnostic problem. We reviewed protocols and publications on the removal, fixation, slicing and sampling of these fetal- and perinatal brains. In addition, we describe a technique to facilitate the removal of severely hydrocephalic brains with very thin cerebral walls from the skull by replacing the intraventricular fluid with agar in-situ. Furthermore, we present a method for post-fixation pre-embedding in agar to facilitate slicing, macroscopic examination and sampling of fragile and macerated brains.

Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer's disease neuropathology.

BACKGROUND: Genome-wide association studies have established clusterin (CLU) as a genetic modifier for late-onset Alzheimer's disease (AD). Both protective and risk alleles have been identified which may be associated with its expression levels. However, the physiological function of clusterin in the central nervous system remains largely unknown. METHODS: We examined Clu expression in mouse brains by immunohistochemistry and high-resolution imaging. We performed electrophysiological recordings and morphological analysis of dendritic spines in wild-type and Clu knockout mice. We tested synaptic function of astrocytic Clu using neuron-glia co-cultures and by AAV-mediated astroglial Clu expression in vivo. Finally, we investigated the role of astrocytic Clu on synaptic properties and amyloid pathology in 5xFAD transgenic mouse model of AD. RESULTS: We show that astrocyte secreted Clu co-localizes with presynaptic puncta of excitatory neurons. Loss of Clu led to impaired presynaptic function and reduced spine density in vivo. Neurons co-cultured with Clu-overexpressing astrocytes or treated with conditioned media from HEK293 cells transfected with Clu displayed enhanced excitatory neurotransmission. AAV-mediated astroglial Clu expression promoted excitatory neurotransmission in wild-type mice and rescued synaptic deficits in Clu knockout mice. Overexpression of Clu in the astrocytes of 5xFAD mice led to reduced Aß pathology and fully rescued the synaptic deficits. CONCLUSION: We identify Clu as an astrocyte-derived synaptogenic and anti-amyloid factor; the combination of these activities may influence the progression of late-onset AD.

The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.

Cognitive decline in amyotrophic lateral sclerosis: Neuropathological substrate and genetic determinants.

Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer's disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups.

Neuropathology of genetically defined malformations of cortical development-A systematic literature review.

AIMS: Malformations of cortical development (MCD) include a heterogeneous spectrum of clinical, imaging, molecular and histopathological entities. While the understanding of genetic causes of MCD has improved with the availability of next-generation sequencing modalities, genotype-histopathological correlations remain limited. This is the first systematic review of molecular and neuropathological findings in patients with MCD to provide a comprehensive overview of the literature. METHODS: A systematic review was performed between November 2019 and February 2020. A MEDLINE search was conducted for 132 genes previously linked to MCD in order to identify studies reporting macroscopic and/or microscopic findings in patients with a confirmed genetic cause. RESULTS: Eighty-one studies were included in this review reporting neuropathological features associated with pathogenic variants in 46 genes (46/132 genes, 34.8%). Four groups emerged, consisting of (1) 13 genes with well-defined histological-genotype correlations, (2) 27 genes for which neuropathological reports were limited, (3) 5 genes with conflicting neuropathological features, and (4) 87 genes for which no histological data were available. Lissencephaly and polymicrogyria were reported most frequently. Associated brain malformations were variably present, with abnormalities of the corpus callosum as most common associated feature. CONCLUSIONS: Neuropathological data in patients with MCD with a defined genetic cause are available only for a small number of genes. As each genetic cause might lead to unique histopathological features of MCD, standardised thorough neuropathological assessment and reporting should be encouraged. Histological features can help improve the understanding of the pathogenesis of MCD and generate hypotheses with impact on further research directions.

Clinicopathological investigation of the background of cognitive decline in elderly schizophrenia.

OBJECTIVE: We have often observed dementia symptoms or severe neurocognitive decline in the long-term course of schizophrenia. While there are epidemiological reports that patients with schizophrenia are at an increased risk of developing dementia, there are also neuropathological reports that the prevalence of Alzheimer's disease (AD) in schizophrenia is similar to that in normal controls. It is difficult to distinguish, based solely on the clinical symptoms, whether the remarkable dementia symptoms and cognitive decline seen in elderly schizophrenia are due to the course of the disease itself or a concomitant neurocognitive disease. Neuropathological observation is needed for discrimination. METHODS: We conducted a neuropathological search on three cases of schizophrenia that developed cognitive decline or dementia symptoms after a long illness course of schizophrenia. The clinical symptoms of total disease course were confirmed retrospectively in the medical record. We have evaluated neuropathological diagnosis based on not only Hematoxylin-Eosin and Klüver-Barrera staining specimens but also immunohistochemical stained specimens including tau, ß-amyloid, pTDP-43 and α-synuclein protein throughout clinicopathological conference with multiple neuropathologists and psychiatrists. RESULTS: The three cases showed no significant pathological findings or preclinical degenerative findings, and poor findings consistent with symptoms of dementia were noted. CONCLUSION: Although the biological background of dementia symptoms in elderly schizophrenic patients is still unclear, regarding the brain capacity/cognitive reserve ability, preclinical neurodegeneration changes in combination with certain brain vulnerabilities due to schizophrenia itself are thought to induce dementia syndrome and severe cognitive decline.

The role of neuropathology in the management of newly diagnosed glioblastoma: a systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma (GBM) QUESTION : For adult patients with newly diagnosed GBM does testing for Isocitrate Dehydrogenase 1 or 2 (IDH 1/2) mutations afford benefit beyond standard histopathology in providing accurate classification and outcome prognostication? Level III IDH 1/2 mutational status by immunohistochemistry (IHC) and/or sequencing is suggested for classification and prognostic information. Level III Non-canonical IDH 1/2 mutations are very rare in patients aged 55 or older and universal testing of variant mutations by sequence analysis is not suggested for this age range. QUESTION: For adult patients with lower grade infiltrating astrocytomas (WHO grades II and III) can the IDH-wildtype status designation supersede histopathology to predict prognosis and biologic relevance to eventual behavior as a GBM? Level III The designation of infiltrating astrocytomas (WHO grades II and III) as IDH-wildtype is not suggested as sufficient for a higher grade designation alone. Level III It is suggested that IDH-wildtype WHO grades II and III astrocytomas be tested for molecular-genetic alterations typical of IDH-wildtype GBM such as EGFR amplification, gain of chromosome 7/loss of chromosome 10 and TERT-p mutation to substantiate prediction of behavior similar to IDH-wildtype glioblastoma. Level III It is suggested that a diagnosis of diffuse astrocytic glioma, IDH-wildtype, with molecular features of GBM, WHO grade IV be rendered for infiltrating astrocytomas that lack histologic criteria of GBM but harbors molecular-genetic alterations of IDH-wildtype glioblastoma. QUESTION: For adult patients with newly diagnosed infiltrating glioma arising in the midline does testing for H3-K27M mutations provide information beyond that gained by histopathology for accurate classification and outcome prognostication? Level III It is suggested that infiltrating gliomas arising in midline anatomic locations be tested for the H3-K27M mutation as they tend to exhibit WHO grade IV behavior even if they lack histologic criteria for glioblastoma.

Concomitant LATE-NC in Alzheimer's disease is not associated with increased tau or amyloid-ß pathological burden.

AIMS: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is present in approximately 50% of Alzheimer's disease (AD) cases and is associated with accelerated cognitive decline. Studies indicate a potential synergistic relationship between LATE-NC and hyperphosphorylated tau. It is unknown if LATE-NC is an independent driver of cognitive impairment or exerts its influence through synergistic relationships with tau. This cliniconeuropathological study investigated the impact of LATE-NC on quantified measures of AD-associated pathology and its impact on clinical measures. METHODS: A total of 61 AD cases underwent neuropathological assessment for LATE-NC and quantitative assessment [area covered by immunoreactivity (IR)] for early conformational tau (MC-1), late-stage hyperphosphorylated tau (AT8) and amyloid-ß in the amygdala and five neocortical regions. Clinical measures included age of disease onset, final Mini-Mental State Examination (MMSE) score and rate of cognitive decline. RESULTS: LATE-NC was present in 41 AD cases (AD/LATE-NC; 67.2%). No significant differences in MC-1-IR, AT8-IR or 4G8-IR were observed in any region between AD/LATE-NC and AD without LATE-NC, indicating no accelerated aggregation or hyperphosphorylation of tau proteins in the AD/LATE-NC cases. Final MMSE was significantly lower in AD/LATE-NC cases and was significantly associated with LATE-NC score even when controlled for the presence of both MC-1-IR and AT8-IR (P = 0.009). CONCLUSION: The presence of LATE-NC in AD is not associated with an increase in the burden of early or late tau or Aß pathology. LATE-NC is associated with a lower final MMSE score independent of tau pathology.