Brain Pathology In Patients Research Articles

Blood Biomarkers for Alzheimer's Disease: Current Status and Prospects

Blood biomarkers are minimally invasive, are available at a relatively low cost, and are easily accessible; therefore, they are expected to play a pivotal role in the diagnosis of dementia. Measurement of the amyloid-β ratio and phosphorylated tau in plasma has shown high potential for accurate detection of brain pathology in patients with Alzheimer's disease. Studies have investigated blood biomarkers that reflect neurodegeneration and neuroinflammation in patients with dementia. Challenges associated with blood biomarker use include the lack of robustness of the test and the role of confounders that potentially prevent their immediate clinical application. Further real-world studies are warranted to validate the usefulness of blood biomarkers in dementia management. Appropriate recommendations for the use of blood biomarkers for dementia have been published for physicians and investigators, both in Japan and overseas. Considering the versatility of blood biomarkers, they should be cautiously introduced for clinical use.

Brain pathology in patients with congenital heart disease.

Brain pathology in patients with congenital heart disease (CHD) is associated with neuro-developmental delay. Imaging studies support vascular etiology for both white and gray matter lesions. In this retrospective study, we described the pathological changes in the brains of patients with CHD. Last twenty autopsy cases in pediatric patients with CHD at our institution were retrieved and autopsy reports were reviewed. Available hematoxylin-eosin, special, and immunostains were evaluated, and at least one section from each case was stained with anti-glial fibrillary acidic protein (GFAP), anti-amyloid precursor protein (APP), and anti-HLA-DR antibody. Staining pattern of these immunostains was compared to staining pattern in five control cases. Control cases comprised of 2 cases with no significant pathological changes, and 3 cases with telencephalic leukoencephalopathy. The following histological features were assessed: necrotic cells in cortex, hippocampus, and cerebellum, APP and GFAP staining pattern, and the presence of focal lesions and amphophilic globules. Twenty patients (10 males, 10 females) were identified, with age range between 2 weeks and 19 years. The pathological findings were as follows: 10 cases had changes consistent with acute global hypoperfusion, 8 cases showed features consistent with chronic global hypoperfusion, 4 cases presented focal white matter necrosis (2 with intra-vascular emboli), and 16 cases showed diffuse moderate to severe gliosis, including 7 cases with amphophilic globules. Subarachnoid hemorrhages were present in 5 cases, subdural hemorrhage in 4 cases, intra-ventricular hemorrhage in 2 cases, and germinal matrix hemorrhage in 1 case. In conclusion, diffuse gliosis is the prominent pathological feature in CHD cases. Most of the pathological changes are known to occur in cerebral hypoperfusion regardless of primary cause. Better techniques to improve cerebral perfusion are warranted in the management of these patients.

Neurological Sequelae in Patients with COVID-19: A Histopathological Perspective.

Background: Neuroinvasive properties of SARS-CoV-2 have allowed the hypothesis of several pathogenic mechanisms related to acute and chronic neurological sequelae. However, neuropathological correlates have been poorly systematically investigated, being retrieved from reports of single case or limited case series still. Methods: A PubMed search was carried out to review all publications on autopsy in subjects with “COronaVIrus Disease-19” (COVID-19). Among them, we focused on histological findings of the brain, which were compared with those from the authors’ autoptic studies performed in some COVID-19 patients. Results: Only seven studies reported histological evidence of brain pathology in patients deceased for COVID-19, including three with reverse transcription–quantitative polymerase chain reaction evidence of viral infection. All these studies, in line with our experience, showed vascular-related and infection-related secondary inflammatory tissue damage due to an abnormal immune response. It is still unclear, however, whether these findings are the effect of a direct viral pathology or rather reflect a non-specific consequence of cardiovascular and pulmonary disease on the brain. Conclusions: Notwithstanding the limited evidence available and the heterogeneity of the studies, we provide a preliminary description of the relationship between SARS-CoV-2 and brain sequelae. Systematic autoptic investigations are needed for accurate detection and adequate management of these patients.

Pathological Findings in Male Patients With Anti-N-methyl-d-Aspartate Receptor Encephalitis.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common type of autoimmune encephalitis. The disease predominantly affects women (1:5-1:10), with only 3 reports of autopsy findings in women being published to date. The present study reports findings from the first autopsy performed on a man with anti-NMDAR encephalitis. The patient had some scattered lesions in the limbic system with neuronal loss, gliosis, and microglial activation. The temporal and frontal cortices showed additional patchy demyelination. T-lymphocyte infiltration was detectable in the fusiform gyrus lesion. These findings were partly similar to those reported in female patients. Although clinical differences based on the sex of the patient are reported for this disease, the observed pathological similarities potentially help to establish common therapeutic strategies for all patients. Severe testicular damage was additionally observed in the male patient in this study. Biopsy-proven severe testicular damage was also confirmed in another, previously fertile man who became azoospermic. Moreover, serum follicle-stimulating hormone levels, which often increased in response to disturbed spermatogenesis, were elevated, and testosterone/luteinizing hormone ratio reflecting Leydig cell function was low in all 5 male patients in this study. Overall, these findings suggest similar brain pathology in patients of both sexes and severe testicular damage in male patients.

Temporal requirement of dystroglycan glycosylation during brain development and rescue of severe cortical dysplasia via gene delivery in the fetal stage.

Congenital muscular dystrophies (CMDs) are characterized by progressive weakness and degeneration of skeletal muscle. In several forms of CMD, abnormal glycosylation of α-dystroglycan (α-DG) results in conditions collectively known as dystroglycanopathies, which are associated with central nervous system involvement. We recently demonstrated that fukutin, the gene responsible for Fukuyama congenital muscular dystrophy, encodes the ribitol-phosphate transferase essential for dystroglycan function. Brain pathology in patients with dystroglycanopathy typically includes cobblestone lissencephaly, mental retardation, and refractory epilepsy; however, some patients exhibit average intelligence, with few or almost no structural defects. Currently, there is no effective treatment for dystroglycanopathy, and the mechanisms underlying the generation of this broad clinical spectrum remain unknown. Here, we analysed four distinct mouse models of dystroglycanopathy: two brain-selective fukutin conditional knockout strains (neuronal stem cell-selective Nestin-fukutin-cKO and forebrain-selective Emx1-fukutin-cKO), a FukutinHp strain with the founder retrotransposal insertion in the fukutin gene, and a spontaneous Large-mutant Largemyd strain. These models exhibit variations in the severity of brain pathology, replicating the clinical heterogeneity of dystroglycanopathy. Immunofluorescence analysis of the developing cortex suggested that residual glycosylation of α-DG at embryonic day 13.5 (E13.5), when cortical dysplasia is not yet apparent, may contribute to subsequent phenotypic heterogeneity. Surprisingly, delivery of fukutin or Large into the brains of mice at E12.5 prevented severe brain malformation in Emx1-fukutin-cKO and Largemyd/myd mice, respectively. These findings indicate that spatiotemporal persistence of functionally glycosylated α-DG may be crucial for brain development and modulation of glycosylation during the fetal stage could be a potential therapeutic strategy for dystroglycanopathy.

Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study.

Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is believed to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain using data from 1079 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network (MAPP) study. Participants with a clinical diagnosis of urological chronic pelvic pain syndrome (UCPPS) were compared to pain-free controls and patients with fibromyalgia, the prototypical centralized pain disorder. Participants completed questionnaires capturing pain severity, function, and a body map of pain. A subset (UCPPS N = 110; fibromyalgia N = 23; healthy control N = 49) underwent functional and structural magnetic resonance imaging. Patients with UCPPS reported pain ranging from localized (pelvic) to widespread (throughout the body). Patients with widespread UCPPS displayed increased brain gray matter volume and functional connectivity involving sensorimotor and insular cortices (P < 0.05 corrected). These changes translated across disease diagnoses as identical outcomes were present in patients with fibromyalgia but not pain-free controls. Widespread pain was also associated with reduced physical and mental function independent of pain severity. Brain pathology in patients with centralized pain is related to pain distribution throughout the body. These patients may benefit from interventions targeting the central nervous system.

Evaluation of hematological markers in minor head trauma in the emergency room.

A rule exists regarding the use of computed tomography (CT) for patients presenting to the emergency department with head trauma and a Glasgow coma score (GCS) of 15; however, it can be difficult to make this decision due to overcrowded emergency rooms or exaggerated patients complaints. We evaluated patients who presented to the emergency room with minor head trauma, and we aimed to investigate the relationship between brain pathology on CT and hematological markers in order to find markers that help us identify brain pathology in patients with a GCS of 15. This retrospective study included 100 patients with pathologies present on their CT scans and a control group consisting of 100 patients with a normal CT. All data obtained from this study were recorded and evaluated using "Statistical Package for Social Sciences for Windows 20" program. Parametric tests (independent samples test) were used with normally distributed data, while non-parametric tests (Mann-Whitney U test) were used with non-normally distributed data. A p≤0.05 was considered significant. When we divided the cases into two groups based on the presence of pathologies on CT scan, we determined that there were significant differences between the groups in terms of white blood cell (WBC), hemoglobin (Hb), mean platelet volume (MPV), neutrophil (neu), troponin T, neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR). When differentiating the patients that had brain pathologies on CT scan from patients that had normal CT scans, the troponin T cut-off value of 6.16 lead to 90% specificity, and setting the NLR cut-off value at 4.29 resulted in a specificity of 90%. MPV, NLR, and troponin T can be used as parameters that indicate brain pathologies on CT scans of patients presenting to the emergency department with isolated minor head trauma and GCS of 15 when the necessity of a CT scan is otherwise unclear.

Dysglycemia, brain volume and vascular lesions on MRI in a memory clinic population

ObjectiveIt is unclear, if the association between abnormalities in glucose metabolism (dysglycemia) and impaired cognitive functioning is primarily driven by degenerative or vascular brain damage. We therefore examined the relation between dysglycemia and brain volume and vascular lesions on MRI in a memory clinic population. MethodsThe relations between markers of glycemia (HbA1c and fasting glucose levels) and normalized brain volume, medial temporal lobe atrophy and vascular lesions (white matter hyperintensities, lacunes) were assessed in 274 consecutive patients attending a memory clinic, using linear regression analyses. ResultsClinical diagnoses were subjective complaints (n=117), mild cognitive impairment (n=62), Alzheimer's disease (n=61) and other type of dementia (n=34). Twenty patients had a history of diabetes. Across the whole study population there was no relation between HbA1c or fasting glucose and the brain MRI measurements, after adjustments for age, sex and diagnostic group. Secondary analyses after stratification by diabetes status, diagnosis and median age (67years) did not change the results. ConclusionIn this memory clinic population, dysglycemia was not associated with either brain volume or vascular lesions. Apparently, dysglycemia is not associated with a specific class of brain pathology in patients with cognitive complaints.

Expression of proinflammatory cytokines and its relationship with virus infection in the brain of macaques inoculated with macrophage‐tropic simian immunodeficiency virus

The pathogenesis of acquired immunodeficiency syndrome dementia complex (ADC) is still poorly understood. Many studies suggest that proinflammatory cytokines such as IL-1beta and TNF-alpha released by microglia/macrophages or astrocytes play a role in CNS injury. A microscopic finding of a microglial nodule with multinucleated giant cells (MNGCs) is a histopathologic hallmark of ADC and named HIV encephalitis. However, in vivo expression of these cytokines in this microenvironment of HIV encephalitis is not yet clarified. One of the main reasons is complexities of brain pathology in patients who have died from terminal AIDS. In this study, we infected two macaques with macrophage-tropic Simian immunodeficiency virus SIV239env/MERT and examined expression of TNF-alpha and IL-1beta in inflammatory lesions with MNGCs and its relation to virus-infected cells using immunohistochemistry. One macaque showed typical inflammatory lesions with MNGCs in the frontal white matter. Small microglial nodules were also detected in the basal ganglia and the spinal cord. SIVenv positive cells were detected mainly in inflammatory lesions, and seemed to be microglia/macrophages and MNGCs based on their morphology. Expression of IL-1beta and TNF-alpha were detected in the inflammatory lesions with MNGCs, and these positive cells were found to be negative for SIVenv by double-labeling immunohistochemistry or immunohistochemistry of serial sections. There were a few TNF-alpha positive cells and almost no IL-1beta positive cells in the area other than inflammatory lesions. Another macaque showed scattered CD3+ cells and CD68+ cells in the perivascular regions of the white matter. SIVenv and TNF-alpha was demonstrated in a few perivascular macrophages. These findings indicate that virus-infected microglia/macrophages do not always express IL-1beta and TNF-alpha, which suggests an indirect role of HIV-1-infected cells in cytokine-mediated pathogenesis of ADC. Our macaque model for human ADC may be useful for better understanding of its pathogenesis.

Neuropathologic findings in patients with primary autosomal recessive microcephaly

Autosomal recessive primary microcephaly (MCPH, syn. Microcephalia vera) is a rare, genetically heterogeneous disease, in which patients exhibit microcephaly by the 32nd week of gestation. Genetic causes of MCPH subtypes 1–6 include mutations in genes encoding microcephalin (MCPH1), cyclin dependent kinase 5 regulatory associated protein 2 CDK5RAP2 (MCPH3), abnormal spindle-like, microcephaly associated ASPM (MCPH5), centromeric protein J CENPJ (MCPH6) as well as linkage to the two loci 19q13.1–13.2 (MCPH2) and 15q15-q21 (MCPH4). Severe microcephaly is characterized by a significantly reduced occipito-frontal head circumference (OCF) of more than three standard deviations below the mean for age, sex, and ethnicity. Microcephaly correlates closely with reduced brain volume and mental retardation, but patients with MCPH typically do not have further neurological findings. Imaging studies show brains of normal architecture but of reduced size. The latter is particularly evident in the cerebral cortex, which shows a simplified cerebral cortex structure, and there is also a slightly reduced white matter volume. Individual patients with MCPH provide evidence of periventricular neuronal heterotopias suggesting neuronal migration defects. It is not known whether the brain pathology in patients with MCPH is the result of defective cell proliferation/differentiation, cell migration and/or increased cell death. Neuropathological studies, which are rare and were performed at a time when a genetic diagnosis could not be performed, are thus highly warranted. Here, we summarize current knowledge on histological findings in MCPH patients. Infants with Microcephalia vera exhibited a significantly reduced brain volume with an almost preserved convolution pattern and no myelination disturbances. Cytoarchitectonic anomalies, seen predominantly in the first two cortical layers, included the appearance of compact cell clusters in the second layer. This can be interpreted as being indicative of a proliferation/differentiation and/or migration defect.

Education and occupation as proxies for reserve in aMCI converters and AD

Previous reports have shown that higher education is associated with more severe brain pathology in patients with Alzheimer disease (AD), suggesting that these individuals have a functional reserve provided by education, which masks the clinical expression of a higher degree of neurodegeneration. It is unknown if a similar reserve mechanism exists in patients with amnestic mild cognitive impairment (aMCI). The aim of this study was to assess the impact of education and occupation on brain glucose metabolism (rCMRglc) measured with FDG-PET in aMCI and in a very large sample of subjects with probable AD (pAD). A total of 242 patients with pAD, 72 with aMCI, and 144 healthy controls participated in the study. At follow-up, 21 subjects with aMCI progressed to AD. A regression analysis was conducted (SPM2), with education and occupation as independent variables, and rCMRglc as dependent variable, adjusting for demographic data, global cognitive status, and neuropsychological scores. The analysis showed a significant association between higher education/occupation and lower rCMRglc in posterior temporoparietal cortex and precuneus in pAD and aMCI converters, and no correlation in aMCI nonconverters and healthy controls. This means that, when submitted to FDG-PET for diagnostic evaluation, pAD and aMCI converters with higher education/occupation had, for comparable cognitive impairment, a more severe rCMRglc reduction than the ones with lower education/occupation. This study suggests that education and occupation may be proxies for brain functional reserve, reducing the severity and delaying the clinical expression of Alzheimer disease (AD) pathology. The results in aMCI converters suggest that functional reserve is already at play in the predementia phase of AD.

Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats.

An excess of extracellular glutamate in the hippocampus has been linked to the generation of recurrent seizures and brain pathology in patients with medically intractable mesial temporal lobe epilepsy (MTLE). However, the mechanism which results in glutamate excess in MTLE remains unknown. We recently reported that the glutamate-metabolizing enzyme glutamine synthetase is deficient in the hippocampus in patients with MTLE, and we postulated that this deficiency is critically involved in the pathophysiology of the disease. To further explore the role of glutamine synthetase in MTLE we created a novel animal model of hippocampal glutamine synthetase deficiency by continuous (approximately 28 days) microinfusion of methionine sulfoximine (MSO: 0.625 to 2.5 microg/h) unilaterally into the hippocampus in rats. This treatment led to a deficiency in hippocampal glutamine synthetase activity by 82-97% versus saline. The majority (>95%) of the MSO-treated animals exhibited recurrent seizures that continued for several weeks. Some of the MSO-treated animals exhibited neuropathological features that were similar to mesial temporal sclerosis, such as hippocampal atrophy and patterned loss of hippocampal neurons. However, many MSO-treated animals displayed only minimal injury to the hippocampus, with no clear evidence of mesial temporal sclerosis. These findings support the hypothesis that a deficiency in hippocampal glutamine synthetase causes recurrent seizures, even in the absence of classical mesial temporal sclerosis, and that restoration of glutamine synthetase may represent a novel approach to therapeutic intervention in this disease.

Dual Brain Pathology in Patients With Affective Aggressive Episodes

Dual Brain Pathology in Patients With Affective Aggressive Episodes

Establishing norms for age-related changes in proton T1 of human brain tissue in vivo

The goal of this study was to determine the expected normal range of variation in spin-lattice relaxation time ( T 1) of brain tissue in vivo, as a function of age. A previously validated precise and accurate inversion recovery method was used to map T 1 transversely, at the level of the basal ganglia, in a study population of 115 healthy subjects (ages 4 to 72; 57 male and 58 female). Least-squares regression analysis shows that T 1 varied as a function of age in pulvinar nucleus (R 2 = 56%), anterior thalamus (R 2 = 51%), caudate (R 2 = 50%), frontal white matter (R 2 = 47%), optic radiation (R 2 = 39%), putamen (R 2 = 36%), genu (R 2 = 22%), occipital white matter (R 2 = 20%) (all p < 0.0001), and cortical gray matter (R 2 = 53%) ( p < 0.001). There were no significant differences in T 1 between men and women. T 1 declines throughout adolescence and early adulthood, to achieve a minimum value in the fourth to sixth decade of life, then T 1 begins to increase. Quantitative magnetic resonance imaging provides evidence that brain tissue continues to change throughout the lifespan among healthy subjects with no neurologic deficits. Age-related changes follow a strikingly different schedule in different brain tissues; white matter tracts tend to reach a minimum T 1 value, and to increase again, sooner than do gray matter tracts. Such normative data may prove useful for the early detection of brain pathology in patients.