Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups.

Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10-8), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10-9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10-8), PVRL2 (Score = 125.86, P = 1.64 × 10-9), TOMM40 (Score = - 18.58, P = 4.61 × 10-8), and APOE (Score = 75.12, P = 7.26 × 10-26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.

Hippocampal avoidance in whole brain radiotherapy and prophylactic cranial irradiation: a systematic review and meta-analysis.

PURPOSE: We systematically reviewed the current landscape of hippocampal-avoidance radiotherapy, focusing specifically on rates of hippocampal tumor recurrence and changes in neurocognitive function. METHODS: PubMed was queried for studies involving hippocampal-avoidance radiation therapy and results were screened using PRISMA guidelines. Results were analyzed for median overall survival, progression-free survival, hippocampal relapse rates, and neurocognitive function testing. RESULTS: Of 3709 search results, 19 articles were included and a total of 1611 patients analyzed. Of these studies, 7 were randomized controlled trials, 4 prospective cohort studies, and 8 retrospective cohort studies. All studies evaluated hippocampal-avoidance whole brain radiation treatment (WBRT) and/or prophylactic cranial irradiation (PCI) in patients with brain metastases. Hippocampal relapse rates were low (overall effect size = 0.04; 95% confidence interval [0.03, 0.05]) and there was no significant difference in risk of relapse between the five studies that compared HA-WBRT/HA-PCI and WBRT/PCI groups (risk difference = 0.01; 95% confidence interval [- 0.02, 0.03]; p = 0.63). 11 out of 19 studies included neurocognitive function testing. Significant differences were reported in overall cognitive function and memory and verbal learning 3-24 months post-RT. Differences in executive function were reported by one study, Brown et al., at 4 months. No studies reported differences in verbal fluency, visual learning, concentration, processing speed, and psychomotor speed at any timepoint. CONCLUSION: Current studies in HA-WBRT/HA-PCI showed low hippocampal relapse or metastasis rates. Significant differences in neurocognitive testing were most prominent in overall cognitive function, memory, and verbal learning. Studies were hampered by loss to follow-up.

Utility of 5-ALA for fluorescence-guided resection of brain metastases: a systematic review.

PURPOSE: 5-aminolevulinic acid (5-ALA) has demonstrated its utility as an intraoperative imaging adjunct during fluorescence guided resection of malignant gliomas. However, literature regarding 5-ALA-guided resection for brain metastases is limited. We conducted a systematic review to evaluate the efficacy of 5-ALA fluorescence for resection of metastatic brain tumors. METHODS: PubMed was queried for studies involving 5-ALA and brain metastases, and results were screened following PRISMA guidelines. Articles related to 5-ALA and brain metastasis were further assessed based on inclusion and exclusion criteria and results were analyzed for 5-ALA fluorescence rates stratified by tumor primary sites and histological subtypes. RESULTS: Of 421 identified search results, 10 studies were included and a total of 631 patients analyzed. Of these studies, 60% were retrospective in design. The reported rates of 5-ALA fluorescence in included brain metastases ranged from 27.6 to 86.9%, with variability across and within tumor types. No studies concluded improved operative outcomes or survival outcomes related to 5-ALA use. CONCLUSIONS: Current studies regarding 5-ALA fluorescence in brain metastases are limited and do not confirm efficacy for improving extent of resection or post-operative survival. Fluorescence is variable across and within tumor types. Further studies are necessary to evaluate whether specific tumors may benefit from 5-ALA FGS or if changes in delivery protocols or fluorescence quantification may affect intraoperative utility.

Applications of Functional Magnetic Resonance Imaging to the Study of Functional Connectivity and Activation in Neurological Disease: A Scoping Review of the Literature.

BACKGROUND: Functional magnetic resonance imaging (fMRI) has transformed our understanding of brain's functional architecture, providing critical insights into neurological diseases. This scoping review synthesizes the current landscape of fMRI applications across various neurological domains, elucidating the evolving role of both task-based and resting-state fMRI in different settings. METHODS: We conducted a comprehensive scoping review following the Preferred Reporting Items for Systematic Review and Meta-Analyses Extension for Scoping Reviews guidelines. Extensive searches in Medline/PubMed, Embase, and Web of Science were performed, focusing on studies published between 2003 and 2023 that utilized fMRI to explore functional connectivity and regional activation in adult patients with neurological conditions. Studies were selected based on predefined inclusion and exclusion criteria, with data extracted. RESULTS: We identified 211 studies, covering a broad spectrum of neurological disorders including mental health, movement disorders, epilepsy, neurodegeneration, traumatic brain injury, cerebrovascular accidents, vascular abnormalities, neurorehabilitation, neuro-critical care, and brain tumors. The majority of studies utilized resting-state fMRI, underscoring its prominence in identifying disease-specific connectivity patterns. Results highlight the potential of fMRI to reveal the underlying pathophysiological mechanisms of various neurological conditions, facilitate diagnostic processes, and potentially guide therapeutic interventions. CONCLUSIONS: fMRI serves as a powerful tool for elucidating complex neural dynamics and pathologies associated with neurological diseases. Despite the breadth of applications, further research is required to standardize fMRI protocols, improve interpretative methodologies, and enhance the translation of imaging findings to clinical practice. Advances in fMRI technology and analytics hold promise for improving the precision of neurological assessments and interventions.

Brachytherapy in Brain Metastasis Treatment: A Scoping Review of Advances in Techniques and Clinical Outcomes.

Brain metastases pose a significant therapeutic challenge in the field of oncology, necessitating treatments that effectively control disease progression while preserving neurological and cognitive functions. Among various interventions, brachytherapy, which involves the direct placement of radioactive sources into or near tumors or into the resected cavity, can play an important role in treatment. Current literature describes brachytherapy's capacity to deliver targeted, high-dose radiation while minimizing damage to adjacent healthy tissues-a crucial consideration in the choice of treatment modality. Furthermore, advancements in implantation techniques as well as in the development of different isotopes have expanded its efficacy and safety profile. This review delineates the contemporary applications of brachytherapy in managing brain metastases, examining its advantages, constraints, and associated clinical outcomes, and provides a comprehensive understanding of advances in the use of brachytherapy for brain metastasis treatment, with implications for improved patient outcomes and enhanced quality of life.

An analysis of RNA quality metrics in human brain tissue.

Human brain tissue studies have historically used a range of metrics to assess RNA quality. However, few large-scale cross-comparisons of pre-sequencing quality metrics with RNA-seq quality have been published. Here, we analyze how well metrics gathered before RNA sequencing (post-mortem interval (PMI) and RNA integrity number RIN) relate to analyses of RNA quality after sequencing (Percent of counts in Top Ten genes (PTT), 5' bias, and 3' bias) as well as with individual gene counts across the transcriptome. We conduct this analysis across four different human cortical brain tissue collections sequenced with varying library preparation protocols. PMI and RIN have a low inverse correlation, and both PMI and RIN show consistent and opposing correlations with PTT. Unlike PMI, RIN shows strong consistent correlations with measurements of 3' and 5' bias, and RIN also correlates with 3,933 genes across datasets, in comparison to 138 genes for PMI. Neuronal and immune response genes correlate positively and negatively with RIN respectively, suggesting that different gene sets have divergent relationships with RIN in brain tissue. In summary, these analyses suggest that conventional metrics of RNA quality have varying degrees of value, and that PMI has an overall minimal but reproducible effect on RNA quality.

The Power of a Belief System: A Systematic Qualitative Synthesis of Spiritual Care for Patients with Brain Tumors.

Background: Diagnosis with a brain tumor is a critical event in the lives of patients and their families due to poor medical prognoses and complex clinical care. Spiritual care interventions have been known to have meaningful effects in morbid diagnoses and palliative medicine, but their role in the neuro-oncologic patient's experience is poorly understood. This systematic review explores the role of spirituality and its relevance to patient care in the diverse setting of brain tumors. Methods: A comprehensive systematic review was conducted following PRISMA-SR guidelines. PUBMED was queried for studies on spirituality and neuro-oncology. Identified studies included RCTs, interviews, surveys, and case reports that examined spirituality in neuro-oncological clinical care, quality of life, and patient experience. Of 214 articles identified, 21 studies met the inclusion criteria, and the results were narratively synthesized. Results: Spirituality may play a significant role in mental well-being by reconciling existential questions faced by both patients and caregivers, and can serve as a valuable resource to improve mental well-being and reduce rates of palliative caregiver burnout. However, the paucity of studies examining the education and integration of spiritual awareness within the clinical literature warrants further study. Conclusions: While spiritual care interventions may improve the quality of life and mental wellness of patients and their caregivers, it is unclear how spiritual awareness and education should best be implemented. Further research is needed to better understand how key components of spiritual awareness can be integrated into medical education to deepen the patient-physician relationship and improve clinical experiences.

Multi-omics Characterization of Epigenetic and Genetic Risk of Alzheimer Disease in Autopsied Brains from two Ethnic Groups.

Background: Both genetic variants and epigenetic features contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as the hub of both the genetic and epigenetic effects, in Hispanics decedents and generalized the findings to Non-Hispanic Whites (NHW) decedents. Methods: First, we derived the dosage of the CpG site-creating allele of multiple CGSes in each 1 KB window across the genome and we conducted a sliding window association test with clinical diagnosis of AD in 7,155 Hispanics (3,194 cases and 3,961 controls) using generalized linear mixed models with the adjustment of age, sex, population structure, genomic relationship matrix, and genotyping batches. Next, using methylation and bulk RNA-sequencing data from the dorsolateral pre-frontal cortex in 150 Hispanics brains, we tested the cis- and trans-effects of AD associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we checked their enriched pathways. Results: We identified six genetic loci in Hispanics with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score=55.2, P= 4.06×10 -8 ), between VRTN (Score=-19.6, P= 1.47×10 -8 ) and SYNDIG1L (Score=-37.7, P= 2.25×10 -9 ), SPG7 (16q24.3) (Score=40.5, P= 2.23×10 -8 ), PVRL2 (Score=125.86, P= 1.64×10 -9 ), TOMM40 (Score=-18.58, P= 4.61×10 -8 ), and APOE (Score=75.12, P= 7.26×10 -26 ). CGSes in PVRL2 and APOE were also genome-wide significant in NHW. Except for ADAM20 , CGSes in all the other five loci were associated with Hispanic brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L ( P =0.08), brain methylation levels in all the other five loci affected downstream RNA expression in the Hispanics ( P <0.05), and methylation at VRTN and TOMM40 were also associated with RNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and synapse (FDR<0.05). Conclusions: We identified six CpG associated genetic loci associated with AD in Hispanics, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.

Role of nutritional adjuncts in the management of gliomas: A systematic review of literature.

BACKGROUND: A variety of dietary adjuncts are known to affect the pathophysiology of glioma, making them a potential therapeutic adjunct to standard of care. We systematically reviewed clinical outcomes in glioma patients treated with one or more nutritional adjunct and/or an antimetabolite drug. METHODOLOGY: A systematic review of the literature following PRISMA guidelines was performed using Pubmed from inception till February 2023. In total, 22 manuscripts on nutrition representing 828 patients were included in the review. Statistical analyses were performed to compare the outcomes of various adjuncts. RESULTS: The median overall survival (OS) increased for newly diagnosed (21 months) and recurrent cases (10 months) when compared to historical data. For newly diagnosed cases, a ketogenic diet had the highest median OS of all the adjuncts (42.6 months) while in recurrent cases, a low copper diet coupled with 1 g penicillamine had the highest median OS (18.5 months). However, no statistically significant difference was observed in OS or progression-free survival (PFS) of newly diagnosed or recurrent gliomas. CONCLUSION: While nutritional adjuncts may offer a therapeutic benefit in the treatment of glioma, more human subject research is needed to derive meaningful conclusions.

Do Grip Strength Dynamometer Readings Improve After Cervical Spine Surgery?

STUDY DESIGN: Retrospective, cohort study. OBJECTIVES: Hand function can be difficult to objectively assess perioperatively. In patients undergoing cervical spine surgery by a single-surgeon, we sought to: (1) use a hand dynamometer to report pre/postoperative grip strength, (2) distinguish grip strength changes in patients with radiculopathy-only vs myelopathy, and (3) assess predictors of grip strength improvement. METHODS: Demographic and operative data were collected for patients who underwent surgery 2015-2018. Hand dynamometer readings were pre/postoperatively at three follow-up time periods (0-3 m, 3-6 m, 6-12 m). RESULTS: 262 patients (mean age of 59 ± 14 years; 37% female) underwent the following operations: ACDF (80%), corpectomy (25%), laminoplasty (19%), and posterior cervical fusion (7%), with 81 (31%) patients undergoing multiple operations in a single anesthetic setting. Radiculopathy-only was seen in 128 (49%) patients, and myelopathy was seen 134 (51%) patients. 110 (42%) had improved grip strength by ≥10-lbs, including 69/128 (54%) in the radiculopathy-only group, and 41/134 (31%) in the myelopathy group. Those most likely to improve grip strength were patients undergoing ACDF (OR 2.53, P = .005). Patients less likely to improve grip strength were older (OR = .97, P = .003) and underwent laminoplasty (OR = .44, 95% CI .23, .85, P = .014). Patients undergoing surgery at the C2/3-C5/6 levels and C6/7-T1/2 levels both experienced improvement during the 0-3-month time range (C2-5: P = .035, C6-T2: P = .015), but only lower cervical patients experienced improvement in the 3-6-month interval (P = .030). CONCLUSIONS: Grip strength significantly improved in 42% of patients. Patients with radiculopathy were more likely to improve than those with myelopathy. Patients undergoing surgery from the C2/3-C5/6 levels and the C6/7-T1/2 levels both significantly improved grip strength at 3-month postoperatively.

Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration.

BACKGROUND AND OBJECTIVES: Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer disease. However, in the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA affect volumetric changes in the brain related to neurodegenerative disease remains unclear. METHODS: We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between 2 related markers of cerebrovascular disease-MRI-based CMBs and autopsy-based CAA-as independent variables and volumetric markers of neurodegeneration as dependent variables. NOMAS included mostly dementia-free participants age 55 years or older from northern Manhattan. ADNI included participants living in the United States age 55-90 years with a range of cognitive status. EDIS included community-based participants living in Singapore age 60 years and older with a range of cognitive status. BARS included postmortem pathologic samples. RESULTS: We included 2,657 participants with available MRI data and 82 autopsy cases from BARS. In a meta-analysis of NOMAS, ADNI, and EDIS, superficial CMBs were associated with larger gray matter (ß = 4.49 ± 1.13, p = 0.04) and white matter (ß = 4.72 ± 2.1, p = 0.03) volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with 1 CMB (ß = 5.17 ± 2.47, p = 0.04) than in those with ≥2 CMBs (ß = 1.97 ± 3.41, p = 0.56). In BARS, CAA was associated with increased cortical thickness (ß = 6.5 ± 2.3, p = 0.016) but not with increased brain weight (ß = 1.54 ± 1.29, p = 0.26). DISCUSSION: Superficial CMBs are associated with larger morphometric brain measures, specifically white matter volume. This association is strongest in brains with fewer CMBs, suggesting that the CMB/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease.

An immune response characterizes early Alzheimer's disease pathology and subjective cognitive impairment in hydrocephalus biopsies.

Early Alzheimer's disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy ß-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline.

Meningomyeloencephalitis secondary to Mycobacterium haemophilum infection in AIDS.

Infections by opportunistic non-tuberculous mycobacteria (NTM) are rising in global incidence. One emerging, slowly growing NTM is Mycobacterium haemophilum, which can cause skin, lung, bone, and soft tissue infections in immunocompromised patients as well as lymphadenitis in immunocompetent individuals. Detection of this microorganism is difficult using conventional culture-based methods and few reports have documented involvement of this pathogen within the central nervous system (CNS).We describe the neuropathologic autopsy findings of a 39-year-old man with AIDS who died secondary to M. haemophilum CNS infection. He initially presented with repeated bouts of pyrexia, nausea and vomiting, and altered mental status that required numerous hospitalizations. CSF infectious workups were consistently negative. His most recent admission identified hyperintensities within the brainstem by MRI and despite antibiotic therapies for suspected CNS infection, he died. Autopsy revealed a swollen brain with marked widening of the brainstem. Microscopic examination of the brain and spinal cord showed focal lymphohistiocytic infiltrates, gliosis and neuronal loss that were associated with acid-fast bacilli (AFB). The brainstem was the most severely damaged and AFB were found to congregate along arterial territories lending support to the notion of hematogenous spread as a mechanism for the organisms' dissemination. 16S rRNA sequencing on formalin-fixed paraffin-embedded tissue enabled post-mortem identification of M. haemophilum. This sequencing methodology may permit diagnosis on CSF intra-vitam.