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Adolescent-onset heavy cannabis use associated with significantly reduced glial but not neuronal markers and glutamate levels in the hippocampus.
Blest-Hopley, G, O'Neill, A, Wilson, R, Giampietro, V, Lythgoe, D, Egerton, A, Bhattacharyya, S
Addiction biology. 2020;(6):e12827
Abstract
Cannabis use has been associated with adverse mental health outcomes, the neurochemical underpinnings of which are poorly understood. Although preclinical evidence suggests glutamatergic dysfunction following cannabis exposure in several brain regions including the hippocampus, evidence from human studies have been inconsistent. We investigated the effect of persistent cannabis use on the brain levels of N-acetyl aspartate (NAA) and myoinositol, the metabolite markers of neurons and glia, the site of the main central cannabinoid CB1 receptor, and the levels of glutamate, the neurotransmitter directly affected by CB1 modulation. We investigated cannabis users (CUs) who started using during adolescence, the period of greatest vulnerability to cannabis effects and focused on the hippocampus, where type 1 cannabinoid receptors (CBR1) are expressed in high density and have been linked to altered glutamatergic neurotransmission. Twenty-two adolescent-onset CUs and 21 nonusing controls (NU), completed proton magnetic resonance spectroscopy, to measure hippocampal metabolite concentrations. Glutamate, NAA, and myoinositol levels were compared between CU and NU using separate analyses of covariance. CU had significantly lower myoinositol but not glutamate or NAA levels in the hippocampus compared with NU. Myoinositol levels in CU positively correlated with glutamate levels, whereas this association was absent in NU. Altered myoinositol levels may be a marker of glia dysfunction and is consistent with experimental preclinical evidence that cannabinoid-induced glial dysfunction may underlie cannabinoid-induced memory impairments. Future studies using appropriate imaging techniques such as positron emission tomography should investigate whether glial dysfunction associated with cannabis use underlies hippocampal dysfunction and memory impairment in CUs.
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Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer's Disease Cooperative Study-Sponsored DHA Clinical Trial.
Tomaszewski, N, He, X, Solomon, V, Lee, M, Mack, WJ, Quinn, JF, Braskie, MN, Yassine, HN
Journal of Alzheimer's disease : JAD. 2020;(3):975-990
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Abstract
BACKGROUND Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) play key roles in several metabolic processes relevant to Alzheimer's disease (AD) pathogenesis and neuroinflammation. Carrying the APOEɛ4 allele (APOE4) accelerates omega-3 polyunsaturated fatty acid (PUFA) oxidation. In a pre-planned subgroup analysis of the Alzheimer's Disease Cooperative Study-sponsored DHA clinical trial, APOE4 carriers with mild probable AD had no improvements in cognitive outcomes compared to placebo, while APOE 4 non-carriers showed a benefit from DHA supplementation. OBJECTIVE We sought to clarify the effect of APOEɛ4/ɛ4 on both the ratio of plasma DHA and EPA to AA, and on hippocampal volumes after DHA supplementation. METHODS Plasma fatty acids and APOE genotype were obtained in 275 participants randomized to 18 months of DHA supplementation or placebo. A subset of these participants completed brain MRI imaging (n = 86) and lumbar punctures (n = 53). RESULTS After the intervention, DHA-treated APOEɛ3/ɛ3 and APOEɛ2/ɛ3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to ɛ4/ɛ4 carriers. APOEɛ2/ɛ3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to ɛ4/ɛ4 carriers. The change in plasma and cerebrospinal fluid DHA/AA was strongly correlated. Greater baseline and increase in plasma EPA/AA was associated with a lower decrease in the right hippocampal volume, but only in APOE 4 non-carriers. CONCLUSION The lower increase in plasma DHA/AA and EPA/AA in APOEɛ4/ɛ4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation.
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Higher CSF Tau Levels Are Related to Hippocampal Hyperactivity and Object Mnemonic Discrimination in Older Adults.
Berron, D, Cardenas-Blanco, A, Bittner, D, Metzger, CD, Spottke, A, Heneka, MT, Fliessbach, K, Schneider, A, Teipel, SJ, Wagner, M, et al
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019;(44):8788-8797
Abstract
Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTLs). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination, even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC), have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance, and levels of total and phosphorylated tau as well as Aβ42/40 ratio in CSF. We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus, and both increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects, but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline.SIGNIFICANCE STATEMENT Subregions in the human medial temporal lobe are critically involved in episodic memory and, at the same time, affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals, but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related fMRI in combination with measures of tau pathology in CSF, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.
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REST/NRSF transcription factor is overexpressed in hippocampus of patients with drug-resistant mesial temporal lobe epilepsy.
Navarrete-Modesto, V, Orozco-Suárez, S, Alonso-Vanegas, M, Feria-Romero, IA, Rocha, L
Epilepsy & behavior : E&B. 2019;:118-123
Abstract
The Repressor Element-1 Silencing Transcription factor or Neuron-Restrictive Silencer Factor (REST/NRSF) is a zinc finger repressor transcription factor of the Kruppel family. Several studies in experimental models have shown that overexpression of REST/NRSF occurs after the induction of seizures. In the present study, the expression of REST/NRSF (messenger ribonucleic acid (mRNA) and protein) was evaluated in the hippocampus of 28 patients with drug-resistant mesial temporal lobe epilepsy (MTLE) and their correlation with clinical variables and comorbid anxiety and depression. The REST/NRSF protein expression was augmented in an age-dependent manner in the hippocampus of autopsied subjects. However, this condition was not observed in patients with MTLE, in whom overexpression of this transcription factor occurred at both the mRNA and protein levels. The correlations with clinical variables showed that the frequency of epileptic seizures was proportional to the protein expression of REST/NRSF. The results revealed that the overexpression of REST/NRSF was more evident in patients with MTLE without anxiety and depression. Our data indicate that the expression of REST/NRSF is modified in patients with MTLE. This condition has implications in the pathophysiology of this disorder, making it a potential candidate for the optimization of clinical treatments.
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Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus.
Zhao, Y, Jaber, V, Lukiw, WJ
Frontiers in cellular and infection microbiology. 2017;:318
Abstract
Although the potential contribution of the human gastrointestinal (GI) tract microbiome to human health, aging, and disease is becoming increasingly acknowledged, the molecular mechanics and signaling pathways of just how this is accomplished is not well-understood. Major bacterial species of the GI tract, such as the abundant Gram-negative bacilli Bacteroides fragilis (B. fragilis) and Escherichia coli (E. coli), secrete a remarkably complex array of pro-inflammatory neurotoxins which, when released from the confines of the healthy GI tract, are pathogenic and highly detrimental to the homeostatic function of neurons in the central nervous system (CNS). For the first time here we report the presence of bacterial lipopolysaccharide (LPS) in brain lysates from the hippocampus and superior temporal lobe neocortex of Alzheimer's disease (AD) brains. Mean LPS levels varied from two-fold increases in the neocortex to three-fold increases in the hippocampus, AD over age-matched controls, however some samples from advanced AD hippocampal cases exhibited up to a 26-fold increase in LPS over age-matched controls. This "Perspectives" paper will further highlight some very recent research on GI tract microbiome signaling to the human CNS, and will update current findings that implicate GI tract microbiome-derived LPS as an important internal contributor to inflammatory degeneration in the CNS.
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Metacognitive ability correlates with hippocampal and prefrontal microstructure.
Allen, M, Glen, JC, Müllensiefen, D, Schwarzkopf, DS, Fardo, F, Frank, D, Callaghan, MF, Rees, G
NeuroImage. 2017;:415-423
Abstract
The ability to introspectively evaluate our experiences to form accurate metacognitive beliefs, or insight, is an essential component of decision-making. Previous research suggests individuals vary substantially in their level of insight, and that this variation is related to brain volume and function, particularly in the anterior prefrontal cortex (aPFC). However, the neurobiological mechanisms underlying these effects are unclear, as qualitative, macroscopic measures such as brain volume can be related to a variety of microstructural features. Here we leverage a high-resolution (800µm isotropic) multi-parameter mapping technique in 48 healthy individuals to delineate quantitative markers of in vivo histological features underlying metacognitive ability. Specifically, we examined how neuroimaging markers of local grey matter myelination and iron content relate to insight as measured by a signal-theoretic model of subjective confidence. Our results revealed a pattern of microstructural correlates of perceptual metacognition in the aPFC, precuneus, hippocampus, and visual cortices. In particular, we extend previous volumetric findings to show that right aPFC myeloarchitecture positively relates to metacognitive insight. In contrast, decreased myelination in the left hippocampus correlated with better metacognitive insight. These results highlight the ability of quantitative neuroimaging to reveal novel brain-behaviour correlates and may motivate future research on their environmental and developmental underpinnings.
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Hippocampal Response to a 24-Month Physical Activity Intervention in Sedentary Older Adults.
Rosano, C, Guralnik, J, Pahor, M, Glynn, NW, Newman, AB, Ibrahim, TS, Erickson, K, Cohen, R, Shaaban, CE, MacCloud, RL, et al
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2017;(3):209-217
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Abstract
BACKGROUND Greater hippocampal volume is observed in healthy older adults after short-term structured exercise. Whether long-term exposure to real-world physical activity (PA) programs has similar effects for sedentary older adults with impaired mobility and comorbid conditions is not known. HYPOTHESIS A long-term moderate intensity regimen of PA is related to larger volume of the hippocampus in older adults at risk for mobility disability. We further explore whether these associations are modified by factors known to be related to dementia. METHODS Twenty-six sedentary adults at risk for mobility disability participated in a 24-month randomized intervention program of physical activity (PA, N = 10, age: 74.9 years, 7 women) or health education (HE, N = 16, age: 76.8 years, 14 women). Volumes of total hippocampus, dentate gyrus, and cornu ammonis were measured at baseline and at 24-month follow-up using 7-Tesla magnetic resonance imaging. Between-group volumetric differences at 24 months were adjusted for sessions attended and baseline volumes. The contribution of each dementia-related factor was tested separately for education, APOE, diabetes, cardiovascular diseases, white matter hyperintensities, and brain atrophy. RESULTS Between-group differences were significant for left hippocampus, left cornu ammonis, and right hippocampus. Adjustment for regional baseline volume attenuated the associations to statistically nonsignificant for right hippocampus and left conru ammonis; associations for left hippocampus were robust for all adjustments. Results were similar after adjustment for dementia-related factors. CONCLUSIONS In this group of sedentary older adults there was a hippocampal response to a long-term program of moderate-intensity PA. Future studies should examine whether hippocampal response could explain the beneficial effects of PA on cognition for vulnerable older adults.
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Pathway to neural resilience: Self-esteem buffers against deleterious effects of poverty on the hippocampus.
Wang, Y, Zhang, L, Kong, X, Hong, Y, Cheon, B, Liu, J
Human brain mapping. 2016;(11):3757-3766
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Abstract
Human neuroimaging studies have shown that people living in poverty tend to suffer hippocampal atrophy, which leads to impaired memory and learning throughout life. However, behavioral studies demonstrate that poor people with high self-esteem are often exempt from the deleterious effect of poverty and instead possess a happy and successful life. Here we investigated whether high self-esteem can buffer against the deleterious effects of poverty, as indicated by low subjective socioeconomic status (SSS), on the hippocampal gray matter volume (GMV) in a large cohort of young participants (N = 280). As expected, findings revealed that although low (vs. high) SSS was linked with a smaller hippocampal GMV, the deleterious effect of low SSS on hippocampal GMV was alleviated when the participants have high self-esteem. Commonality analyses further confirmed this observation. The current study suggests that positive psychological resources such as self-esteem may provide protection for the hippocampal atrophy in adversity. Hum Brain Mapp 37:3757-3766, 2016. © 2016 Wiley Periodicals, Inc.
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Regulation of body growth.
Lui, JC, Garrison, P, Baron, J
Current opinion in pediatrics. 2015;(4):502-10
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Abstract
PURPOSE OF REVIEW Recent basic studies have yielded important new insights into the molecular mechanisms that regulate growth locally. Simultaneously, clinical studies have identified new molecular defects that cause growth failure and overgrowth, and genome-wide association studies have elucidated the genetic basis for normal human height variation. RECENT FINDINGS The Hippo pathway has emerged as one of the major mechanisms controlling organ size. In addition, an extensive genetic program has been described that allows rapid body growth in the fetus and infant but then causes growth to slow with age in multiple tissues. In human genome-wide association studies, hundreds of loci associated with adult stature have been identified; many appear to involve genes that function locally in the growth plate. Clinical genetic studies have identified a new genetic abnormality, microduplication of Xq26.3, that is responsible for growth hormone excess, and a gene, DNMT3A, in which mutations cause an overgrowth syndrome through epigenetic mechanisms. SUMMARY These recent advances in our understanding of somatic growth not only provide insight into childhood growth disorders but also have broader medical applications because disruption of these regulatory systems contributes to oncogenesis.
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An in vitro seizure model from human hippocampal slices using multi-electrode arrays.
Hsiao, MC, Yu, PN, Song, D, Liu, CY, Heck, CN, Millett, D, Berger, TW
Journal of neuroscience methods. 2015;:154-63
Abstract
Temporal lobe epilepsy is a neurological condition marked by seizures, typically accompanied by large amplitude synchronous electrophysiological discharges, affecting a variety of mental and physical functions. The neurobiological mechanisms responsible for the onset and termination of seizures are still unclear. While pharmacological therapies can suppress the symptoms of seizures, typically 30% of patients do not respond well to drug control. Unilateral temporal lobectomy, a procedure in which a substantial part of the hippocampal formation and surrounding tissue is removed, is a common surgical treatment for medically refractory epilepsy. In this study, we have developed an in vitro model of epilepsy using human hippocampal slices resected from patients suffering from intractable mesial temporal lobe epilepsy. We show that using a planar multi-electrode array system, spatio-temporal inter-ictal like activity can be consistently recorded in high-potassium (8 mM), low-magnesium (0.25 mM) artificial cerebral spinal fluid with 4-aminopyridine (100 μM) added. The induced epileptiform discharges can be recorded in different subregions of the hippocampus, including dentate, CA1 and subiculum. This new paradigm will allow the study of seizure generation in different subregions of hippocampus simultaneously, as well as propagation of seizure activity throughout the intrinsic circuitry of hippocampus. This experimental model also should provide insights into seizure control and prevention, while providing a platform to develop novel, anti-seizure therapeutics.