Hetereogeneity in Neuronal Intrinsic Properties: A Possible Mechanism for Hub-Like Properties of the Rat Anterior Cingulate Cortex during Network Activity.

The anterior cingulate cortex (ACC) is vital for a range of brain functions requiring cognitive control and has highly divergent inputs and outputs, thus manifesting as a hub in connectomic analyses. Studies show diverse functional interactions within the ACC are associated with network oscillations in the β (20-30 Hz) and γ (30-80 Hz) frequency range. Oscillations permit dynamic routing of information within cortex, a function that depends on bandpass filter-like behavior to selectively respond to specific inputs. However, a putative hub region such as ACC needs to be able to combine inputs from multiple sources rather than select a single input at the expense of others. To address this potential functional dichotomy, we modeled local ACC network dynamics in the rat in vitro. Modal peak oscillation frequencies in the β- and γ-frequency band corresponded to GABAAergic synaptic kinetics as seen in other regions; however, the intrinsic properties of ACC principal neurons were highly diverse. Computational modeling predicted that this neuronal response diversity broadened the bandwidth for filtering rhythmic inputs and supported combination-rather than selection-of different frequencies within the canonical γ and β electroencephalograph bands. These findings suggest that oscillating neuronal populations can support either response selection (routing) or combination, depending on the interplay between the kinetics of synaptic inhibition and the degree of heterogeneity of principal cell intrinsic conductances.Wellcome Trus

Dorsal vs. ventral differences in fast Up-state-associated oscillations in the medial prefrontal cortex of the urethane-anesthetized rat.

Cortical slow oscillations (0.1–1 Hz), which may play a role in memory consolidation, are a hallmark of non-rapid eye movement (NREM) sleep and also occur under anesthesia. During slow oscillations the neuronal network generates faster oscillations on the active Up-states and these nested oscillations are particularly prominent in the PFC. In rodents the medial prefrontal cortex (mPFC) consists of several subregions: anterior cingulate cortex (ACC), prelimbic (PrL), infralimbic (IL), and dorsal peduncular cortices (DP). Although each region has a distinct anatomy and function, it is not known whether slow or fast network oscillations differ between subregions in vivo. We have simultaneously recorded slow and fast network oscillations in all four subregions of the rodent mPFC under urethane anesthesia. Slow oscillations were synchronous between the mPFC subregions, and across the hemispheres, with no consistent amplitude difference between subregions. Delta (2–4 Hz) activity showed only small differences between subregions. However, oscillations in the spindle (6–15 Hz)-, beta (20–30 Hz), gamma (30–80 Hz)-, and high-gamma (80–150 Hz)-frequency bands were consistently larger in the dorsal regions (ACC and PrL) compared with ventral regions (IL and DP). In dorsal regions the peak power of spindle, beta, and gamma activity occurred early after onset of the Up-state. In the ventral regions, especially the DP, the oscillatory power in the spindle-, beta-, and gamma-frequency ranges peaked later in the Up-state. These results suggest variations in fast network oscillations within the mPFC that may reflect the different functions and connectivity of these subregions. NEW & NOTEWORTHY We demonstrate, in the urethane-anesthetized rat, that within the medial prefrontal cortex (mPFC) there are clear subregional differences in the fast network oscillations associated with the slow oscillation Up-state. These differences, particularly between the dorsal and ventral subregions of the mPFC, may reflect the different functions and connectivity of these subregions

Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change

The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aβ and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque Aβ to contribute to tau pathology, few studies have examined relative correlative strengths between total Aβ, plaque Aβ and intracellular Aβ with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer’s disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aβ and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aβ and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aβ plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aβ was measured via the Aβ specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aβ may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aβ in controls, the robust correlative relationships observed suggest a physiological association of Aβ production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aβ, but not extracellular Aβ plaques

Evidence for prodromal changes in neuronal excitability and neuroinflammation in the hippocampus in young alpha-synuclein (A30P) transgenic mice

IntroductionNeuronal hyperexcitability and neuroinflammation are thought to occur at early stages in a range of neurodegenerative diseases. Neuroinflammation, notably activation of microglia, has been identified as a potential prodromal marker of dementia with Lewy bodies (DLB). Using a transgenic mouse model of DLB that over-expresses human mutant (A30P) alpha-synuclein (hα-syn) we have investigated whether early neuroinflammation is evident in the hippocampus in young pre-symptomatic animals.MethodsPrevious studies have shown early hyperexcitability in the hippocampal CA3 region in male A30P mice at 2–4 months of age, therefore, in the current study we have immunostained this region for markers of neuronal activity (c-Fos), reactive astrocytes (glial fibrillary acidic protein, GFAP), microglia (ionizing calcium binding adapter protein 1, Iba-1) and reactive microglia (inducible nitric oxide synthase, iNOS).ResultsWe found an interesting biphasic change in the expression of c-Fos in A30P mice with high expression at 1 month, consistent with early onset of hyperexcitability, but lower expression from 2–4 months in male A30P mice compared to wild-type (WT) controls, possibly indicating chronic hyperexcitability. Neuroinflammation was indicated by significant increases in the % area of GFAP and the number of Iba-1+ cells that expressed iNOS immunoreactivity in the CA3 region in 2–4 months A30P male mice compared to WT controls. A similar increase in % area of GFAP was observed in female A30P mice, however, the Iba-1 count was not different between female WT and A30P mice. In WT mice aged 2–4 months only 4.6% of Iba-1+ cells co-expressed iNOS. In contrast, in age matched A30P mice 87% of cells co-expressed Iba-1 and iNOS. Although there was no difference in GFAP immunoreactivity at 1 month, Iba-1/iNOS co-expression was also increased in a cohort of 1 month old A30P mice.DiscussionAbnormal hα-syn expression in A30P mice caused early changes in network excitability, as indicated by c-Fos expression, and neuroinflammation which might contribute to disease progression

Quantitative electroencephalography as a marker of cognitive fluctuations in dementia with Lewy bodies and aid to differential diagnosis

Objective: We investigated for quantitative EEG (QEEG) differences between Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) patients and healthy controls, and for QEEG signatures of cognitive fluctuations (CFs) in DLB. Methods: We analyzed eyes-closed, resting state EEGs from 18 AD, 17 DLB and 17 PDD patients with mild dementia, and 21 age-matched controls. Measures included spectral power, dominant frequency (DF), frequency prevalence (FP), and temporal DF variability (DFV), within defined EEG frequency bands and cortical regions. Results: DLB and PDD patients showed a leftward shift in the power spectrum and DF. AD patients showed greater DFV compared to the other groups. In DLB patients only, greater DFV and EEG slowing were correlated with CFs, measured by the clinician assessment of fluctuations (CAF) scale. The diagnostic accuracy of the QEEG measures was 94% (90.4% - 97.9%), with 92.26% (80.4% – 100%) sensitivity and 83.3% (73.6% - 93%) specificity. Conclusion: Although greater DFV was only shown in the AD group, within the DLB group a positive DFV - CF correlation was found. QEEG measures could classify DLB and AD patients with high sensitivity and specificity. Significance: The findings add to building literature suggesting that EEG is a viable diagnostic and symptom biomarker in dementia, particularly DLB.We thank the Alzheimer’s Society for funding this research as part of the Alzheimer’s Society Doctoral Training center at Newcastle University. This research was also supported the National Institute for Health Research Biomedical Research Centre (NIHR-BRC), the Newcastle Hospitals NHS Charity, the Northumberland, Tyne and Wear NHS Foundation Trust, the Wellcome Trust (grant numbers: BH120812, BH120878) and by the Alzheimer’s Research UK. S.G. was supported by the NIHR MedTech In vitro diagnostic Co-operatives scheme (ref MIC-2016–014)

Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change

The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aβ and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque Aβ to contribute to tau pathology, few studies have examined relative correlative strengths between total Aβ, plaque Aβ and intracellular Aβ with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer’s disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aβ and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aβ and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aβ plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aβ was measured via the Aβ specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aβ may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aβ in controls, the robust correlative relationships observed suggest a physiological association of Aβ production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aβ, but not extracellular Aβ plaques

Clinical and Non-Clinical Cardiovascular Disease Associated Pathologies in Parkinson’s Disease

Despite considerable breakthroughs in Parkinson’s disease (PD) research, understanding of non-motor symptoms (NMS) in PD remains limited. The lack of basic level models that can properly recapitulate PD NMS either in vivo or in vitro complicates matters. Even so, recent research advances have identified cardiovascular NMS as being underestimated in PD. Considering that a cardiovascular phenotype reflects sympathetic autonomic dysregulation, cardiovascular symptoms of PD can play a pivotal role in understanding the pathogenesis of PD. In this study, we have reviewed clinical and non-clinical published papers with four key parameters: cardiovascular disease risks, electrocardiograms (ECG), neurocardiac lesions in PD, and fundamental electrophysiological studies that can be linked to the heart. We have highlighted the points and limitations that the reviewed articles have in common. ECG and pathological reports suggested that PD patients may undergo alterations in neurocardiac regulation. The pathological evidence also suggested that the hearts of PD patients were involved in alpha-synucleinopathy. Finally, there is to date little research available that addresses the electrophysiology of in vitro Parkinson’s disease models. For future reference, research that can integrate cardiac electrophysiology and pathological alterations is required

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

The amyloid cascade hypothesis states that Aβ and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of Aβ and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between Aβ and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimer’s diseases (AD) cases (n=21), biochemical and immunohistochemical measures of Aβ and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional Aβ and AT-8 tau, such increases in Aβ immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between Aβ plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular Aβ within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular Aβ may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and Aβ as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of Aβ production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional Aβ load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between Aβ and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular Aβ but not extracellular Aβ plaques

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

The amyloid cascade hypothesis states that Aβ and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of Aβ and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between Aβ and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimer’s diseases (AD) cases (n=21), biochemical and immunohistochemical measures of Aβ and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional Aβ and AT-8 tau, such increases in Aβ immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between Aβ plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular Aβ within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular Aβ may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and Aβ as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of Aβ production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional Aβ load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between Aβ and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular Aβ but not extracellular Aβ plaques

Accuracy of Xpert Ultra in Diagnosis of Pulmonary Tuberculosis among Children in Uganda: a Substudy from the SHINE Trial.

Childhood tuberculosis (TB) presents significant diagnostic challenges associated with paucibacillary disease and requires a more sensitive test. We evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Ultra) compared to other microbiological tests using respiratory samples from Ugandan children in the SHINE trial. SHINE is a randomized trial evaluating shorter treatment in 1,204 children with minimal TB disease in Africa and India. Among 352 samples and one cervical lymph node fine needle aspirate, one sample was randomly selected per patient and tested with the Xpert MTB/RIF assay (Xpert) and with Lowenstein-Jensen medium (LJ) and liquid mycobacterial growth indicator tube (MGIT) cultures. We selected only uncontaminated stored sample pellets for Ultra testing. We estimated the sensitivity of Xpert and Ultra against culture and a composite microbiological reference standard (any positive result). Of 398 children, 353 (89%) had culture, Xpert, and Ultra results. The median age was 2.8 years (interquartile range [IQR], 1.3 to 5.3); 8.5% (30/353) were HIV infected, and 54.4% (192/353) were male. Of the 353, 31 (9%) were positive by LJ and/or MGIT culture, 36 (10%) by Ultra, and 16 (5%) by Xpert. Sensitivities (95% confidence intervals [CI]) were 58% (39 to 65% [18/31]) for Ultra and 45% (27 to 64% [14/31]) for Xpert against any culture-positive result, with false positives of <1% and 5.5% for Xpert and Ultra. Against a composite microbiological reference, sensitivities were 72% (58 to 84% [36/50]) for Ultra and 32% (20 to 47% [16/50]) for Xpert. However, there were 17 samples that were positive only with Ultra (majority trace). Among children screened for minimal TB in Uganda, Ultra has higher sensitivity than Xpert. This represents an important advance for a condition which has posed a diagnostic challenge for decades