No abstract

The wide variety of cell types and their biophysical complexities pose a challenge in our ability to understand oscillatory activities produced by cellular‐based computational network models. This challenge stems from their high‐dimensional and multiparametric natures. To overcome this, we implement a solution by linking minimal and detailed models of CA1 microcircuits that generate intrahippocampal (3–12 Hz) theta rhythms. We leverage insights from minimal models to guide explorations of more detailed models and obtain a cellular perspective of theta generation. Our findings distinguish the pyramidal cells as the theta rhythm initiators and reveal that their activity is regularized by the inhibitory cell populations, supporting a proposed hypothesis of an “inhibition‐based tuning” mechanism. We find a strong correlation between input current to the pyramidal cells and the resulting local field potential theta frequency, indicating that intrinsic pyramidal cell properties underpin network frequency characteristics. This work provides a cellular‐based foundation from which in vivo theta activities can be explored.

Our study aimed to: 1)investigate the diagnostic utility of CSF Aβ42, t-tau, and p-tau to differentiate normal-pressure-hydrocephalus(NPH) from Alzheimer's-disease(AD) and normal-controls; and 2) investigate if age and ventricular size affect the levels of CSF biomarkers in NPH patients. We recruited 131 participants: (a)Suspected-NPH: 72 with ventriculomegaly and clinical symptoms of NPH. These participants were then divided into two groups of 1)Probable-NPH (N = 38) and 2)Unlikely-NPH (n = 34) based on whether participants experienced gait improvement after removal of a large amount of CSF; (b)AD group: 30 participants with CSF biomarkers and cognitive symptoms consistent with AD; (c)Control-group: 29 participants who were cognitively and functionally normal. Lower levels of CSF Aβ42 and p-tau were observed in the probable-NPH compared to the normal controls(444.22 ± 163.3 vs. 1213.75 ± 556.5; and 26.05 ± 9.2 vs. 46.16 ± 13.3 pg/mL; respectively). Lower levels of CSF p-tau and t-tau were found in the probable-NPH compared to the AD(26.05 ± 9.2 vs. 114.95 ± 28.2; and 193.29 ± 92.3 vs. 822.65 ± 311.5 pg/mL; respectively) but the CSF-Aβ42 was low in both the probable-NPH and AD. CSF-Aβ42 correlated with age and Evans-index only in the probable-NPH(r = 0.460, p = 0.004; and r = −0.530, p = 0.001; respectively). Our study supports the hypothesis that agerelated atrophy results in better Aβ42 clearance in the CSF because of the increase in the interstitial space. Normal pressure hydrocephalus (NPH) is a syndrome associated with enlarged ventricles without marked elevation in cerebrospinal fluid (CSF) pressure 1. Clinical symptoms include gait and balance impairment, cognitive deficits, and urinary urgency/incontinence 1. In both NPH and Alzheimer's disease (AD) decreased CSF levels of the amyloid β−42 (Aβ42) have been found; however, in contrast to AD, total tau (t-tau) and phospho-tau (p-tau) levels are not increased in NPH cases 2,3. It has been hypothesized that the low Aβ42 in the presence of low t-tau and p-tau is due to the decrease in interstitial space that precludes amyloid precursor protein (APP) fragments and tau proteins from being effectively cleared by CSF and consequently the levels of these proteins decrease in the CSF 4. This hypothesis was based on two major observations: 1) low levels of all APP fragments (i.e., Aβ38, Aβ40, Aβ42, sAPPα, and sAPPβ) in CSF obtained both by lumbar and ventricular methods of patients with NPH compared to health controls, which all increased back to normal after shunting 1 and 2) Aβ clearance from the interstitial fluid is increased during sleep when the size of interstitial space increases by 60% 5. The aims of our study were to: 1) investigate the diagnostic utility of CSF Aβ42, t-tau, and p-tau to differentiate NPH from AD and normal controls; and 2) investigate if age and ventricular size affect the levels of these CSF biomarkers in NPH patients. Answers to these questions would improve understanding of CSF Aβ42, t-tau, and p-tau production/clearance and facilitate ...