Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents

© 2016 The Author(s). The basic mechanism of the major neurodegenerative diseases, including neurogenic pain, needs to be agreed upon before rational treatments can be determined, but this knowledge is still in a state of flux. Most have agreed for decades that these disease states, both infectious and non-infectious, share arguments incriminating excitotoxicity induced by excessive extracellular cerebral glutamate. Excess cerebral levels of tumor necrosis factor (TNF) are also documented in the same group of disease states. However, no agreement exists on overarching mechanism for the harmful effects of excess TNF, nor, indeed how extracellular cerebral glutamate reaches toxic levels in these conditions. Here, we link the two, collecting and arguing the evidence that, across the range of neurodegenerative diseases, excessive TNF harms the central nervous system largely through causing extracellular glutamate to accumulate to levels high enough to inhibit synaptic activity or kill neurons and therefore their associated synapses as well. TNF can be predicted from the broader literature to cause this glutamate accumulation not only by increasing glutamate production by enhancing glutaminase, but in addition simultaneously reducing glutamate clearance by inhibiting re-uptake proteins. We also discuss the effects of a TNF receptor biological fusion protein (etanercept) and the indirect anti-TNF agents dithio-thalidomides, nilotinab, and cannabinoids on these neurological conditions. The therapeutic effects of 6-diazo-5-oxo-norleucine, ceptriaxone, and riluzole, agents unrelated to TNF but which either inhibit glutaminase or enhance re-uptake proteins, but do not do both, as would anti-TNF agents, are also discussed in this context. By pointing to excess extracellular glutamate as the target, these arguments greatly strengthen the case, put now for many years, to test appropriately delivered ant-TNF agents to treat neurodegenerative diseases in randomly controlled trials

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches.

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this

Amyloid β: one of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer's disease

© 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd. This review concerns how the primary inflammation preceding the generation of certain key damage-associated molecular patterns (DAMPs) arises in Alzheimer's disease (AD). In doing so, it places soluble amyloid β (Aβ), a protein hitherto considered as a primary initiator of AD, in a novel perspective. We note here that increased soluble Aβ is one of the proinflammatory cytokine-induced DAMPs recognized by at least one of the toll-like receptors on and in various cell types. Moreover, Aβ is best regarded as belonging to a class of DAMPs, as do the S100 proteins and HMBG1, that further exacerbate production of these same proinflammatory cytokines, which are already enhanced, and induces them further. Moreover, variation in levels of other DAMPs of this same class in AD may explain why normal elderly patients can exhibit high Aβ plaque levels, and why removing Aβ or its plaque does not retard disease progression. It may also explain why mouse transgenic models, having been designed to generate high Aβ, can be treated successfully by this approach

Do questionnaires reflect their purported cognitive functions?

Questionnaires are used widely across psychology and permit valuable insights into a person's thoughts and beliefs, which are difficult to derive from task performance measures alone. Given their importance and widespread use, it is vital that questionnaires map onto the cognitive functions they purport to reflect. However, where performance on naturalistic tasks such as imagination, autobiographical memory, future thinking and navigation is concerned, there is a dearth of knowledge about the relationships between task performance and questionnaire measures. Questionnaires are also typically designed to probe a specific aspect of cognition, when instead researchers sometimes want to obtain a broad profile of a participant. To the best of our knowledge, no questionnaire exists that asks simple single questions about a wide range of cognitive functions. To address these gaps in the literature, we recruited a large sample of participants (n=217), all of whom completed a battery of widely used questionnaires and performed naturalistic tasks involving imagination, autobiographical memory, future thinking and navigation. We also devised a questionnaire that comprised simple single questions about the cognitive functions of interest. There were four main findings. First, imagination and navigation questionnaires reflected performance on their related tasks. Second, memory questionnaires were associated with autobiographical memory vividness and not internal (episodic) details. Third, imagery questionnaires were more associated with autobiographical memory vividness and future thinking than the questionnaires purporting to reflect these functions. Finally, initial exploratory analyses suggested that a broad profile of information can be obtained efficiently using a small number of simple single questions, and these modelled task performance comparably to established questionnaires in young, healthy adults. Overall, while some questionnaires can act as proxies for behaviour, the relationships between memory and future thinking tasks and questionnaires are more complex and require further elucidation

Characterizing Strategy Use During the Performance of Hippocampal-Dependent Tasks

Recalling the past, thinking about the future, and navigating in the world are linked with a brain structure called the hippocampus. Precisely, how the hippocampus enables these critical cognitive functions is still debated. The strategies people use to perform tasks associated with these functions have been under-studied, and yet, such information could augment our understanding of the associated cognitive processes and neural substrates. Here, we devised and deployed an in-depth protocol to examine the explicit strategies used by 217 participants to perform four naturalistic tasks widely acknowledged to be hippocampal-dependent, namely, those assessing scene imagination, autobiographical memory recall, future thinking, and spatial navigation. In addition, we also investigated strategy use for three laboratory-based memory tasks, one of which is held to be hippocampal-dependent – concrete verbal paired associates (VPA) – and two tasks, which are likely hippocampal-independent – abstract VPA and the dead or alive semantic memory test. We found that scene visual imagery was the dominant strategy not only when mentally imagining scenes, but also during autobiographical memory recall, when thinking about the future and during navigation. Moreover, scene visual imagery strategies were used most frequently during the concrete VPA task, whereas verbal strategies were most prevalent for the abstract VPA task and the dead or alive semantic memory task. The ubiquity of specifically scene visual imagery use across a range of tasks may attest to its, perhaps underappreciated, importance in facilitating cognition, while also aligning with perspectives that emphasize a key role for the hippocampus in constructing scene imagery

The relationship between hippocampal subfield volumes and autobiographical memory persistence

Structural integrity of the human hippocampus is widely acknowledged to be necessary for the successful encoding and retrieval of autobiographical memories. However, evidence for an association between hippocampal volume and the ability to recall such memories in healthy individuals is mixed. Here we examined this issue further by combining two approaches. First, we focused on the anatomically distinct subregions of the hippocampus where more nuanced associations may be expressed compared to considering the whole hippocampal volume. A manual segmentation protocol of hippocampal subregions allowed us to separately calculate the volumes of the dentate gyrus/CA4, CA3/2, CA1, subiculum, pre/parasubiculum and uncus. Second, a critical feature of autobiographical memories is that they can span long time periods, and so we sought to consider how memory details persist over time by conducting a longitudinal study whereby participants had to recall the same autobiographical memories on two visits spaced 8 months apart. Overall, we found that there was no difference in the total number of internal (episodic) details produced at Visits 1 and 2. However, further probing of detail subcategories revealed that specifically the amount of subjective thoughts and emotions included during recall had declined significantly by the second visit. We also observed a strong correlation between left pre/parasubiculum volume and the amount of autobiographical memory internal details produced over time. This positive relationship was evident for particular facets of the memories, with remembered events, perceptual observations and thoughts and emotions benefitting from greater volume of the left pre/parasubiculum. These preliminary findings expand upon existing functional neuroimaging evidence by highlighting a potential link between left pre/parasubiculum volume and autobiographical memory. A larger pre/parasubiculum appears not only to protect against memory decay, but may possibly enhance memory persistence, inviting further scrutiny of the role of this brain region in remote autobiographical memory retrieval

The trauma film paradigm as an experimental psychopathology model of psychological trauma: intrusive memories and beyond

A better understanding of psychological trauma is fundamental to clinical psychology. Following traumatic event(s), a clinically significant number of people develop symptoms, including those of Acute Stress Disorder and/or Post Traumatic Stress Disorder. The trauma film paradigm offers an experimental psychopathology model to study both exposure and reactions to psychological trauma, including the hallmark symptom of intrusive memories. We reviewed 74 articles that have used this paradigm since the earliest review (Holmes & Bourne, 2008) until July 2014. Highlighting the different stages of trauma processing, i.e. pre-, peri- and post-trauma, the studies are divided according to manipulations before, during and after film viewing, for experimental as well as correlational designs. While the majority of studies focussed on the frequency of intrusive memories, other reactions to trauma were also modelled. We discuss the strengths and weaknesses of the trauma film paradigm as an experimental psychopathology model of trauma, consider ethical issues, and suggest future directions. By understanding the basic mechanisms underlying trauma symptom development, we can begin to translate findings from the laboratory to the clinic, test innovative science-driven interventions, and in the future reduce the debilitating effects of psychopathology following stressful and/or traumatic events

Verbal Paired Associates and the Hippocampus: The Role of Scenes

It is widely agreed that patients with bilateral hippocampal damage are impaired at binding pairs of words together. Consequently, the verbal paired associates (VPA) task has become emblematic of hippocampal function. This VPA deficit is not well understood and is particularly difficult for hippocampal theories with a visuospatial bias to explain (e.g., cognitive map and scene construction theories). Resolving the tension among hippocampal theories concerning the VPA could be important for leveraging a fuller understanding of hippocampal function. Notably, VPA tasks typically use high imagery concrete words and so conflate imagery and binding. To determine why VPA engages the hippocampus, we devised an fMRI encoding task involving closely matched pairs of scene words, pairs of object words, and pairs of very low imagery abstract words. We found that the anterior hippocampus was engaged during processing of both scene and object word pairs in comparison to abstract word pairs, despite binding occurring in all conditions. This was also the case when just subsequently remembered stimuli were considered. Moreover, for object word pairs, fMRI activity patterns in anterior hippocampus were more similar to those for scene imagery than object imagery. This was especially evident in participants who were high imagery users and not in mid and low imagery users. Overall, our results show that hippocampal engagement during VPA, even when object word pairs are involved, seems to be evoked by scene imagery rather than binding. This may help to resolve the issue that visuospatial hippocampal theories have in accounting for verbal memory