Chronic pain causes Tau-mediated hippocampal pathology and memory deficits

Guerreiro, Sara; Guimarães, Marco Rafael; Silva, Joana M; Dioli, Chrysoula; Vamvaka-Iakovou, Anastasia; Sousa, Raquel; Gomes, Patrícia; Megalokonomou, Anastasia; Campos-Marques, Carlos; Cunha, Ana Margarida; Almeida, Armando; Sousa, Nuno; Leite‐Almeida, Hugo; Sotiropoulos, Ioannis

doi:10.1038/s41380-022-01707-3

Cited by 15 publications

(9 citation statements)

References 40 publications

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“…This study was undertaken with the hypothesis that hippocampus microstructure is a sensitive metric to relay early alterations and may provide a crucial link between aberrant neurogenesis in response to chronic pain and volumetric changes. 33 , 34 , 37 , 70 , 81 , 94 Subregion and longitudinal axis analyses identified that patients with TN have hippocampal diffusivity alterations in multiple structural and functional domains. First, we discovered subregion-specific reductions in FA, specifically contralateral subregions CA2/3 and CA4 and bilateral hippocampal body.…”

Section: Discussionmentioning

confidence: 99%

Hippocampus diffusivity abnormalities in classical trigeminal neuralgia

Hanycz,

Noorani,

Hung

et al. 2024

PR9

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Introduction: Patients with chronic pain frequently report cognitive symptoms that affect memory and attention, which are functions attributed to the hippocampus. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by paroxysmal attacks of unilateral orofacial pain. Given the stereotypical nature of TN pain and lack of negative symptoms including sensory loss, TN provides a unique model to investigate the hippocampal implications of chronic pain. Recent evidence demonstrated that TN is associated with macrostructural hippocampal abnormalities indicated by reduced subfield volumes; however, there is a paucity in our understanding of hippocampal microstructural abnormalities associated with TN. Objectives: To explore diffusivity metrics within the hippocampus, along with its functional and structural subfields, in patients with TN. Methods: To examine hippocampal microstructure, we utilized diffusion tensor imaging in 31 patients with TN and 21 controls. T1-weighted magnetic resonance images were segmented into hippocampal subfields and registered into diffusion-weighted imaging space. Fractional anisotropy (FA) and mean diffusivity were extracted for hippocampal subfields and longitudinal axis segmentations. Results: Patients with TN demonstrated reduced FA in bilateral whole hippocampi and hippocampal body and contralateral subregions CA2/3 and CA4, indicating microstructural hippocampal abnormalities. Notably, patients with TN showed significant correlation between age and hippocampal FA, while controls did not exhibit this correlation. These effects were driven chiefly by female patients with TN. Conclusion: This study demonstrates that TN is associated with microstructural hippocampal abnormalities, which may precede and potentially be temporally linked to volumetric hippocampal alterations demonstrated previously. These findings provide further evidence for the role of the hippocampus in chronic pain and suggest the potential for targeted interventions to mitigate cognitive symptoms in patients with chronic pain.

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Section: Discussionmentioning

confidence: 99%

Hippocampus diffusivity abnormalities in classical trigeminal neuralgia

Hanycz,

Noorani,

Hung

et al. 2024

PR9

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“…Hugo et al found that, compared with Tau +/+ mice, the response of Tau KO mice to acute noxious stimuli is decreased, whereas their pain-related behaviors are augmented under tonic inflammatory pain stimulation [ 9 ]. Later, they found that mice with spared nerve injury exhibit Tau hyperphosphorylation in the hippocampus owing to impaired autophagy, which in turn induces depressive-like behavior and cognitive impairment but not anxiety [ 10 , 29 ]. In the von Frey test, Tau KO mice with spared nerve injury exhibit improved cognitive impairment but no pain relief.…”

Section: Discussionmentioning

confidence: 99%

Tau Accumulation in the Spinal Cord Contributes to Chronic Inflammatory Pain by Upregulation of IL-1β and BDNF

Zhang,

Chen,

Wang

et al. 2023

Neurosci. Bull.

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Microtubule-associated protein Tau is responsible for the stabilization of neuronal microtubules under normal physiological conditions. Much attention has been focused on Tau’s contribution to cognition, but little research has explored its role in emotions such as pain, anxiety, and depression. In the current study, we found a significant increase in the levels of p-Tau (Thr231), total Tau, IL-1β, and brain-derived neurotrophic factor (BDNF) on day 7 after complete Freund's adjuvant (CFA) injection; they were present in the vast majority of neurons in the spinal dorsal horn. Microinjection of Mapt-shRNA recombinant adeno-associated virus into the spinal dorsal cord alleviated CFA-induced inflammatory pain and inhibited CFA-induced IL-1β and BDNF upregulation. Importantly, Tau overexpression was sufficient to induce hyperalgesia by increasing the expression of IL-1β and BDNF. Furthermore, the activation of glycogen synthase kinase 3 beta partly contributed to Tau accumulation. These findings suggest that Tau in the dorsal horn could be a promising target for chronic inflammatory pain therapy.

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“…11 Finally, a recent study in a mouse model of chronic neuropathic pain found that chronic pain is associated with tau-mediated hippocampal atrophy and cognitive deficits. 12 To our knowledge, no study has examined the association between chronic pain status and biomarkers of neurodegeneration in the cerebrospinal fluid (CSF), and advanced neuropsychological testing. Yet, such results would not only unveil the influence of chronic pain on neuronal function but would also help identify individuals at risk for developing AD, most likely to benefit from targeted preventive measures.…”

mentioning

confidence: 99%

“…Also, a recent genome‐wide association study in the UK Biobank found that genetic variants significantly associated with multisite chronic pain are located in genes involved in neurogenesis and synaptic signaling, pathways also altered in AD 11 . Finally, a recent study in a mouse model of chronic neuropathic pain found that chronic pain is associated with tau‐mediated hippocampal atrophy and cognitive deficits 12 …”

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confidence: 99%

Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function

Sadlon,

Takousis,

Ankli

et al. 2023

Annals of Neurology

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ObjectiveDebate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative.MethodsParticipants were classified using the ATN (amyloid, tau, neurodegeneration) classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, analysis of covariance models identified differences in cerebrospinal fluid (CSF) levels of amyloid β1–42, phosphorylated tau 181 (ptau181), total tau (t‐tau), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analyzed. Linear mixed effect models examined longitudinal changes.ResultsThe study included 995 individuals, with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non‐Alzheimer pathophysiology and chronic pain showed increased CSF levels of t‐tau and sTREM2. Chronic pain was associated with increased tumor necrosis factor α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid‐positive and neurodegeneration‐negative chronic pain patients showed higher memory function cross‐sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group.InterpretationOur study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm these findings. ANN NEUROL 2023

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Chronic pain causes Tau-mediated hippocampal pathology and memory deficits

Cited by 15 publications

References 40 publications

Hippocampus diffusivity abnormalities in classical trigeminal neuralgia

Hippocampus diffusivity abnormalities in classical trigeminal neuralgia

Tau Accumulation in the Spinal Cord Contributes to Chronic Inflammatory Pain by Upregulation of IL-1β and BDNF

Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function

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