A second dimension of somatosensory system injury? Thalamic volume loss and neuropathic pain in adults with cerebral palsy and periventricular white matter injury.

Objectives: Lemniscal (motor-related) and spinothalamic (neuropathic pain-related) somatosensory abnormalities affect different subsets of adults with cerebral palsy (CP). Lemniscal/motor abnormalities are associated with posterior thalamic radiation white matter disruption in individuals with CP and white matter injury. We tested the hypothesis that neuropathic pain symptoms in this population are rather associated with injury of the somatosensory (posterior group nuclei) thalamus. Methods: In this cross-sectional study, communicative adults with CP and bilateral white matter injury and neurotypical control participants volunteered to self-report pain symptoms and undergo research MRI. Posterior group thalamic nuclei volume was computed and correlated against neuropathic pain scores. Results: Participants with CP (n=6) had, on average, 24% smaller posterior group thalamic volumes (95% CI [10-39%]; corrected p=0.01) than control participants. More severe volume loss was correlated with more severe neuropathic pain scores (ρ=-0.87 [-0.99,-0.20]; p=0.02). Discussion: Association with thalamic volume loss suggests that neuropathic pain in adults with CP may frequently be central neuropathic pain. Complementing assessments of white matter microstructure, regional brain volumes hold promise as diagnostic biomarkers for central neuropathic pain in individuals with structural brain disorders.

Conserved age-related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline of social associative memories.

In humans, associative memories are more susceptible to age-related cognitive decline (ARCD) than are recognition memories. Reduced cAMP/cGMP signaling in the hippocampus may contribute to ARCD. Here, we found that both aging and traumatic brain injury-associated dementia increased the expression of the cAMP/cGMP-degrading enzyme phosphodiesterase 11A (PDE11A) in the human hippocampus. Further, age-related increases in hippocampal PDE11A4 mRNA and protein were conserved in mice, as was the increased vulnerability of associative versus recognition memories to ARCD. Interestingly, mouse PDE11A4 protein in the aged ventral hippocampus (VHIPP) ectopically accumulated in the membrane fraction and filamentous structures we term "ghost axons." These age-related increases in expression were driven by reduced exoribonuclease-mediated degradation of PDE11A mRNA and increased PDE11A4-pS117/pS124, the latter of which also drove the punctate accumulation of PDE11A4. In contrast, PDE11A4-pS162 caused dispersal. Importantly, preventing age-related increases in PDE11 expression via genetic deletion protected mice from ARCD of short-term and remote long-term associative memory (aLTM) in the social transmission of food preference assay, albeit at the expense of recent aLTM. Further, mimicking age-related overexpression of PDE11A4 in CA1 of old KO mice caused aging-like impairments in CREB function and remote social-but not non-social-LTMs. RNA sequencing and phosphoproteomic analyses of VHIPP identified cGMP-PKG-as opposed to cAMP-PKA-as well as circadian entrainment, glutamatergic/cholinergic synapses, calcium signaling, oxytocin, and retrograde endocannabinoid signaling as mechanisms by which PDE11A deletion protects against ARCD. Together, these data suggest that PDE11A4 proteinopathies acutely impair signaling in the aged brain and contribute to ARCD of social memories.

Cerebral palsy and the placenta: A review of the maternal-placental-fetal origins of cerebral palsy.

Accumulating evidence from clinical and neuropathological study has identified a number of seemingly disparate associations carrying a predisposition for cerebral palsy (CP). We narratively reviewed clinical studies reporting associations between prenatal and perinatal environmental factors and the risk of developing CP. As expected, some processes with direct central nervous system involvement (e.g. perinatal hypoxic-ischemic encephalopathy or infectious encephalomalacia) carry >10% absolute risk of CP. Other acute perinatal processes including placental abruption, uterine rupture, and neonatal sepsis are also associated with increased risk of CP but carry <3% absolute risk of CP. Indirect markers of chronic placental insufficiency such as fetal and placental growth patterns are associated with increased risk of CP, and risk of CP in infants with growth abnormalities born extremely preterm exceeds 10%. We synthesize these findings within a framework of risk accumulating across several defined pre- and perinatal developmental windows. Causal links remain incompletely understood, but genetic background, the intrauterine environment, general fetal health, and fetal neurologic health all appear to contribute.

Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions.

BACKGROUND: Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound-particularly for interleukin 6 (IL-6)-possibly due to differences in sex, species/strain, and/or the brain regions studied. METHODS: As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate. RESULTS: In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1ß in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1ß. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments. CONCLUSIONS: Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.

Alterations in cyclic nucleotide signaling are implicated in healthy aging and age-related pathologies of the brain.

It is not only important to consider how hormones may change with age, but also how downstream signaling pathways that couple to hormone receptors may change. Among these hormone-coupled signaling pathways are the 3',5'-cyclic guanosine monophosphate (cGMP) and 3',5'-cyclic adenosine monophosphate (cAMP) intracellular second messenger cascades. Here, we test the hypothesis that dysfunction of cAMP and/or cGMP synthesis, execution, and/or degradation occurs in the brain during healthy and pathological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Although most studies report lower cyclic nucleotide signaling in the aged brain, with further reductions noted in the context of age-related diseases, there are select examples where cAMP signaling may be elevated in select tissues. Thus, therapeutics would need to target cAMP/cGMP in a tissue-specific manner if efficacy for select symptoms is to be achieved without worsening others.