Abstract
Brain degeneration, including that caused by traumatic brain injury (TBI) often leads to severe bladder dysfunction, including incontinence and lower urinary tract symptoms; with the causes remaining unknown. Male C57BL/6J mice underwent repetitive moderate brain injury (rmdTBI) or sham injury, then mice received either cis P-tau monoclonal antibody (cis mAb), which prevents brain degeneration in TBI mice, or control (IgG). Void spot assays revealed age-dependent incontinence in IgG controls 8 months after injury, while cis mAb treated or sham mice showed no dysfunction. No obvious bladder pathology occurred in any group. Urodynamic cystometry in conscious mice revealed overactive bladder, reduced maximal voiding pressures and incontinence in IgG control, but not sham or cis mAb treated mice. Hyperphosphorylated tau deposition and neural tangle-like pathology occurred in cortical and hippocampal regions only of IgG control mice accompanied with post-traumatic neuroinflammation and was not seen in midbrain and hindbrain regions associated with bladder filling and voiding reflex arcs. In this model of brain degeneration bladder dysfunction results from rostral, and not hindbrain damage, indicating that rostral brain inputs are required for normal bladder functioning. Detailed analysis of the functioning of neural circuits controlling bladder function in TBI should lead to insights into how brain degeneration leads to bladder dysfunction, as well as novel strategies to treat these disorders.
Highlights
Overactive bladder, incontinence and other bladder symptoms often occur in patients with neurodegenerative disease or brain injury, and can lead to significant debility, striking loss of self-esteem, depression, and the need for long term institutionalization[1,2,3,4]
Histology on brain slices reveals robust tau hyper phosphorylation a long with post-traumatic neuroinflammation in the cortex but not in the mid and hindbrain regions where the periaqueductal gray (PAG) and Pontine Micturition Center (PMC) are found. These results indicate that Traumatic brain injury (TBI) and possibly other forms of brain degeneration disrupt normal bladder function likely by altering profoundly the normal neural traffic to PMC and PAG bladder control centers, and not by direct damage to the control centers themselves
Experimental treatment setup (Red arrows, repetitive moderate brain injury (rmdTBI), Black arrows, antibody/IgG injection; green lines, bladder histopathology). (b) Bladder sections of sham, rmdTBI + IgG, and rmdTBI + cis P-tau monoclonal antibody (cis mAb) mice were subjected to hematoxylin & eosin staining at 8 months after injury
Summary
Overactive bladder, incontinence and other bladder symptoms often occur in patients with neurodegenerative disease or brain injury, and can lead to significant debility, striking loss of self-esteem, depression, and the need for long term institutionalization[1,2,3,4]. Traumatic brain injury (TBI) represents a leading cause of death and disability among people under the age of 45 in the United States[12]. In many respects CTE resulting from TBI resembles other forms of degenerative brain injury, including Alzheimer’s disease[15,16], Lewy Body Dementia[17], and Parkinson’s disease[18,19]. Our previous report showed similar tau pathologies in diffuse axons in brain sections from 8 athletes, and 8 athletes plus military service, who were diagnosed post-mortem with CTE, along with 8 age-matched normal controls[25,26]. A pathological signature of CTE brains is neurofibrillary tangles made of hyperphosphorylated tau with an indistinguishable pattern[12,13,27]. Cis P-tau can be effectively eliminated by cis pT231-tau monoclonal antibody (cis pT231-tau mAb, or cis mAb), which is strikingly potent in treating the molecular, neurologic and behavior defects of mice suffering various types of TBI26,40,41
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