Fight Aging!

Neurodegenerative conditions are characterized by increasing amounts of molecular waste in the brain, such as amyloid-β, α-synuclein, tau, and a few others. In the case of Alzheimer's disease, evidence suggests that the condition starts because the drainage of cerebrospinal fluid (CSF) out of the brain through the cribriform plate declines with age. The plate becomes ossified and less porous as the inflammatory, altered biochemistry of aging changes cell behavior for the worse. This loss of drainage allows many varied forms of molecular waste to build up to harmful levels in at least some parts of the brain.

The cribriform plate isn't the only path by which CSF drains from the brain, but it is the one that drains the area of the brain, the olfactory bulb, where Alzheimer's pathology and amyloid-β aggregation first develops. The biotech startup Leucadia Theraputics was founded to develop assays and therapies based on this view of the origin of Alzheimer's disease. The staff there have demonstrated - in ferrets rather than mice, because mice don't normally exhibit any of the biochemistry of Alzheimer's disease - that artificially blocking drainage through the cribriform plate causes an accelerated buildup of molecular waste and cognitive impairment.

Today's open access materials, from another team, provide good supporting evidence for the CSF drainage view of Alzheimer's disease. The researchers show that the ossification of the cribriform plate with age in mice clearly reduces CSF drainage. We'd expect to see much the same in other mammalian species. Given a model like this, it would be interesting to see whether or not cognitive decline in normal aged mice correlates in any way with CSF flow through the cribriform plate. Given the lack of naturally occurring Alzheimer's mechanisms in mice, and the presence of other drainage pathways that are less impacted by age, that could go either way.

Cerebrospinal fluid drainage kinetics across the cribriform plate are reduced with aging

Continuous circulation and drainage of cerebrospinal fluid (CSF) are essential for the elimination of CSF-borne metabolic products and neuronal function. While multiple CSF drainage pathways have been identified, the significance of each to normal drainage and whether there are differential changes at CSF outflow regions in the aging brain are unclear.

Here, dynamic in vivo imaging of near infrared fluorescently-labeled albumin was used to simultaneously visualize the flow of CSF at outflow regions on the dorsal side (transcranial and -spinal) of the central nervous system. This was followed by kinetic analysis, which included the elimination rate constants for these regions. In addition, tracer distribution in ex vivo tissues were assessed, including the nasal/cribriform region, dorsal and ventral surfaces of the brain, spinal cord, cranial dura, skull base, optic and trigeminal nerves and cervical lymph nodes.

Based on the in vivo data, there was evidence of CSF elimination, as determined by the rate of clearance, from the nasal route across the cribriform plate and spinal subarachnoid space, but not from the dorsal dural regions. Using ex vivo tissue samples, the presence of tracer was confirmed in the cribriform area and olfactory regions, around pial blood vessels, spinal subarachnoid space, spinal cord and cervical lymph nodes, but not for the dorsal dura, skull base, or the other cranial nerves. Also, ex vivo tissues showed retention of tracer along brain fissures and regions associated with cisterns on the brain surfaces, but not in the brain parenchyma. Aging reduced CSF elimination across the cribriform plate but not that from the spinal SAS nor retention on the brain surfaces.

Collectively, these data show that the main CSF outflow sites were the nasal region across the cribriform plate and from the spinal regions in mice. In young adult mice, the contribution of the nasal and cribriform route to outflow was much higher than from the spinal regions. In older mice, the contribution of the nasal route to CSF outflow was reduced significantly but not for the spinal routes. This kinetic approach may have significance in determining early changes in CSF drainage in neurological disorder, age-related cognitive decline, and brain diseases.