Decreased Cerebrospinal Fluid Flow is Associated with Cognitive Decline

Many neurodegenerative conditions are associated with the accumulation of forms of metabolic waste in the central nervous system, protein aggregates that form solid deposits between or within cells. Tauopathies such as frontotemporal dementia are associated with tau aggregates, synucleinopathies such as Parkinson's disease with α-synuclein, and amyloidoses with varying forms of amyloid, such as the amyloid-β found in elevated amounts in Alzheimer's disease patients. Alzheimer's itself is an amyloidosis that also becomes a tauopathy in its later stages. These protein aggregates and their surrounding halos of harmful biochemistry disrupt normal brain function and, in the worse cases, kill neurons. Eventually they kill the patient.

With the exception of certain inherited conditions, in which cellular biochemistry is broken due to an unfortunate and unlucky mutation, why is it that protein aggregates form in significant amounts only in older individuals? This seems an important question to keep in mind when working towards therapies for neurodegenerative conditions. In Alzheimer's disease, amyloid-β builds up for a decade or more prior to the point at which its consequences become noticeable. But why? In recent years researchers have found ever more supporting evidence for the hypothesis that impaired drainage of cerebrospinal fluid is an important factor. Metabolic wastes in the brain can be carried away for disposal via the various pathways for drainage of cerebrospinal fluid. These pathways falter or become occluded with age, however, and the degree to which that happens in any given individual may well be an important determinant of risk of dementia.

Several groups are working on approaches to the treatment and prevention of neurodegenerative conditions based on the impaired drainage hypothesis. Some of these lines of work have left the laboratories and entered commercial development. To pick two examples, Leucadia Therapeutics is quite far along towards means of restoring cerebrospinal fluid drainage through the cribriform plate, while EnClear Therapies is working on filtration of harmful metabolic waste from cerebrospinal fluid in a process akin to apheresis of blood. We can hope that these first efforts will be joined by others in the years ahead, and also hope that means of rejuvenation that target the underlying molecular damage of aging will prove to at least partially reverse loss of drainage of cerebrospinal fluid.

Decreased Cerebrospinal Fluid Flow Is Associated With Cognitive Deficit in Elderly Patients

The cerebrospinal fluid (CSF) is an important part of the central nervous system, as it allows exchange of water, small molecules, and proteins between the brain parenchyma and arterial and venous blood, by either passive diffusion or active transport. The CSF therefore plays an important role in regulating brain homeostasis, waste clearance, as well as intracranial pressure and blood supply. During aging, CSF turnover can be disrupted which could contribute to the etiology of age-related neurocognitive disorders. Several studies revealed that patients with Alzheimer's disease (AD) have disrupted CSF pressure, turnover, and oscillations. Moreover, biomarkers for AD are found in the CSF, and their abundance was shown to have predictive value for clinical progression.

The increase of intracranial pressure during the cardiac cycle causes a flow from the blood and brain interstitial fluid to the CSF, and a net CSF flow toward its extracerebral compartment and venous blood. Since this CSF flow is important for protein clearance from the brain, it is possible that impaired CSF flow could be associated with cognitive decline. Moreover, CSF flow is linked with brain perfusion, defects of which are known causes of neurocognitive disorders in the elderly. A number of studies suggested that the choroid plexus and the ventricular walls degenerate with the progression of AD, but none could determine whether disrupted CSF flow causes cognitive decline, or whether it is a by-product of AD or normal aging.

To the authors' knowledge, there are no published studies that investigated the relationship between CSF flow alterations and cognitive deficit in the elderly, adjusting for cardiovascular risk factors for the development of neurocognitive disorders. The purpose of this study was therefore to evaluate the association of CSF flow in the brain ventricles and cervical spine with cognitive deficit in a cohort of elderly patients admitted to our geriatric unit for non-acute reasons. The hypothesis was that reduced CSF flow would be associated with cognitive deficit.

The cohort comprised 71 women and 21 men, aged 73 to 96 years. Patients with lower CSF flow had significantly worse memory, visuo-constructive capacities, and verbal fluency. It is therefore possible that CSF flow alterations are responsible for at least a part of the cognitive deficit observed in our patients. Better diagnosis and treatment of CSF flow alterations in geriatric patients suffering from neurocognitive disorders is therefore recommended.

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