Yet More Evidence for Impaired Drainage of Cerebrospinal Fluid in Aging

Leucadia Therapeutics is one of the young companies shepherded by the Methuselah Fund, in this case working on an Alzheimer's treatment predicated on a theory of the disease that views impaired drainage of cerebrospinal fluid as an important cause. Alzheimer's disease is a condition characterized by a build up of protein aggregates, and one of the ways in which the brain normally removes these aggregates is through drainage of cerebrospinal fluid out into the body. The passages for that drainage, like most other bodily systems, fail over time. An increasing amount of supporting evidence for this to contribute to age-related disease has emerged in recent years.

In the example here, researchers arrive at the consideration of failing cerebrospinal fluid drainage from a quite different position, the study of hydrocephalus, or excess accumulation of cerebrospinal fluid in the brain. This is not uncommon in older individuals, and there is a noted overlap with Alzheimer's disease - it is not hard to join the dots between these two areas of research. Evidence for one tends to support the other, and the various research groups exploring the physiology of drainage in the brain may well wind up converging on the same destination.

Syndromes of progressive neurological disturbances in the setting of normal cerebrospinal fluid (CSF) pressure have been termed as "normal pressure hydrocephalus" (NPH). Patients without known precipitating factors are diagnosed with idiopathic NPH (iNPH), the mechanism of which remains largely unknown. However, the steep increase in the incidence of iNPH in individuals who are 60 years of age or older suggests an association with aging. Some recent studies have emphasized on the primary role of abnormal water/blood drainage or viscoelasticity changes in the brain parenchyma as the likely mechanisms underlying age-related development of the disease.

Nevertheless, since the initial reports, the immediate improvement in symptoms following removal of CSF through a lumbar tap has not only been useful for clinical purposes, but has also suggested abnormal perfusion as the direct cause of clinical manifestations. Despite the body of evidence demonstrating changes in blood flow following the "tap test" (TT), there are no established diagnostic criteria based on blood flow imaging. It is critical that iNPH be diagnosed sufficiently early to enable CSF diversion using a shunt where appropriate to prevent irreversible damage. Thus, there is a need for novel, non-invasive techniques to assess this condition in the elderly population.

Recently, mapping the low-frequency phase in a blood oxygenation level-dependent (BOLD) signal time-series has been proposed as a clinically useful biomarker in cerebrovascular diseases. In the present study, we acquired resting-state BOLD magnetic resonance imaging (MRI) scans before and after a spinal TT, and compared the BOLD lag maps to evaluate the effect of treatment on brain perfusion in subjects with iNPH.

We observed an abnormal phase in the periventricular region where the deep veins converge. Under healthy conditions, the phase or relative drainage time in this region consistently exhibited a late venous phase. This abnormally long drainage or "wash-out" time in iNPH was normalized by TT, while the global mean of the phase remained stable. Collectively, these results permit an interpretation that a part of the deep venous system is drained by collaterals in iNPH instead of the normal route via the internal cerebral veins. The broad change after TT may reflect the normalization of this state, involving a change in the drainage pattern. Altered venous drainage has been observed in chronic NPH and the periventricular area may be one of the commonly affected sites of this venous inefficiency.

The fact that both normal aging and abnormalities in iNPH (which is corrected by TT) involve deep venous insufficiency may have etiological implications, as this suggests altered venous drainage in the absence of pathological ventricular dilation. Accordingly, for example, a causal relationship between hydrocephalus and periventricular edema may be questioned. It can also imply an initiating role of venous congestion in brain compliance reduction which develops during both pathological and aging processes. Although the concept of venous inefficiency as the cause of hydrocephalus is not new, it has not been linked to aging. Although the role of CSF in the mechanism cannot be inferred from the present data, it is interesting that affected areas encompass regions related to CSF turnover.



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