Few scientists doubt that backed-up clearance of detritus from the brain correlates with accumulation of amyloid plaques and neurofibrillary tangles. But which comes first? Data presented at the 9th Kuopio Alzheimer Symposium suggests that, at least in some cases, the plumbing might be the problem. Per Kristian Eide, University of Oslo, Norway, reported that the cerebrospinal fluid does not drain properly in people who have normal-pressure hydrocephalus. Is there an AD connection, you may ask? In people with this brain condition, the incidence of dementia, and amyloid and tangle pathology, far exceeds that of the general population. Eide’s data support the idea that sluggish drainage of CSF may cause AD pathology.
- People with normal-pressure hydrocephalus have enlarged ventricles.
- Most also have a cognitive impairment.
- Molecules clear slowly from their brains, perhaps worsening Alzheimer's pathology.
A rare condition, idiopathic normal-pressure hydrocephalus typically manifests as a troika of symptoms, that is, a gradual loss of balance, bladder control, and cognition (Williams et al., 2016). It primarily affects older people, and about 6 percent of octogenarians are estimated to have the disorder (Jaraj et al., 2014; Iseki et al., 2022). Brain scans show that these people have enlarged ventricles filled with CSF.
On autopsy or biopsy, a small majority of people with NPH and dementia also have amyloid plaques and neurofibrillary tangles, the hallmarks of AD pathology (Cabral et al., 2011; Koivisto et al., 2016). In many cases, the tangles can be sparse, with little evidence of neurodegeneration, suggesting that there might be an opportunity to intervene early in their AD progression (Libard and Alafuzoff, 2019).
Indeed, some people who have a shunt surgically implanted in their brain to drain the CSF make remarkable recoveries and their cognition improves (Adams et al., 1965; McGirt et al., 2005; Liu et al., 2016). However, this is far from true for everyone. Researchers in Ville Leinonen’s lab at Kuopio University Hospital reported that four years after this procedure, 80 percent of people had cognitive decline and 46 percent had either Alzheimer's or vascular dementia (Koivisto et al., 2013).
What causes NPH? In some cases, called “noncommunicating NPH,” it can be a blockage that restricts CSF flow between the brain's ventricles. In “communicating NPH,” the obstruction occurs after CSF leaves the ventricles. In many cases the cause is unknown.
To study the flow of CSF in idiopathic NPH, Eide and colleagues tested the MRI contrast agent gadobutrol. This gadolinium compound is used in animals to image the glymphatic system, by which interstitial fluid moves through the brain and exchanges with the cerebrospinal fluid (Aug 2012 news; Mar 2013 news).
In Kuopio, Eide showed that when the tracer is injected into the spine of a healthy volunteer, it slowly spreads into the parenchyma of the brain (Ringstad et al., 2018). This distribution peaks up to a day later, Eide said (see image above). Because the resolution of MRI is only around 1 mm, it can't depict the exact path the tracer takes.
Even so, Eide showed that it flows beside arteries, without penetrating them. This is in keeping with the idea that fluid in the brain spreads by the paravascular glymph system, whereby CSF flows into the parenchyma along arteries, and drains out of it along veins (Aug 2012 news). In keeping with this, the strongest spread of gadobutrol into the parenchyma occurred around major arteries. Eide thinks that the pulsing of the arteries helps to gently push the fluid along.
Does this paravascular transport system change in iNPH? Geir Ringstad at Oslo University Hospital compared gadobutrol clearance among eight healthy controls and 15 people with iNPH (Ringstad et al., 2017). Ringstad found that, in iNPH, the tracer is slow to enter and exit the Sylvan fissure. This major sulcus separates the frontal and parietal lobes from the temporal lobe. It is a main point of entry for gadobutrol into the parenchyma from the CSF. What’s more, once the agent was in the parenchyma, it cleared more slowly than it did in healthy controls.
Following these findings, Eide and colleagues modeled how gadobutrol drains from the brain into the blood. First, some background. Scientists know that the meninges and dural membranes of mouse and human brains contain a set of lymph vessels that likely sieve interstitial fluid pushed through the brain by the glymph system (Aspelund et al., 2015; Louveau et al., 2015; Oct 2017 news). Eide and colleagues had found that gadobutrol squeezes from the interstitial fluid into the parasagittal dura at the top of a person's brain, which houses some of these lymph vessels (Ringstad and Eide, 2020). Eide believes that the parasagittal dura serves as a bridge between the CSF and the lymph, and ultimately, the blood.
Now for the blood modeling. Markus Herberg Hovd and colleagues in Eide’s lab injected gadobutrol into the CSF of 161 volunteers, then measured it in blood samples taken at intervals for up to 48 hours (Hovd et al., 2022). Of these people, 28 were healthy controls, 63 had iNPH, and 70 had another form of hydrocephalus or CSF disorder. At the Kuopio conference, Eide showed how Hovd used the blood data to model the pharmacokinetics of brain clearance, arriving at a formula that closely matched the empirical data.
He then plugged blood sample data for each volunteer into the formula to determine clearance pharmacodynamics of each volunteer (see graphs below), including how long it took half of the tracer to clear the CSF, time to maximum concentration in the blood (Tmax), the peak concentration in blood (Cmax), and the lag time before the tracer appeared in the blood (Tlag).
The first thing Hovd noticed was that the model indicated that the volunteers, even the controls, were markedly different from one another on all those parameters. “This considerable variability really surprised us,” said Eide. Still, differences emerged between the groups. For example, in 11 people who had communicating hydrocephalus, the Cmax was about 30 percent lower than in controls. In 13 people who had a pineal cyst, Tlag was more than twice as long. That said, people with iNPH had the most dramatic changes. Both their Tlag and Tmax were longer than in the reference group, meaning the tracer hung around longer in their brains. Ultimately, gadobutrol reached higher concentrations in the blood of people with iNPH, but Eide thinks this happened because their kidneys were affected, too, and cleared the tracer more slowly.
It remains to be seen whether this abnormal CSF drainage in iNPH contributes to AD pathology, as has been shown in animal models. Next, Eide plans to measure gadobutrol clearance in people with mild cognitive impairment.—Tom Fagan.
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