Amyloid-Beta Imaging in Normal Pressure Hydrocephalus

People with normal pressure hydrocephalus (NPH) have different combinations of gait difficulty, urinary problems and cognitive impairment, though gait difficulty invariably is a prominent feature. This deficit combination is disabling, and untreated people may have to be managed in a long-term care facility.

Shunt surgery may alleviate symptoms, particularly the gait deficit. But even at reputable medical centers, the risk of complications ranges from 15 to 30 percent or more, which makes both doctors and patients cautious about surgery.

Many centers commonly use temporary cerebrospinal fluid (CSF) removal, with either a large-volume spinal tap or external CSF drainage, or both, as a way to help predict surgical outcomes.

The average age for shunt surgery is about 75 years, and 40 percent of cognitively normal people this age have significant amyloid-beta (Aβ) deposition, either in pathological studies or as demonstrated by Aβ PET scans. Consequently, a brain biopsy at the time of shunt surgery will frequently demonstrate Alzheimer's disease pathology.

CSF studies measuring Aβ42, total tau (t-tau) and phospho tau (p-tau) are strongly associated with Alzheimer's disease diagnosis and Aβ PET results. In idiopathic NPH, a pattern has emerged that patients often have low CSF Aβ42, but normal t-tau and p-tau. This pattern may also be found in Lewy body dementia.

But as this finding is not specific, the CSF alone cannot be used to indicate an underlying Alzheimer's disease pathogenesis. However, none of these studies has simultaneously completed Aβ brain PET scans and measured CSF biomarkers.

This could be very important, as Roy Hamilton, M.D., of the University of Pennsylvania and colleagues — using brain biopsy at the time of the shunt — have shown that moderate Alzheimer's disease pathology indicates a poor surgical outcome.

Dr. Graff-Radford's laboratory hypothesizes that people with an abnormal Aβ brain PET scan or a low CSF Aβ42 plus high t-tau or p-tau, or both, will not improve cognitively with shunt surgery. However, gait may improve, as the lab suspects that many people at the average age of shunt surgery (75 years) may have both Alzheimer's disease and NPH.

In this pilot study, the lab is using Aβ PET, CSF Aβ42, and t-tau or p-tau to prospectively evaluate — in a blinded fashion — people committed to shunt surgery and then determine the relationship of these biomarkers to outcomes related to gait, cognition and urinary control improvement in the short term (three months) and long term (one year).

  • Primary specific aim. Evaluate the relationship of Aβ PET, CSF Aβ42, and t-tau or p-tau measures to NPH shunt prognosis on gait change (measured on a video-documented Tinetti scale), cognitive change (measured using the Repeatable Battery for the Assessment of Neuropsychological Status), and urinary control (measured using the Urogenital Distress Inventory-6).
  • Secondary specific aim. Evaluate the relationship of Aβ PET, CSF Aβ42, and t-tau or p-tau measures to NPH shunt prognosis on memory (measured using the California Verbal Learning Test), naming (measured using the Boston Naming Test), and executive function (measured using the Trail Making Test parts A and B, Stroop Test, and semantic and phonemic fluency).