Cortical Biopsy Predicts Response to Shunting in Normal Pressure Hydrocephalus

Daniel M. Keller, PhD

May 17, 2010

May 17, 2010 (Philadelphia, Pennsylvania) — The presence of certain biomarkers may help neurosurgeons distinguish which patients with normal pressure hydrocephalus (NPH) will benefit from shunting the cerebral ventricles from those who will not.

NPH is characterized by a triad of gait disturbance, cognitive deficits, and bladder incontinence. The cerebral ventricles are distended but cerebrospinal fluid (CSF) pressure is normal. A common treatment is the placement of a ventriculoperitoneal shunt to reduce even the normal pressure. However, about 30% of patients are not helped by shunting.

Researchers led by Sebastian Koga, MD, senior neurosurgery resident at the University of Virginia in Charlottesville, propose that NPH is a tau protein disorder that is along the same spectrum as Alzheimer's disease (AD). Dr. Koga said at least 15 genetic mutations are responsible for tau protein abnormalities. In its hyperphosphorylated state, the tau protein self-assembles into intracellular neurofibrillary tangles that are neurotoxic and cause mechanical damage to the brain.

The hypothesis of this prospective, longitudinal study was that cerebral protein assays could predict which patients would respond to CSF diversion by placement of a shunt. Dr. Koga described 51 patients (average age, 76.6 years) here at the American Association of Neurological Surgeons 2010 Annual Meeting.

Advanced Disease

He and colleagues at the University of Virginia performed a cortical biopsy, tracked patients' clinical course, assayed for biomarkers in the CSF, and genotyped for the APOEε4 allele, which has been implicated in the development of some cases of AD.

AD changes begin in the hippocampus and move superiorly. Similarly, NPH changes seen in the biopsy tissue, taken from the middle frontal gyrus, would indicate advanced disease. Clinical follow-up was an average of 26 months.

By measuring changes in patients' gait, incontinence, and memory (as assessed by AD score), the researchers classified outcomes as better, the same, or worse.

An AD score of less than 2 relates to partial or complete resolution of symptoms or no change; a score of 3 indicates transient improvement followed by decline; and a score greater than 4 indicates moderate to severe clinical decline.

"The ones who actually improved after shunting amounted to only 47%," Dr. Koga reported. Twenty-one percent remained the same, "but 30% of them continued to decline and were significantly worse at every point along the 26-month course," he said (P < .001; 2% lost to follow-up).

The cortical biopsy findings predicted clinical decline and which patients would respond or not to shunting. The patients whose status declined all demonstrated a significantly higher AD score and numbers of neuritic plaques and neurofibrillary tangles and immune staining for tau protein.

Dr. Koga said that β-amyloid plaques have been more predictive than tau protein staining. The researchers are now analyzing biomarkers in CSF as a less invasive approach to stratifying candidates for shunting.

Table. Outcomes After Shunting

Clinical Course AD Score (Range, 0 – 6) Neuritic Plaque Score (Range, 0 – 3)
Better 1.82 1.00
Same 2.20 1.33
Worse 4.57* 2.23*

AD = Alzheimer's disease; * P < .001.

"The perioperative complication rate [at 90 days] was...10%, which is fairly high for an elective procedure whose value is unknown," Dr. Koga said. Complications consisted of shunt occlusion, need for revision, infection, and subdural hematoma. Therefore, less invasive methods to predict good surgical candidates are critical.

Several "tauproteinopathies" are associated with mutations in a locus on chromosome 17, among them AD, frontotemporal dementia, Picks' disease, progressive supranuclear palsy, and now, possibly, NPH. Dr. Koga said future work aims to create protein profiles of the various forms of senile dementia to reveal their causes and to better characterize them, rather than depending on variable or vague clinical symptoms.

Looking ahead, Dr. Koga envisioned that shunting could prove useful in AD or Parkinson's disease, as well as other conditions associated with abnormal tau proteins.

Accumulation of Tau Protein

Gary Steinberg, MD, PhD, professor of neurosurgery and the neurosciences at Stanford University School of Medicine in California, said that despite neurosurgeons and neurologists having studied NPH for several years, the development of tests to predict benefit from surgery has not been very good.

He added that for a study like Dr. Koga's, it is important how the diagnosis is made. He noted that "normal pressure hydrocephalus is simply based on some clinical symptoms and a [magnetic resonance] scan or [computed tomogram] showing the size of the ventricles." He explained that some of the patients could have ventriculomegaly from atrophy related to AD, in which the ventricles may appear enlarged when really the rest of the brain has shrunk.

However, he emphasized that tau proteins are important in terms of various degenerative diseases and even in traumatic brain injuries as mild as concussions.

"What's surfacing from autopsies of certain athletes involved in high-impact sports, boxers, and now even some football players is that there is accumulation of tau, which has detrimental effects," he said. "tau may be an epiphenomenon rather than a causative may be just occurring in conjunction with a disease that has another pathophysiology."

Dr. Koga and Dr. Steinberg have disclosed no relevant financial relationships.

American Association of Neurological Surgeons (AANS) 2010 Annual Meeting: Abstract 703. Presented May 4, 2010.


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