Used largely as a last-ditch option for taming unruly motor symptoms in some Parkinson disease patients, deep brain stimulation (DBS) might hold potential for treating dementia as well. As reported in this month’s Archives of Neurology, a Parkinson disease dementia (PDD) patient has responded well to a new DBS approach involving stimulation of both the tried-and-true subthalamic nucleus as well as the nucleus basalis of Meynert (NBM).

The NBM is a group of basal forebrain neurons with abundant cortical projections, and this acetylcholine-rich region is known to degenerate in both Alzheimer disease and PDD. Given the role of the NBM in both dementias, and the fact that many PDD patients present with coexisting AD pathology, deep brain stimulation targeting the NBM —i.e., boosting its residual output—appeared a reasonable strategy for relieving the cognitive symptoms of PDD. First author Hans-Joachim Freund of the International Neuroscience Institute, Hannover, Germany, and colleagues got the chance to test this hunch in a patient with slow-progressing PD whose motor symptoms had become unresponsive to dopaminergic drugs and who had begun to decline cognitively as well.

The case study may have come at an opportune time. As a PD therapy, deep brain stimulation showed its mettle earlier this year, relieving motor symptoms more effectively than did top-notch non-invasive treatments in a randomized trial of 355 PD patients (Deuschl et al., 2009 and ARF related news story; see also commentary, Okun and Foote, 2009). DBS has traditionally targeted the subthalamic nucleus (STN), and in fewer cases the globus pallidus, brain areas that receive heavy dopaminergic input. However, “the dual procedure of stimulating the STN and NBM is as best we know a unique approach,” wrote co-author Jens Kuhn, University of Cologne, Germany, in an e-mail to ARF.

Led by senior investigator Volker Sturm, also at the University of Cologne, the researchers evaluated the 71-year-old PD patient with neuropsychological tests one week before implanting DBS electrodes and again after treatment in four phases: 1) STN only, 2) combined STN and NBM, 3) STN only, and 4) combined STN and NBM. Before surgery, the patient “seemed helpless and absent-minded,” the authors wrote, noting lack of attention, impaired judgment, reduced spontaneous speech, and memory deficits, among other symptoms. After the first treatment phase (STN only), he improved in tests measuring motor skills and processing speed but showed no gains in memory performance. Additional stimulation of the NBM, however, brought marked cognitive improvement, especially on the Auditory Verbal Learning Test. When the researchers turned off NBM stimulation, the patient’s performance worsened on all neuropsychological measures, nearly dropping to pre-surgery levels and remaining there for almost three months of STN-only stimulation. Upon restart of NBM stimulation, the man’s cognitive function improved noticeably within 24 hours and returned to the levels attained after the second treatment phase (STN and NBM).

To this day, more than 18 months after his electrodes were implanted in January 2008, the researchers have seen no change in the patient’s cognitive functioning, Kuhn wrote in an e-mail to the Alzforum. “This is particularly astounding, as the preoperative course was characterized by a rapid deterioration of cognitive function,” he wrote. “The reasonably stable state since the operation indicates that this rapid decline has come to a halt.” More details will come in a future publication, Kuhn noted. He said his research center has initiated a pilot study to evaluate the safety and efficacy of stereotactic NBM stimulation (without STN) in AD patients.—Esther Landhuis

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  1. While the results in this patient, who was treated by a reputable DBS team, are interesting, I would caution the public not to make too much of this one case. First, it is widely known that performing standard STN DBS surgery on PD patients with even early dementia can severely worsen their cognitive condition. One would expect that inserting four DBS electrodes (rather than the standard two) through the frontal lobes will increase that risk further and that such complications will arise if more of these procedures are performed. Second, the NBM is a thin ribbon of tissue and the electrical field created with the stimulation parameters employed extended well beyond this area. Moreover, the authors provided neither microelectrode recording data nor a post-operative MRI to prove that the electrodes were within the NBM. Third, between weeks 25 and 29, as shown in Figure 2, there is a downward trend in all of their cognitive measures. Finally, I would view with great skepticism any claims that stimulation is neuroprotective, especially based on results in one patient. A neuroprotective role for DBS has been proposed in the past but has never been proven.

    View all comments by Ron Alterman

References

News Citations

  1. PD Studies Highlight Deep Brain Stimulation, New Role for α-Synuclein

Paper Citations

  1. . Neurostimulation for Parkinson disease. JAMA. 2009 Jan 7;301(1):104-5. PubMed.
  2. . Enough is enough: moving on to deep brain stimulation in patients with fluctuating Parkinson disease. Arch Neurol. 2009 Jun;66(6):778-80. PubMed.

Further Reading

Primary Papers

  1. . Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol. 2009 Jun;66(6):781-5. PubMed.