The Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease (CAPSIT‐PD): Tolerability of Preoperative Neuropsychological Testing for Deep Brain Stimulation in Parkinson's Disease

Abstract

Objective

We examined tolerability of preoperative neuropsychological testing (the Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease [CAPSIT‐PD] protocol) for DBS. We also examined factors that may influence tolerability, including fatigue, global cognitive function, depression, and patient‐based characteristics.

Methods

In this retrospective study, we reviewed preoperative neuropsychological testing results from 35 patients who were scheduled to undergo DBS. We examined the overall tolerability of the full battery and the tolerability of each test. We placed attention on a test's placement in the fixed order of the battery to measure whether there was a clustering of poorly tolerated tests toward the end of the battery as an indication of fatigue. Spearman's rank correlation was used to determine the relationship between tolerability and (1) global cognitive function, (2) depression, and (3) patient‐based characteristics.

Results

Fourteen subjects (40%) were able to tolerate the full battery and completed all 10 tests. The domains that were least tolerated pertained to executive function and procedural memory. There was a consistent time‐based tolerability pattern that was observed. There was a significant correlation between tolerability and global cognitive function (ρ = 0.344; P = 0.043), but not depression (P = 0.197). There was a significant correlation between tolerability and age (ρ = −0.491; P = 0.003) and disease duration (ρ = −0.442; P = 0.008), but not UPDRS‐III scores (P = 0.284).

Conclusion

Our results have shown limited tolerability of the full neuropsychological battery as outlined by the CAPSIT‐PD protocol. We suggest the consideration of updating the neuropsychological assessment used in the CAPSIT‐PD protocol.

The Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease (CAPSIT‐PD) was published in 1999 with the goal of providing the minimal requirements for a common patient evaluation protocol for surgical interventions, including DBS, in Parkinson's disease (PD).1 As part of the cognitive and mood preoperative assessment for DBS candidacy, the CAPSIT‐PD committee recommended the following tests:

• General and mood evaluation: (1) Mattis Dementia Rating Scale (MDRS) and (2) Montgomery and Asberg Depression Rating Scale (MADRS)

• Executive function: (1) verbal fluency: letters F, A, and S (FAS); (2) Paced Auditory Serial Addition Test (PASAT); (3) Odd Man Out (OMO); and (4) Modified Brown Peterson Paradigm (MBPP)

• Explicit memory: (1) Rey Auditory and Verbal Learning Test (RAVLT) and (2) visual amnesic battery of Signoret

• Procedural memory: short version of Tower of Hanoi

Centers that perform DBS have adapted the CAPSIT‐PD protocol to fit the needs of their individual institutions.2 Factors, such as fatigability, baseline cognitive impairment, duration of testing, and disease duration, may influence neuropsychological performance,3 but have not fully been explored in the DBS population. We aimed to assess tolerability of the full CAPSIT‐PD protocol with minor substitutions of the originally outlined tests. We also examined factors that may influence tolerability, including fatigability, global cognitive function, and depression.

Methods

In this retrospective study, we reviewed preoperative neuropsychological testing results from 35 patients who were scheduled to undergo DBS. All PD subjects met the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria.4 The diagnosis of PD was confirmed by L.V.M., and after interview, medical history, physical examination, chart review, and off‐on evaluation (off being defined as 12 hours since their last dose of PD medication), they were deemed potentially appropriate DBS candidates. The second step in the evaluation was a neuropsychological evaluation, the core of which was defined by the CAPSIT‐PD protocol:

• General and mood evaluation: (1) MDRS and (2) MADRS

• Executive function: (1) verbal fluency: FAS; (2) PASAT; (3) OMO; (4) MBPP; (5) Symbol Digit Modalities Test (SDMT); and (6) Digit Ordering

• Explicit memory: RAVLT

• Procedural memory: Tower of London (TOL)

Tests were mainly derived from the CAPSIT‐PD protocol, but additional tests (the SDMT and Digit Ordering) were chosen for accessibility, previous use, and familiarity. The 10 tests were presented on a single visit in a fixed order during a clinically on state (after off‐on evaluation), typically in the early afternoon: (1) MADRS; (2) MDRS; (3) RAVLT; (4) MBPP; (5) OMO; (6) FAS; (7) Digit Ordering; (8) SDMT; (9) PASAT; and (10) TOL. The full battery was estimated to require 90 to 120 minutes for full completion. The on state was derived by supratherapeutic levodopa intake followed by resumption of the regular medication schedule. Subjects were permitted to take their medication during the interview if needed to maintain the best on state (Fig. 1).

Figure 1.

Tolerability pattern for neuropsychological battery based on fixed order of administration.

The tolerability analysis was based on all subjects who were presented with the 10 assessments. Failure to complete a given test was typically owing to confusion or frustration (as assessed by B.B.) and was counted as failed tolerability. We tabulated the overall tolerability of the full battery and the tolerability of each test. We placed attention on a test's placement in the fixed order of the battery to measure whether there was a clustering of poorly tolerated tests toward the end of the battery as an indication of fatigability.

Statistical Analysis

SPSS software (version 16.0; SPSS, Inc., Chicago, IL) was used for statistical analysis. To examine the effects of global cognitive function and depression on tolerability, subjects were ranked according to MDRS scores, MADRS scores, and total number of tests completed (tolerability). Spearman's rank correlation was used to determine the relationship between tolerability and (1) global cognitive function and (2) depression. Demographic and clinical data included age, disease duration, and motor subscore of the UPDRS (UPDRS‐III). We also assessed whether age, disease duration, and UPDRS‐III subscores contributed to tolerability.

Results

Thirty‐five PD subjects were evaluated using the protocol. At the time of evaluation, the average age of subjects was 63.5 ± 7.6, duration of disease was 10.8 ± 6.5 years, and UPDRS‐III score was 24.7 ± 12.4.

Fourteen subjects (40%) were able to tolerate the full battery and completed all 10 tests. For the general cognitive and behavioral assessments, all subjects were able to complete the MDRS and MADRS. For executive function assessment, all subjects completed Digit Ordering whereas 34 completed the FAS, SDMT, and OMO (97%). Twenty‐five subjects completed MBPP (74%), whereas only 16 completed the PASAT (46%). For explicit memory, all subjects were able to complete the RAVLT. For procedural memory, 21 subjects (40%) were able to complete the TOL task. The domains that were least tolerated pertained to executive function (MBPP and PASAT) and procedural memory (TOL).

Given the observation that tolerability was less than 90% for three tests, (MBPP, PASAT, and TOL), we examined whether order of testing played a role in tolerability. There was a consistent time‐based tolerability pattern that was observed for two of the three examinations (PASAT and TOL) (Figure 1).

There was a significant correlation between global cognitive function and tolerability (ρ = 0.344; P = 0.043) given that subjects with higher MDRS scores also had significantly better tolerability. Tolerability was negatively associated with age (ρ = −0.491; P = 0.003) and disease duration (ρ = −0.442; P = 0.008). There was no correlation with tolerability and UPDRS‐III scores (P = 0.284) or depression (P = 0.197).

Discussion

Our results indicate that all subjects were able to complete the general and mood evaluations (MDRS and MADRS) as outlined by CAPSIT‐PD. However, our results have shown limited tolerability of the full neuropsychological battery as outlined by the CAPSIT‐PD protocol given that less than half of the subjects could complete the full battery. The CAPSIT‐PD protocol recommended a single test (Tower of Hanoi) to assess procedural memory. We considered this test too difficult and time‐consuming and therefore chose the TOL as a shortened version. However, even with this choice, two thirds of subjects could not tolerate the testing. Goldman et al.5 evaluated the International Parkinson and Movement Disorder Society (MDS) Task Force criteria for PD with mild cognitive impairment6 and recommended that, within each cognitive domain to be assessed, two tests need to be administered to achieve accurate domain assessment. The original CAPSIT‐PD battery as well as ours did not meet this more recent two‐test recommendation. Whereas executive function was covered by multiple well‐tolerated tests and explicit memory was at least assessed by one well‐tolerated test, the poorly tolerated TOL test left us with a population of patients without information on preoperative procedural memory. With incomplete preoperative baseline data on a core cognitive domain, the evaluation and interpretation of cognitive changes postoperatively is compromised. Other shorter tests for procedural memory might be considered to replace TOL in further adaptations of the CAPSIT‐PD protocol.

We hypothesized that patient‐based characteristics could potentially explain aspects of tolerability and therefore examined the association of tolerability with age, disease duration, parkinsonism severity, global cognitive status, depression, and the timing of the tests as a measure of fatigability.

Our results show that increased age was associated with poor tolerability. It may be that older individuals are more susceptible to fatigue, but studies are conflicting.7, 8 On the other hand, our results show that increased disease duration is associated with decreased tolerability and this is supported by other studies. Distressing fatigue has been associated with longer disease duration in PD.8 Additionally, this decreased tolerability may be related to the cognitive burden of aging or evolving disease, but this remains to be explored.

We also found that that global cognitive function is related to tolerability. Subjects with higher baseline global cognitive function based on MDRS scores were better able to tolerate the neuropsychological battery. Thus, tolerability may be a good marker for global cognitive function. Reduced tolerability may be specifically related to domain‐specific impairment. A clear relationship between tolerability and executive testing is difficult to define, because, among the tests for executive dysfunction, two were poorly tolerated, whereas the others were completed by all or most subjects. It is well known that PD subjects have particular impairment in executive function tasks as part of their “frontostriatal” profile,9, 10 so we considered this domain particularly important to assess preoperatively It is less clear whether procedural memory impairment is related to basal ganglia dysfunction in PD,11 and our results are not able to make this determination because only one test (TOL) was included and poorly tolerated. Last, our results did not show a clear relationship between tolerability and parkinsonism severity or depression.

We postulated that tolerability would be, at least partly, explained by fatigability. Our findings confirm that the two least‐tolerated tests occurred at the very end of the examination. Fatigue is a well‐described nonmotor symptom in PD and has a significant impact on cognitive performance.3, 12 At our institution, preoperative neuropsychological testing is typically 90 to 120 minutes in duration, but at other institutions may last up to 180 minutes,2 potentially amplifying the effect of fatigue on tolerability. Fatigue may also be aggravated by the duration of the total preoperative assessment, which may, in addition to neuropsychological testing, also include off‐on testing on the same day. Though this clustering of testing may be efficient and convenient for the patient, it may also lead to increased fatigue and have an impact on tolerability. Furthermore, subjects obtaining DBS typically have motor fluctuations and their medication state during the neuropsychological evaluation may impact their performance and tolerability. Therefore, efforts should be made to perform testing in the best on state.

Ultimately, reduced tolerability results in a substantial amount of missing data preoperatively regarding subjects’ baseline neuropsychological profile. Because of this, domain‐specific impairment cannot be followed longitudinally in a reliable manner and the full impact of DBS on cognition may not be completely appreciated in those with reduced tolerability.

One limitation to our study is that the order of testing may affect the interpretation of our results. TOL is a challenging test that requires significant planning,13, 14 and PASAT15 has been shown to be difficult even for individuals with high intellectual capacity. Because of this, both of these tests are placed at the end of the examination at our institution to ensure maximal completion of the battery. In order to fully understand whether tolerability is related to fatigability or owing to order effect, tests need to be given in a random order. Another limitation to our study is that the magnitude of the correlations described are in the low‐to‐moderate range and need to be interpreted with caution and we have a relatively small sample size. Last, we did not explore the impact of anxiety on tolerability. Given that anxiety is a frequent nonmotor symptom in PD,6 the impact of anxiety on tolerability should also be explored in further studies.

In terms of practical recommendations, we suggest the consideration of updating the CAPSIT‐PD protocol by (1) selecting at least two tests per domain that can be readily completed by all subjects, (2) implementing procedures to reduce subject fatigue (giving subjects time to rest and shortening testing time into multiple sessions), and (3) providing testing in an order in which difficult tests alternate with easier tests to ensure maximal completion and coverage of all domains. Ultimately, improved tolerability of preoperative neuropsychological testing will allow clinicians to accurately describe the baseline neuropsychological profile of PD patients undergoing DBS so that the full long‐term cognitive impact of DBS can be more accurately assessed.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, Execution, Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

G.D.P.: 1A, 1B, 1C, 2A, 3A, 3B

V.P.: 1B, 1C, 2A, 3B

B.B.: 1C, 2A, 3B

B.O.: 2A

C.G.G.: 1A, 2A, 3B

L.V.M.: 2A, 3B

Disclosures

Funding Sources and Conflicts of Interest: The authors received funding from the Department of Neurological Sciences at Rush University. The authors report no conflicts of interest.

Financial Disclosures for previous 12 months: C.G.G. reports the following disclosures for consulting or Advisory Board Membership with honoraria: Acadia (Deborah Wood Associates), AstraZeneca, Avanir, Boston Scientific, Clearview, Health Advances, Chelsea Pharmaceuticals (Link Medical Communications), ICON Pricespective LLC, MED‐IQ Educational Services, Neurocrine, Pfizer, Teva, and WPP Group Kantor Health LLC. He reports grant/research funding from the National Institutes of Health (NIH) and the Michael J. Fox Foundation (MJFF). C.G.G. directs the Rush Parkinson's Disease Research Center that receives support from the Parkinson's Disease Foundation. He directs the translation program for the MDS‐UPDRS and UDysRS and receives funds from the MDS for this effort. He has received honoraria from the University of California, University of Luxembourg, University of Rochester, and World Parkinson Coalition. He receives royalties from Oxford University Press, Elsevier Publishers, and Wolters Kluwer Health–Lippincott, Wilkins and Wilkins. He receives salary from Rush University Medical Center. L.V.M. has received honorarium for teaching courses from Medtronic, Inc., Minneapolis, MN. He has also received fellowship funds from Medtronic and has a clinical trial agreement with Medtronic. He has a clinical trial agreement with US WorldMeds LLC and AbbVie through Quintiles, Avanir Pharmaceuticals, Inc./MJFF, St. Jude Medical, Inc, and the NIH (research grant no.: R01 NS40902).