Neuropsychological Test Performances And Depression in Early-Stage De Novo Parkinson’s Disease

Abstract

Objective: Evaluate neuropsychological test performance in depressed patients with early-stage Parkinson's disease.

The relationship between early Parkinson's disease and memory is a topic of great interest. Studies have shown that although people with Parkinson's disease may face challenges in movement and mobility, they can still have excellent memories. In addition, people with Parkinson's disease may become better memorizers because they use more brain areas to remember.

Some studies have also shown that the impact of Parkinson's disease on memory is not direct, but many other factors affect it. For example, common accompanying symptoms such as depression, anxiety, and sleep problems may affect patients' cognitive function, especially in memory and attention.

Although Parkinson's disease may bring certain challenges, we must not forget that it is just a part of our lives. Many patients can get more satisfaction and fulfillment in their lives by actively coping with the disease, taking medication, exercising and rehabilitation methods, and maintaining a positive attitude towards life.

Therefore, although the impact of Parkinson's disease on life is inevitable, we should always maintain a positive attitude and live with hope. By working with doctors, professional therapists, and patient support organizations, we can help patients overcome these challenges and have a healthier and happier life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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Method: Data from 422 participants from the Parkinson's Progression Marker Initiative were examined. The Geriatric Depression Scale-15 was used to categorize depressed and non-depressed participants. 

Neuropsychological tests measured verbal learning/memory, processing speed, visuospatial ability, verbal fluency, and working memory. Demographic and clinical variables were compared using independent samples t-tests and chi-square analyses.

Linear regression models were fit to adjust for age, years of education, and symptom duration.

Results: The non-depressed group (n = 280) was significantly older; t(246.08) = 2.25, p = .026 and had higher education; t(420) = 2.35, p = .019; and longer duration of PD symptoms; t(170.58) = −2.13, p = .035 than the depressed group (n = 142). 

The non-depressed group performed better on a working memory task than the depressed group, t(420) = 2.05, p = .041, but the results did not appear to be of clinical significance. There was no significant difference between other cognitive domains. The results were not influenced by age, education, or disease duration.

Conclusions: Among patients with early-stage, untreated Parkinson's disease, depression does not appear to affect neuropsychological test performance. Clinicians should demonstrate caution in over-interpreting the influence of depression on cognition in this population.

Keywords: Neurocognitive disorders; Depression; Parkinson's disease; Neuropsychology; Cognitive dysfunction; Early diagnosis.

Introduction

According to the Parkinson's Disease Foundation, Parkinson's disease (PD) is one of the most common neurodegenerative disorders and it is estimated that approximately one million Americans are currently diagnosed with this disorder (Marras et al., 2018). 

PD is most commonly known as a movement disorder due to primarily motor symptoms such as tremors, slowed movement (bradykinesia), and impaired posture and balance. However, non-motor symptoms, such as cognitive decline, are also prevalent in PD. 

Previous research has established that up to 45% of participants with de novo PD meet the criteria for mild cognitive impairment (MCI) within 2–4 years of diagnosis (Wyman-Chick et al., 2017). 

Other non-motor symptoms, such as anxiety and depression, are also common in PD and affect about 40% of PD patients, even within the early stages of the disease (Weintraub et al., 2015).

Previous researchers have demonstrated that anxiety and depression are negatively associated with cognitive performance in patients with PD relative to healthy controls (Fonoff et al., 2015; Kuzis, Sabe, Tiberti, Leiguarda, & Starkstein, 1997; Lee et al., 2018; Lehrner et al., 2014; Ng, Chander, Tan, & Kandiah, 2015; Starkstein, Mayberg, Leiguarda, Preziosi, & Robinson, 1992; Troster et al., 1995; Weintraub et al., 2015). 

These findings have also been demonstrated when comparing depressed/anxious and non-depressed/anxious patients with PD (Ehgoetz Martens et al., 2016; Kuzis et al., 1997; Norman, Troster, Fields, & Brooks, 2002; Troster et al, 2015b), but there is inconsistency regarding the cognitive domains that are impacted by mood symptoms. 

For example, some studies comparing PD patients with and without depression have found that patients with PD and depression had more severe cognitive deficits in verbal fluency, auditory attention, and abstract reasoning (Kuzis et al., 1997), whereas other studies with similar methodology have found that PD patients with depression had stronger deficits in short-term memory, concept formation, and working memory (Uekermann et al., 2003). 

Also, an area of disagreement in this research is the directionality of the relationship between depression and cognitive decline in patients with PD. Petkus, Filoteo, Schiehser, Gomez, and Petzinger (2019) found that worse cognitive performance was associated with more severe depressive symptoms, but more severe depressive symptoms were not associated with worse cognitive performance. 

This finding suggests cognitive functioning may contribute to depressive symptoms. In summary, previous research has established that depression affects cognition in PD patients compared to healthy controls as well as in depressed vs. non-depressed PD patients with several years of disease duration (Fonoff et al., 2015; Kuzis et al., 1997; Norman et al., 2002; Troster et al., 1995b; Uekermann et al., 2003). 

It has also been established that depression (Weintraub et al., 2015) and cognitive impairment (Wyman-Chick, et al., 2017) are often present in the early stages of the disease. 

However, to our knowledge, there has not been any research comparing cognitive performances between depressed and non-depressed individuals with early-stage, untreated PD. 

The main goal of the current study is to evaluate the effect of depression on cognition in an early-stage, untreated PD group. 

Based upon previous research, it was hypothesized that patients with early-stage PD who experience clinically significant depressive symptomatology would demonstrate lower neuropsychological test performances than those without depression.

Methods

Participants

Archival data for the present study were obtained from the Parkinson Progression Marker Initiative (PPMI) database. Information about the aims of the PPMI study, collection sites, and methodology has previously been published (Marek et al., 2011) and is available on the PPMI website (http://www.ppmi-info.org/study-design). 

This study was approved by the institutional review board at the senior author's institution. Utilizing data from the PPMI, we examined data from 422 participants with untreated PD who had been diagnosed within the previous 2 years. 

Participants enrolled in PPMI were required to (1) have an asymmetric resting tremor or asymmetric bradykinesia with the presence of at least one other symptom of resting tremor, bradykinesia, or rigidity; (2) have a recent PD diagnosis; (3) be untreated with PD medications; (4) have a dopamine transporter deficit on imaging; and (5) not have dementia as determined by the site investigator.

Assessments

The PPMI study includes neuropsychological tests that are widely used in clinical practice and assess several domains including learning, memory, working memory, visuospatial ability, verbal fluency, and processing speed. 

The tests included in PPMI are discussed subsequently. The Hopkins Verbal Learning Test-Revised (HVLT-R) is a 12-item verbal memory task. Standard test administration includes three learning trials (immediate recall) and a 20- to 25-minute delay where participants are asked to recall the words previously learned (delayed recall; Brandt, 1991). 

Letter–number sequencing (LNS) is a test of attention and working memory, in which the participant is asked to listen to a series of numbers and letters of increasing lengths and repeat numbers and letters from the lowest in each series, providing numbers first, then the letters (Wechsler, 1997). 

Judgment of line orientation (JLO) is a test of visual perception where participants are asked to estimate the angle between two line segments (Benton et al., 1978), and PPMI participants completed only the odd-numbered items. 

For the verbal fluency task, participants were asked to name as many animals as they could within 60 s (Straus et al., 2006). 

Finally, the participants were administered the Symbol Digit Modalities Test (SDMT), which is a timed number–symbol transcription task in which participants are asked to match numbers to unique symbols as quickly as they can in 90 s (Smith, 1982).

The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III was used to measure motor symptoms for the participants in the study, and all participants were un-medicated at the time of administration. 

Lower scores on the MDS-UPDRS reflect fewer and/or less severe motor symptoms (Goetz et al., 2008). Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15) (Sheikh & Yesavage, 1986). 

Of the 15 items, 10 indicated the presence of depression when answered positively, whereas the rest (question numbers 1, 5, 7, 11, 13) indicated depression when answered negatively. 

Scores of 0–5 are considered normal; 6–8 indicate mild depression; 9–11 indicate moderate depression; and 12–15 indicate severe depression. For this study, a cutoff score of ≤5 was used to indicate the absence of clinical depression.

Statistical analyses

Demographic and clinical variables for the two groups were compared using independent samples t-tests and chi-square analyses. Neuropsychological test scores were compared between depressed and non-depressed groups using independent samples t-tests. Linear regression models were fit to adjust for age, years of education, and symptom duration. All analyses used an alpha level of p < 0.05 to determine significance.

Results

Based upon the GDS-15, 280 participants were categorized in the non-depressed group (M = 4.47, SD = 0.80) and 142 participants were included in the depressed group (M = 6.78, SD = 1.13), t(420) = −24.22, p < .001. 

The two groups differed significantly in terms of age, education, and duration of disease symptoms, but they did not differ significantly in the severity of motor symptoms. Overall, the non-depressed group was significantly older, had higher levels of education, and had a longer length of disease duration than the depressed group (see Table 1). 

Chi-square analyses revealed that the two groups did not differ in terms of gender (p = .964), handedness (p = .928), or side of onset of PD symptoms (p = .587). 

In terms of cognition, the groups did not differ significantly in their performances on the HVLT-R, JLO, SDMT, or category fluency tasks; however, the non-depressed group performed better on LNS than the depressed group, t(420) = 2.05, p = .041 (see Table 2). These results remained when we adjusted for age, years of education, and duration of symptoms. 

The binary logistic regression model performed to determine if test performance could predict whether the participants were in the depressed or the non-depressed group was not statistically significant, χ2 (7) = 6.671, p = .464.

Discussion

In this study, both the PD participants with depression and PD patients without depression demonstrated similar cognitive performances in learning/memory, visuospatial ability, processing speed, and verbal fluency. 

However, the participants with depression performed significantly worse on a working memory task than did participants without depression. Although the differences in working memory were significantly different between depressed and non-depressed groups, the difference in raw scores and standardized scores does not appear to be of clinical significance. 

There were significant differences in demographics between the two groups, as the non-depressed group was older and more educated and had a longer length of disease duration than the depressed group. 

However, these factors did not significantly affect the results of the cognitive performances between depressed and non-depressed de-novo PD participants and the differences did not appear to be of clinical significance. 

The groups did not differ in the severity of motor symptoms. Although previous researchers have demonstrated that PD patients with depression have worse cognitive performance when compared to non-depressed PD patients (Ehgoetz Martens et al., 2016; Fonoff et al., 2015; Kuzis et al., 1997; Norman, Troster, Fields, & Brooks, 2002; Troster et al., 1995b; Uekermann et al., 2003), these studies included participants in the later stages of the disease process who were treated with anti-parkinsonian medication(s), including levodopa. 

Levodopa has been found to have an impact on cognition, but the impact is variable and may depend on the stage of the disease (Poletti & Bonuccelli, 2013). This may also help to explain the reason there was no significant difference in cognitive scores among the early-stage, de novo PD groups. 

The current study had several strengths adding to the applicability of the results, such as the use of a large dataset and the use of cognitive assessments that are widely used in current clinical practice. 

A limitation of the current study is that the mean GDS-15 score for the non-depressed group was approximately 4, which was close to the depression cutoff score of ≤ 5, and it is possible that subclinical depressive symptoms may have been present in the non-depressed group, and had an influence on the results. In conclusion, this study provides evidence that depression largely does not influence cognition in early-stage de novo PD. Clinicians should be cautious in interpreting the impact of depressive symptomatology on cognition in this population.

Conflict of Interest

None declared.

Acknowledgments

Data used in the preparation of this article were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. 

PPMI-a public-private partnership-is funded by the Michael J. Fox Foundation (MJFF) for Parkinson's Research and funding partners, including AbbVie, Avid Radiopharmaceuticals, Biogen, Britsol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, and UCB. The MJFF was not involved in the data analysis for this article. 

A portion of the results from this manuscript will be presented as a poster at the National Academy of Neuropsychology in San Diego, CA, in November 2019.

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