Depressive Symptoms and Cognitive Improvement in Patients with Dementia with Lewy Bodies

Abstract

Background:

Although dementia with Lewy bodies (DLB) is a degenerative disease involving irreversible pathological changes and subsequent progressive cognitive decline, some patients have presented with improved cognitive function at follow-ups. Their clinical and neuropsychological characteristics and the factors influencing this improvement remain unclear.

Objective:

To investigate differences in clinical and neuropsychological characteristics between DLB patients with and without cognitive improvement at a one-year follow-up, and to identify predictive factors of cognitive improvement.

Methods:

This retrospective study included 60 DLB patients, 28 patients in the improved group, and 32 patients in the non-improved group. A multiple linear regression model was used to compare changes in cognitive function test scores between groups over the course of one year. Binary logistic regression analysis was performed to determine the odds ratios (ORs) of depressive symptoms as a predictor for cognitive improvement.

Results:

The improved group showed significant increases in immediate and delayed verbal memory function in one year over the non-improved group. We also found that baseline depressive symptoms were associated with an increased probability of cognitive improvement (OR 1.234, CI 1.043– 1.460).

Conclusion:

Depressive symptoms at baseline were related to a higher probability of a cognitive improvement at one-year follow-up. In addition, immediate and delayed verbal memory function showed significant improvement during one year in improved patients compared to non-improved patients.

Keywords

Cognitive improvement dementia with Lewy bodies depressive symptoms

INTRODUCTION

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia with a prevalence of 7.5% in the clinical population [1]. DLB is characterized as dementia accompanied by cognitive fluctuation, visual hallucinations, parkinsonism, and rapid eye movement sleep behavior disorder (RBD) [2, 3]. As supportive clinical features, neuropsychiatric symptoms including depression, apathy, anxiety, and delusion are commonly present [2, 3].

Although DLB is a degenerative disease involving irreversible pathologic change and subsequent progressive cognitive decline, patients with improved cognitive function at follow-ups are also observed in clinical settings. This cognitive improvement has been described in several studies before; however, it was not investigated as the focus of interest, and cognitive function was evaluated with only a Mini-Mental State Examination (MMSE) score, representing global cognitive status without information about concrete cognitive domains [4, 5].

Numerous factors may contribute to this cognitive improvement, considering that the clinical characteristics of DLB can include cognitive fluctuation, deficits in attention, and depressive symptoms [6]. Those with depressive symptoms might temporarily perform poorly in cognitive tests, performances which might be rescued if depressive symptoms were resolved [7]. Research regarding cognitive improvement, its causes or influential factors, or patterns of cognitive dysfunction in specified cognitive domains, however, is scarce. In this study we evaluated the differences in the clinical and neuropsychological characteristics between DLB patients with improved cognitive function and those with unchanged or declined cognitive function at one-year follow-up and whether there is predictive factor for cognitive improvement, especially among cognitive fluctuation, depressive symptoms, and attention deficit. We focused on cognitive fluctuation as a core symptom of DLB, depressive symptoms as a neuropsychiatric symptom of DLB, and attention deficit as a commonly affected cognitive domain in patients with DLB [2, 8].

MATERIALS AND METHODS

Population

A retrospective, longitudinal, and observational study was conducted at the Seoul National University Bundang Hospital in the Republic of Korea. We included patients with a diagnosis of probable DLB according to McKeith’s criteria at initial assessment from January 2009 to December 2017 [2] who also received a one-year follow-up including a neuropsychological assessment. Neurologist in the memory clinic evaluated clinical DLB features, demographics, disease history, and current medications for each patient. Cognitive fluctuation was measured with the Mayo Fluctuation Questionnaire [9]. Parkinsonism was assessed by the presence or absence of bradykinesia, gait difficulty, rest tremor, and rigidity, and isoflupane single-photon emission computed tomography (¹²³I-FP-CIT SPECT) was conducted to confirm parkinsonism. Sleep behavior suggestive of RBD was evaluated and confirmed with polysomnography (PSG) in part. Patients with a history of bipolar disorder, psychotic disorder, or other neurodegenerative disease were excluded.

This study design was approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-1812-510-106).

Table 1

Demographics by group

	All (n = 60)	Improved (n = 28)	Non-improved (n = 32)	p ^*
Age, y	77.6±6.6	77.3±7.1	77.7±6.2	0.824
Female	34 (56.7)	16 (57.1)	18 (56.3)	0.944
Education, y	9 (6, 12)	6 (6, 12)	9.5 (6, 16)	0.101
Follow-up duration, days	364 (354, 386)	363 (353, 380)	366 (357, 397)	0.371
Cognitive fluctuation	33 (55.0)	14 (50.0)	19 (59.4)	0.466
Visual hallucination	39 (65.0)	17 (60.7)	22 (68.8)	0.515
RBD	39 (65.0)	19 (67.9)	20 (62.5)	0.664
Parkinsonism
Bradykinesia	34 (56.7)	18 (64.3)	16 (47.1)	0.265
Tremor	16 (26.7)	7 (25.0)	9 (28.1)	0.785
Rigidity	15 (25.0)	8 (28.6)	7 (21.9)	0.550
Medication
Antiparkinson	21 (35.0)	9 (32.1)	12 (37.5)	0.664
Antidepressant	38 (63.3)	18 (64.3)	20 (62.5)	0.886
Anticholinesterase inhibitor	59 (98.3)	28 (100.0)	31 (96.9)	0.346

Data are presented as number (%), mean±standard deviation, or median (interquartile range). RBD, rapid eye movement sleep behavior disorder. ^*Comparison between improved and non-improved.

Data collection

Data collected included age, sex, years of education, medical history, neurological examination, neuropsychological assessment results (at baseline and one-year follow-up), ¹²³I-FP-CIT SPECT results, PSG results, and medications that were prescribed at the initial assessment such as antiparkinson medication, antidepressants, and anticholinesterase inhibitors.

Cognitive assessment

We evaluated the global cognitive status with the MMSE [10], dementia severity with Clinical Dementia Rating (CDR) scale [11], and depressive symptoms with the short form of the Geriatric Depression Scale (GDpS) [12]. Additionally, extensive neuropsychological assessments were performed to measure attention, language, verbal and visual memory, visuoconstructive function, and frontal executive function. We used the Digit Span Test for attention [13], the Korean version of the Boston Naming Test for language [14], the Seoul Verbal Learning Test for verbal memory [15], the Rey Complex Figure Test (RCFT) for visuoconstructive function and visual memory [16], the categorical and phonemic fluency test of the Controlled Oral Word Association Test [17], and the Stroop color reading test for executive function [18]. For statistical analysis, scores for the MMSE, CDR, and GDpS were used as raw scores. The scores for specified neuropsychological tests were converted to standardized scores (z-scores), which were adjusted for age, sex, and educational level.

We categorized patients into improved and non-improved groups. We considered DLB to be a neurodegenerative disease with progressive cognitive decline, and thus assumed that patients with DLB would show equal or poorer MMSE scores at follow-ups if undergoing a stable disease progression course. Patients who showed unchanged or declined MMSE scores at one-year follow-up were assigned to the non-improved group, whereas those who with an improved MMSE score at one-year follow-up were placed in the improved group.

Statistical analysis

To compare demographics, cognitive assessment results at baseline and changes in cognitive assessment scores between groups, the Pearson chi-squared test for categorical variables, the Mann-Whitney U test for non-normally distributed continuous variables, and Student’s t-test for normally distributed continuous variables were performed. Multiple linear regression analysis adjusted for age, sex, and education level was conducted to evaluate differences in cognitive changes between groups.

To examine the predictive factors of cognitive improvement, we included depressive symptoms, which showed a significant difference between groups in the baseline comparison, whereas the factors of cognitive fluctuation and attention deficit revealed no significant differences between the groups. We evaluated whether depressive symptoms could predict cognitive improvement using univariable and multivariable logistic regression analysis, and all variables were chosen in a single step. Statistical significance was set at≤0.05. We used IBM SPSS version 25 (IBM, Armonk, NY, USA) for the analyses.

RESULTS

Demographics of study population

A total of 60 patients were included in this study. The mean age of patients was 77.6 years, and 34 (56.7%) were female. The improved group contained 28 patients, and the non-improved group contained 32 patients. Demographic data according to group are shown in Table 1. No significant differences in measured characteristics, including demographic information, follow-up duration, DLB features, and medication use were observed between groups. PSG was performed in 11 of the 39 patients reporting RBD symptoms, including six from the improved group and five from the non-improved group, and RBD was confirmed in all 11 of them. ¹²³I-FP-CIT SPECT was performed in 30 patients among 41 patients reporting parkinsonism, including 16 from the improved group and 14 from the non-improved group, and abnormal findings were shown in 23 of these 30 patients with 11 from the improved group and 12 from the non-improved group. No significant differences in abnormal findings on PSG or ¹²³I-FP-CIT SPECT between groups were observed (data not shown).

Cognitive assessment at baseline

Neuropsychological test results at baseline according to groups are shown in Table 2. The improved group had significantly more severe depressive symptoms than the non-improved group. The improved group also demonstrated lower MMSE values, higher CDR scores, and poorer performance on SVLT immediate recall and delayed recall tests, all of which were statistically significant. In other tests, with the exception of the Korean Boston Naming Test, RCFT copy, RCFT delayed recall, categorical fluency, and Stroop color test, the improved group showed poorer scores than the non-improved group; however, these differences were not statistically significant.

Table 2

Neuropsychological test scores at baseline by group

	All (n = 60)	Improved (n = 28)	Non-improved (n = 32)	p ^*
MMSE	18.7±4.3	16.5±3.6	20.6±4.0	0.000
CDR	1 (0.5, 1)	0.5 (0.5, 1)	1 (0.5, 1)	0.014
Geriatric Depression Scale	8.6±3.8	10.1±3.3	7.3±3.9	0.006
Digit Span Forward Test	– 0.64 (– 1.02,0.20)	– 0.85 (– 1.13,– 0.17)	– 0.0 (– 0.88,0.36)	0.079
Digit Span Backward Test	– 1.0 (– 1.27,– 0.32)	– 1.04 (– 1.26,– 0.32)	– 1.0 (– 1.31,– 0.32)	0.794
Korean Boston Naming Test	– 1.32 (– 1.46,– 0.61)	– 1.16 (– 1.46,– 0.41)	– 1.35 (– 1.46,– 0.74)	0.414
SVLT Immediate recall	– 1.34 (– 1.43,– 1.17)	– 1.39 (– 1.44,– 1.32)	– 1.31 (– 1.41,– 1.14)	0.045
SVLT Delayed recall	– 1.41 (– 1.45,– 1.32)	– 1.41 (– 1.45,– 1.39)	– 1.37 (– 1.43,– 1.23)	0.020
SVLT Recognition	– 1.34 (– 1.45,– 0.75)	– 1.40 (– 1.46,– 1.15)	– 1.15 (– 1.44,– 0.46)	0.060
RCFT Copy	– 1.45 (– 1.46,– 1.32)	– 1.44 (– 1.46,– 1.34)	– 1.46 (– 1.46,– 1.23)	0.960
RCFT Delayed recall	– 1.37 (– 1.43,– 1.09)	– 1.36 (– 1.43,– 1.09)	– 1.37 (– 1.43, – 1.14)	0.917
RCFT Recognition	– 1.30 (– 1.45,– 0.97)	– 1.33 (– 1.45,– 0.38)	– 1.30 (– 1.45,– 1.16)	0.627
Categorical fluency	– 1.27 (– 1.42,– 0.89)	– 1.42 (– 1.46,– 1.06)	– 1.43 (– 1.46,– 1.10)	0.372
Phonemic fluency	– 1.13 (– 1.41,– 0.58)	– 1.14 (– 1.41,– 0.64)	– 1.04 (– 1.39,– 0.60)	0.672
Stroop Colors Test	– 1.43 (– 1.46,– 1.08)	– 1.42 (– 1.46,– 1.06)	– 1.43 (– 1.46,– 1.10)	0.795

Data are presented as mean±standard deviation, or median (interquartile range). Raw scores were used for MMSE, CDR, and Geriatric Depression Scale, and z-scores were used for the rest of the neuropsychological tests. MMSE, Mini-Mental State Examination; CDR, clinical dementia rating scale; SVLT, Seoul Verbal Learning Test; RCFT, Rey Complex Figure Test. ^*Comparison between improved and non-improved.

Change in cognitive function after one year

Changes in the neuropsychological test scores after one year are presented in Table 3. In all tests, the improved group showed improvement at the one-year follow-up. In particular, scores in SVLT immediate recall, SVLT delayed recall, RCFT copy and CDR improved significantly compared to those from the non-improved group. Depressive symptoms, as represented by GDpS score, were also reduced in the improved group, although this change was not statistically significant.

Table 3

Changes in scores in cognitive assessment after one year by group

Change in	Improved (n = 28)	Non-improved (n = 32)	p
MMSE	4.11±2.84	– 3.03±4.03	0.000
CDR	– 0.214±0.46	0.339±0.45	0.000
Geriatric Depression Scale	– 2.26±3.13	– 1.07±4.72	0.276
Digit Span Forward Test	0.180±0.573	– 0.207±0.960	0.122
Digit Span Backward Test	0.333±0.706	– 0.001±0.770	0.162
Korean Boston Naming Test	0.085±0.723	– 0.017±0.622	0.598
SVLT Immediate recall	0.267±0.446	– 0.032±0.375	0.017
SVLT Delayed recall	0.228±0.409	– 0.049±0.277	0.010
SVLT Recognition	0.363±0.715	– 0.003±0.799	0.104
RCFT Copy	0.129±0.409	– 0.122±0.308	0.021
RCFT Delayed recall	0.025±0.414	– 0.076±0.183	0.355
RCFT Recognition	0.023±0.966	0.052±0.513	0.913
Categorical fluency	– 0.029±0.580	– 0.088±0.515	0.731
Phonemic fluency	0.237±0.655	– 0.105±0.590	0.095
Stroop Colors Test	0.168±0.492	– 0.079±0.431	0.112

Data are presented as mean±standard deviation. Raw scores were used for MMSE, CDR, and Geriatric Depression Scale, and z-scores were used for the rest of the neuropsychological tests. MMSE, Mini-Mental State Examination; CDR, clinical dementia rating scale; SVLT, Seoul Verbal Learning Test; RCFT, Rey Complex Figure Test.

In a multiple linear regression analysis adjusted for age, gender, and education level, a significant improvement in scores for SVLT immediate recall, SVLT delayed recall, and CDR were observed in the improved group compared to the non-improved group (Table 4).

Predictor of cognitive instability

GDpS at baseline was assessed as a predictor of cognitive instability using logistic regression analysis. In univariable analysis, a higher GDpS score at baseline was associated with an increased risk for cognitive instability at the one-year follow-up with an odds ratio (OR) of 1.238 (95% confidence interval [CI], 1.049– 1.460). In a multivariable analysis adjusted for age, gender, and education level, the OR of GDpS at baseline was 1.234 (CI 95% 1.043– 1.460) with statistical significance, representing a predictive value of GDpS for cognitive instability (Table 5).

DISCUSSION

This study found that DLB patients with higher GDpS scores at baseline might predict improvement in cognitive test performance at a one-year follow-up. Immediate and delayed verbal memory function was significantly improved at one-year follow-up in the improved group over the non-improved group.

Several studies have evaluated longitudinal cognitive changes in patients with DLB. Depending on the study design, patients with DLB showed an annual decline on MMSE scores of 2– 4 points [4, 5]. In these studies, cognitive improvement was also described. In a large, retrospective multicenter study including 835 patients with DLB, 18% of them had higher MMSE scores at a two-year follow-up over their baseline values [4]. In a five-year follow-up prospective cohort study, MMSE score fluctuation was also depicted [5]. However, to our knowledge, no study has focused on the cause of this cognitive improvement in patients with DLB. Considering the clinical characteristics of DLB, attentional fluctuation was assumed to be a possible cause of inconsistent cognitive function test results [6, 19].

Table 4

Change in cognitive function after one year according to group with the multiple linear regression model. The dependent variable was the change in each cognitive assessment score. The independent variables were group (improved versus non-improved), age, gender, and education level. β values (standard error, SE) of the dependent variable are presented by group

Change in	β (SE)	p
CDR	– 0.308 (0.116)	0.010
Geriatric Depression Scale	1.156 (1.158)	0.145
Digit Span Forward Test	– 0.322 (0.267)	0.236
Digit Span Backward Test	– 0.374 (0.242)	0.132
Korean Boston Naming Test	– 0.136 (0.211)	0.523
SVLT Immediate recall	– 0.352 (0.134)	0.012
SVLT Delayed recall	– 0.244 (0.105)	0.025
SVLT Recognition	– 0.343 (0.247)	0.173
RCFT Copy	– 0.200 (0.115)	0.091
RCFT Delayed recall	– 0.125 (0.121)	0.312
RCFT Recognition	– 0.083 (0.273)	0.762
Categorical fluency	– 0.215 (0.183)	0.248
Phonemic fluency	– 0.237 (0.230)	0.310
Stroop Colors Test	– 0.339 (0.167)	0.051

Raw scores were used for CDR and Geriatric Depression Scale, and z-scores were used for the rest of the neuropsychological tests. CDR, clinical dementia rating scale; SVLT, Seoul Verbal Learning Test; RCFT, Rey Complex Figure Test.

Table 5

Depressive symptoms at baseline as a predictor of cognitive instability at one-year follow-up using logistic regression analysis

Univariable	Odds ratio (95% CI)	p
Geriatric Depression Scale at baseline	1.238 (1.049– 1.460)	0.011
Multivariable
Age	0.985 (0.900– 1.078)	0.742
Gender (female)	0.567 (0.149– 2.156)	0.405
Education	0.900 (0.787– 1.030)	0.126
Geriatric Depression Scale at baseline	1.234 (1.043– 1.460)	0.014

CI, confidence interval.

Depressive symptoms are frequently reported by patients with DLB and included as supportive clinical features among diagnostic criteria [2, 3]. Cognitive decline has been associated with a worsening of depressive symptoms in patients with dementia [20, 21]. Our finding that DLB patients with higher GDpS scores at baseline showed cognitive improvement at follow-up might indicate that depressive symptoms themselves could lead to test result differences, and suggests that a reduction in depressive symptoms might lead to improvement in cognitive function. Although GDpS score increases in the improved group were not significantly different from those in the non-improved group in our study, this topic is worthy of further investigation with a larger sample and longer follow-up period.

Another finding was that performance in SVLT immediate and delayed recall showed significant improvement during follow-up in the improved group compared to the non-improved group. Verbal memory function is relatively preserved in patients with DLB compared with patients with Alzheimer’s disease [22 –24]. Our results could be interpreted that verbal memory function is not impaired by irreversible pathological change and could be amenable to change depending on psychological status and attention at the time of tests. It could also be that our sample might include patients with different types of Lewy body pathology. A longitudinal clinical-pathological study demonstrated that affected cognitive domains vary among Lewy body pathological types, and can be nigral predominant, limbic-type, or neocortical-type [25]. Neocortical-type Lewy body pathology is associated with more variability in cognitive performance longitudinally compared to nigral or limbic-type pathologies. From this perspective, differences in cognitive change between the improved and non-improved groups in our study might be influenced by different pathological types.

Some limitations in our study should be noted. Most important, our sample size was small, and only one follow-up time point was analyzed. Because our study included a longitudinal extensive neuropsychological assessment while other studies have focused on MMSE scores at follow-ups, however, we believe these results to be of clinical significance moving forward.

In conclusion, this study demonstrated that in DLB patients, increased depressive symptoms were associated with a higher probability of cognitive improvement at one-year follow-up. In addition, a significant improvement in immediate and delayed verbal memory function was also observed after one year in the improved group compared to the non-improved group.

Footnotes

ACKNOWLEDGMENTS

This research received no external funding.

Authors’ disclosures available online ().

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