Recall and Recognition Discriminability in Parkinson’s Disease and Huntington’s Disease

Abstract

Background:

Parkinson’s disease (PD) and Huntington’s disease (HD) are two neurodegenerative diseases affecting frontal-striatal function and memory ability. Studies using the original California Verbal Learning Test (CVLT) to examine recall and recognition abilities between these groups have produced mixed findings. Some found that individuals with HD demonstrate worse recall and recognition than those with PD, whereas others reported comparable performance.

Objective:

We utilized multiple indices of recall and recognition discriminability, provided by the second and third editions of the CVLT (CVLT-II and CVLT-3, respectively), that allow for a more thorough assessment of more nuanced aspects of verbal memory function.

Methods:

We examined differences between individuals with PD (n = 72) and those with HD (n = 77) on CVLT-II indices of recall discriminability (immediate, short delay free and cued, long delay free and cued) and recognition discriminability (total, source, semantic, and novel) using standardized scores while controlling for education and Dementia Rating Scale-2 scores.

Results:

The HD group performed significantly worse than the PD group on all measures of recall and recognition discriminability (ps < 0.05), and group differences were associated with large Cohen’s d effect sizes.

Conclusions:

Our findings suggest that individuals with HD are more impaired than individuals with PD in more nuanced aspects of recall and recognition memory function. These CVLT indices yield more thorough assessments of recall and recognition memory function and have the potential to improve efforts to characterize and distinguish profiles of memory loss in different neurodegenerative populations, including PD and HD.

Keywords

Parkinson’s disease Huntington’s disease California Verbal Learning Test verbal memory recall recognition discriminability

INTRODUCTION

Early memory tests used in clinical settings, which included a measure of yes/no recognition memory, only took into account the number of target items that were correctly endorsed. This scoring method is now known to be problematic because individuals with a “yes” response bias typically yield a high hit rate and also a high false positive rate, leading to a potentially inflated assessment of recognition memory ability. To deal with this issue, the original version of the California Verbal Learning Test (CVLT) [1], included a measured called recognition discriminability, which provided a single score that was based on the examinee’s ability to endorse target items and reject distractor items. In addition to recognition memory measures, the original CVLT also included various measures of recall, which were based on the total number of targets recalled. One potential problem with this scoring method is that this approach may lead to an inaccurate assessment of recall abilities because intrusions are not accounted for in this measure. As a result, the second and third editions of the CVLT (CVLT-II and CVLT-3, respectively) include measures of recall memory called recall discriminability. Much like measures of recognition discriminability, these recall discriminability measures provide a single score that takes into account targets recalled and intrusions. A paper published by Delis and colleagues [2], demonstrated that these recall discriminability measures were superior to traditional measures in distinguishing recall performance in individuals with Alzheimer’s disease (AD) and Huntington’s disease (HD). However, no studies to date have utilized these recall and recognition discriminability measures to explore more nuanced memory differences between HD and Parkinson’s disease (PD), two neurodegenerative diseases that primarily affect subcortical regions of the brain, but are associated with different pathologies.

Memory impairment has been well documented in patients with frontal-striatal dysfunction [3 –5], including individuals with PD [3, 5] or HD [4]. The pathological changes in PD are characterized by neuronal loss in the substantia nigra pars compacta and locus coeruleus [6]. In HD, the loss of neurons occurs in the caudate nuclei and other structures within the basal ganglia [7]. These neuronal alterations occur early in the course of the disease and worsen with disease progression.

Although variable, deficits in verbal episodic memory are often observed in both PD and HD [8 –11]. Relative to healthy controls, individuals with HD have been shown to demonstrate impaired performance across a majority of indices found on the CVLT, a well-validated measure of episodic memory [1]. Generally, individuals with HD exhibit poor recall, increased perseverations, and a greater than normal improvement on recognition memory compared to recall performance [12, 13]. Individuals with PD also show impaired performances on multiple CVLT indices compared to healthy adults. Typically, individuals with PD show poor recall, increased cued-recall intrusions, and poor recognition characterized by increased false positive errors [14, 15].

However, few studies have investigated differences in verbal memory loss between PD and HD. Studies comparing these two diseases are of importance given that both adversely affect frontal-striatal loop function, but are associated with different pathologies. Furthermore, the studies that have been conducted have produced mixed findings. Some have found that individuals with HD perform worse than individuals with PD on immediate recall [14], short delayed recall [14], and total recognition discriminability [16]. However, other studies have not found any group differences in immediate and delayed recall [17], or total recognition discriminability [14, 17]. Methodological differences may explain some of the discrepancies in these findings. Two of the three studies had a relatively small sample size (approximately 20 individuals per group) [14, 16]. One of the studies [16] did not control for age, sex, or dementia severity— all of which are factors that have been shown to influence verbal learning and memory test performances [18, 19]. Additionally, while two studies used the original CVLT [1] to assess verbal episodic memory, one [17] used the Hopkins Verbal Learning Test-Revised (HVLT-R) [20]. Relative to the HVLT, the CVLT provides additional indices that may be helpful in elucidating more nuanced distinctions in verbal memory function between populations of interest. Given PD and HD are both subcortical neurodegenerative diseases, but are different in the nature/extent of subcortical pathology, additional studies exploring corresponding differences between the two populations in more nuanced aspects of verbal memory function are warranted. Such studies would provide further insight into how the different pathologies associated with these two disease affect verbal memory abilities. In addition, prior studies comparing HD and PD on verbal memory tests have produced mixed findings, involved relatively small samples, and did not consistently control for important demographic and cognitive variables.

In the aforementioned studies, recall was measured by examining the number of correct target words recalled by the participant. As noted previously, this method for assessing recall ability does not take into account intrusion and may lead to a less accurate assessment of recall memory. Additionally, previous studies focusing on recognition discriminability have only analyzed differences in total recognition discriminability (the ability to distinguish targets from all distractors). However, The CVLT-II provides three additional subtypes of recognition discriminability (source, semantic, and novel), which are useful in that they allow for the assessment and characterization of more nuanced aspects of recognition memory function. Source recognition discriminability refers to the ability to distinguish targets from List B distractors. Semantic recognition discriminability refers to the ability to distinguish targets from distractors that are semantically related to targets (whether found on List B or novel). Finally, novel recognition discriminability refers to the ability to distinguish targets from novel distractors (i.e., those not presented on List B).

In sum, the recall and recognition discriminability measures that are available on more recent editions of the CVLT (CVLT-II and CVLT-3) may be used to examine differences between PD and HD in more nuanced aspects of recall and recognition memory function in an effort to better characterize and elucidate distinctions in the verbal memory loss that are associated with these two neurodegenerative disorders. Thus, the objective of the present study was to examine recall discriminability (immediate, short delay free and cued, long delay free and cued) and recognition discriminability (total, source, semantic, novel) differences between individuals with PD and those with HD using the CVLT-II.

MATERIALS AND METHODS

Participants

Research participants included individuals diagnosed with PD (n = 72) and individuals diagnosed with HD (n = 77). The Dementia Rating Scale-2 (DRS-2) [21] was administered to all participants to provide an assessment of global cognitive function. Demographic information, disease characteristics, and global cognitive functioning scores for the HD and PD groups are provided in Table 1. PD participants were recruited from a pool of research subjects followed by the laboratory of J. Vincent Filoteo, Ph.D at the University of California, San Diego (UCSD). Those with PD were administered the Unified Parkinson’s Disease Rating Scale by a neurologist and were diagnosed were diagnosed by a board-certified neurologist who specializes in movement disorders using UK Brain Bank criteria [22]. Exclusion criteria for the PD group included dementia diagnosis based on formal criteria [23], past treatment with deep brain stimulation, use of anticholinergic or neuroleptic medications, presence of other neurological conditions, significant medical illness, substance use disorders, or severe psychiatric illness or severe mental illness. For this study, PD participants completed neuropsychological testing while on their normal medication regimen. All participants were taking one or more dopaminergic medications.

Table 1

Mean (standard deviation) demographic data, disease characteristics, and DRS scores for Parkinson’s disease (PD) and Huntington’s disease (HD) groups

Variable	PD	HD
N	72	77
Age (Years)	69.60 (8.14)	51.22 (12.12)
Education (Years)	16.58 (2.05)	14.48 (2.34)
Gender (M/F)	50/22	34/43
DRS-2 Total	138 (5.15)	125.03 (14.98)
Levodopa Equivalent Dosage (mg/day)	707.96 (505.57)	–
UPDRS	20.52 (13.32)	–
UHDRS Total Motor Score	–	37.13 (17.15)
UHDRS Total Functional Capacity	–	7.16 (2.29)
CAG repeats		44.50 (3.56)

DRS-2, Mattis Dementia Rating Scale – Second Edition; UPDRS, Unified Parkinson’s Disease Rating Scale; UHDRS, Unified Huntington’s Disease Rating Scale.

Individuals with HD were recruited from the Huntington’s Disease Clinical Research Center (HDCRC) at UCSD. The HD group was administered the Unified Huntington’s Disease Rating Scale (UHDRS) [24] by a senior staff neurologist at the HDCRC. Individuals with HD were diagnosed with definite HD on the basis of unequivocal motor signs on the UHDRS and a positive family history of HD. Additionally, all HD participants had a CAG repeat length of greater than 39, indicating that they carried the fully penetrant genetic mutation for HD. Exclusion criteria for HD participants in the study included a history of other neurological disorders, a severe psychiatric illness or severe mental illness, or history of traumatic brain injury. All procedures were in compliance with guidelines on human experimentation, were approved by the Institutional Review Boards at San Diego State University and UCSD, and all participants provided signed consent.

CVLT-II administration

The CVLT-II [25] is a verbal learning and memory assessment composed of a list of words from different semantic categories. The CVLT-II provides a multitude of verbal learning and memory indices, including immediate recall, free and cued recall over short and long delays, and recognition memory. Short- and long-delay tests of recall were separated by an interval of approximately 20 minutes, during which other nonverbal neuropsychological measures were administered. Immediate, short delay free recall (SDFR), short delay cued recall (SDCR), long delay free recall (LDFR), and long delay cued recall (LDCR) were the primary recall discriminability measures of interest in this study. Additionally, total, source, semantic, and novel were the primary recognition discriminability measures of interest in this study. CVLT-II data were scored using CVLT-II software [26]. Standardized scores corrected for age and gender were used as the dependent variable in all analyses.

RESULTS

A Pearson χ² analysis revealed that our PD sample had a significantly higher percentage of men versus women than our HD sample, χ²(2, N = 149) = 9.68, p < 0.01. Separate one-way analysis of variance (ANOVA) tests revealed that our PD sample was significantly older F(1, 147) = 116.40, p < 0.001, completed more education F(1, 147) = 36.79, p < 0.001, and had higher DRS-2 scores F(1, 147) = 48.36, p < 0.001 than our HD sample. Group differences in demographic variables were accounted for in all analyses by using age and gender corrected standardized scores, and entering education into the model as a covariate. DRS-2 scores were also entered into the model as a covariate to account for differences in global cognitive functioning.

Analysis of covariance tests (ANCOVA) revealed individuals with HD performed significantly worse than individuals with PD on all recall and recognition discriminability measures, and group differences were associated with large Cohen’s d effect sizes (ps < 0.05; see Table 2). Adjustments for a false discovery rate (FDR) of 0.05 were applied in the analyses of age group differences on the CVLT-II indices [27]. Original p values are presented in Table 2, and all p values retained significance following the adjustments.

Table 2

Results from Analysis of Covariance Tests comparing those with Parkinson’s disease (PD) or Huntington’s disease (HD) on recall and recognition discriminability measures

			PD	HD
Discriminability	Subtype	F	M (SD)	M (SD)	p	d
	Immediate^*	6.37	–0.67 (1.31)	–1.78 (1.15)	0.013	0.903
	SDFR^*	8.29	–0.41 (1.29)	–1.62 (1.27)	0.005	0.945
Recall	SDCR^*	4.68	–0.42 (1.29)	–1.51 (1.38)	0.032	0.813
	LDFR^*	9.50	–0.38 (1.27)	–1.55 (1.21)	0.002	0.942
	LDCR^*	7.68	–0.35 (1.23)	–1.47 (1.18)	0.006	0.932
	Total^*	5.55	–0.53 (1.17)	–1.67 (1.29)	0.020	0.932
Recognition	Source^*	5.81	–0.35 (1.21)	–1.60 (1.44)	0.017	0.937
	Semantic^*	5.55	–0.52 (1.20)	–1.53 (1.21)	0.020	0.837
	Novel^*	4.79	–0.63 (1.23)	–1.77 (1.36)	0.030	0.883

SDFR, short delay free recall; SDCR, short delay cued recall; LDFR, long delay free recall; LDCR, long delay cued recall.

An exploratory analysis was conducted to examine the proportion of individuals with HD and PD who performed in the normal, mildly impaired, and impaired range based standardized LDFR scores, a core measure of memory ability. Those with a z-score of – 2.0 or lower were classified as impaired. Individuals in with z-scores between – 1.5 and – 2.0 were classified as mildly impaired, while those with a z-score higher than – 1.5 were classified as normal. In the PD group, 79.17% of participants were classified as normal compared to 45.46% in the HD group. 13.89% of the PD group were classified as mildly impaired compared to 25.98% in the HD group. Finally, 7% of participants in the PD were classified as impaired compared to 28.57% in the HD group. A Pearson χ² revealed significant differences between the number of PD and HD individuals in the three different classifications, χ² (2, N = 149) = 19.152, p < 0.001. We used the adjusted residuals method [28] to evaluate individual cell contributions to the χ² results. The findings indicated that the number of individuals classified as “normal” was significantly higher in the PD group and significantly lower in the HD group than would be expected by chance (adjusted residual = 4.2). In addition, the number of individuals classified as “impaired” was significantly lower in the PD group and significantly higher in the HD group (adjusted residual = 3.4) than would be expected by chance. However, there was no significant difference in the number of individuals classified as “mildly impaired” for both PD and HD groups.

DISCUSSION

The present study explored differences between individuals with PD and those with HD on recall and recognition discriminability measures included in the CVLT-II. Previous literature comparing PD and HD on recall and recognition abilities have found mixed results [14 , 17]. Furthermore, these studies did not utilize more thorough discriminability measures that account for intrusion and false positive errors. Such measures are important in that they provide improved assessments and characterizations of more nuanced aspects of recall and recognition memory function. The present study has attempted to elucidate discrepancies in existing findings regarding verbal memory function between PD and HD by utilizing more refined measures of recall and recognition discriminability, while controlling for important demographic variables and global cognitive function.

The present study found that individuals with HD performed significantly worse than those with PD on all subtypes of recall (immediate, SDFR, SDCR, LDFR, LDCR) and recognition (total, source, semantic, novel) discriminability. These findings suggest that even when controlling for demographic factors and global cognitive impairment (DRS scores), individuals with HD as a group have more severe episodic memory impairments than those with PD. These findings are largely similar to those found in Massman and colleagues [14], with the exception that the present study found evidence for worse total recognition discriminability in HD relative to PD, whereas no group difference on this measure was observed in the Massman et al. [14] study. This discrepancy may be related to slight differences between the nonparametric and parametric formulas that are used to calculate total recognition discriminability (TRD) on the CVLT-I compared to the CVLT-II and CVLT-III. The CVLT-II and CVLT-III use a parametric d’ formula to calculate recognition discriminability, as this formula better accounts for the unequal number of target and distractor items found on the CVLT yes/no recognition memory trial. The parametric d’ formula yields a contrast score that incorporates false positive errors as an inverse proportion [29; d’ = z(hits) – z(false positives)], rather than a percentage. Previous research has suggested that the impact of false positive errors on total recognition discriminability scores may be inadvertently reduced in the application of the parametric d’ formula in certain populations that are susceptible to high false positive rates [30]. Consequently, the magnitude of group differences on TRD may vary across applications of nonparametric and parametric formulas for TRD, although both formulas have been able to highlight group differences on this construct. In an exploratory analysis of hits and false positives, we found that individuals with HD had a significantly higher number of false positives than individuals with PD (p < 0.05), yet the two groups did not differ in number of hits. This exploratory finding begs the question of whether the observed difference in TRD scores between groups may be even larger when applying the nonparametric formula used on the original CVLT. Nonetheless, because a group difference was observed in the context of the parametric d’ formula and a larger sample in the present study, the findings offer strong evidence that recognition discriminability is indeed worse in HD than in PD.

In the present study, PD outperformed HD on all recall and recognition discriminability indices in light of the observation that the range of scores within each group was fairly similar across most of these indices. An exploratory examination of scores on long delay free recall (LDFR)— which is often considered a representation of core memory abilities— revealed that the proportion of individuals who were impaired on LDFR was significantly higher in the HD group than the PD group, although both groups consisted of individuals who fell in the range of normal, mildly impaired, and impaired memory function based on LDFR scores. Thus, the analysis of LDFR scores reaffirms the notion that the observed differences between PD and HD on recall and recognition discriminability scores is indeed attributable to there being a greater degree of memory dysfunction in HD relative to PD, rather than an absence of memory dysfunction in PD altogether.

A potential limitation to the present study is that the two groups were recruited and tested at two separate academic medical centers within San Diego, and completed two different batteries of neuropsychological tests. In addition, the samples in the present study are heterogeneous in their cognitive and disease severity. This heterogeneity may have contributed to the discrepancies in findings between this study and previous studies investigating recall and recognition memory between individuals with PD or HD [14 , 17]. Future studies should investigate recall and recognition differences between individuals with PD or HD as a function of their cognitive or disease stage. Furthermore, the PD group in the present study was comprised of solely non-demented individuals. Individuals in later stages of PD (PD-MCI, PDD) may exhibit more profound memory loss relative to non-demented individuals with PD. Future studies should investigate the extent and nature of recall and recognition discriminability decline in individuals in later stages of PD, including PD-MCI and/or PDD. However, the present findings, in addition to those of future studies that address the aims mentioned above, may assist in both improving characterizations of and distinctions between profiles of memory loss associated with PD and HD throughout their cognitive or disease stages, as well as in informing interventions focused on the successful implementation of tailored compensatory memory strategies in PD and HD.

In conclusion, the present findings suggest that individuals with HD are more impaired than individuals with PD in more nuanced aspects of both recall and recognition memory function, even when controlling for global cognitive functioning. These findings highlight the utility of more refined measures of recall and recognition discriminability in enhancing the characterizations of and distinctions between profiles of memory loss associated with the two subcortical neurodegenerative diseases that are associated with frontal-striatal dysfunction.

CONFLICT OF INTEREST

Dean C. Delis, Ph.D. is an author of the CVLT and receives royalties for the test. There are no other conflicts of interest to be declared by the authors.

Footnotes

ACKNOWLEDGMENTS

This research was supported by Department of Veterans Affairs Merit Award CX12004 awarded to J. Vincent Filoteo and a Huntington’s Disease Society of America Center of Excellence grant to Jody Corey-Bloom. Paul E. Gilbert was supported by a National Institutes of Health/National Institute on Aging Grant P30AG059299. Emily J. Van Etten was supported by National Institutes of Health Grant R25AG043364. The authors thank all of the participants for their contributions to this study.

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