Abstract
Objective:
To evaluate the role of apolipoprotein E (APOE) ∊4 allele on cognitive, neuropsychiatric, and motor features in a sample of Bulgarian patients with late-onset Parkinson’s disease (LOPD, age at onset > 55 years).
Methods:
A total of 16 patients with LOPD having APOE ∊3/∊4 genotype were compared to 30 patients with LOPD having APOE ∊3/∊3 genotype and 20 healthy control individuals. Detailed cognitive assessment and evaluation of neuropsychiatric and motor symptoms were performed.
Results:
The patients with LOPD had significantly lower scores in all cognitive domains compared to controls. The patients with LOPD carrying an ∊4 allele showed some significant differences in their cognitive, motor, and neuropsychiatric features.
Conclusions:
The data suggest a role of the APOE genotype as a disease-modifying factor.
Keywords: APOE, ∊4 allele, cognitive, LOPD, motor, neuropsychiatric
Introduction
Parkinson’s disease (PD) is characterized by motor (rest tremor, bradykinesia, rigidity, and postural instability) and nonmotor features (cognitive, neuropsychiatric, autonomic, sensory, and sleep disturbances). Cognitive impairment is a major nonmotor feature of PD, and according to published data, mild cognitive impairment (MCI) is presented approximately in a quarter of the patients with PD. 1 Dementia is also frequent (about 30%), with 4 to 6 times higher incidence rate as compared to the control group. 2 In terms of 20 years of disease duration, more than 80% of patients with PD are expected to develop dementia (PD dementia). 3 Although different cognitive subtypes exist, the affected domains could be executive functions, attention, visuospatial functions, memory, and language abilities. 4 In addition, as a result of the complex neurotransmitter changes in the brain, a range of neuropsychiatric symptoms (delusions, hallucinations, depression, apathy, agitation, irritability, and others) could be presented. 5
The apolipoprotein E (APOE) ∊4 allele is considered a risk factor for Alzheimer’s disease (AD). According to the published data, it shows association with earlier age at onset, 6 more severe memory loss, 7 and a pattern of behavioral changes. 8
In patients with PD, the significance of APOE genotype is controversial, but some authors suggest association of APOE ∊4 allele with dementia 9 and earlier development of psychotic symptoms. 10 It’s effect on the motor symptoms is unclear. In the current study, we aimed to explore the role of APOE ∊4 allele for the motor, cognitive, and neuropsychiatric features in patients with late-onset PD (LOPD, onset after 55 years).
Methods
After ethical approval, the study was performed at the Clinic of Neurology—University Hospital Alexandrovska,” Sofia. A written informed consent was obtained from each participant. Clinical assessment and genetic testing were performed separately in relation to each other, and a blind of the results was maintained.
All 66 participants had complete physical and neurological examination. The 46 patients with LOPD were diagnosed in accordance with the clinical diagnostic criteria of the “United Kingdom Parkinson's Disease Society Brain Bank Criteria.” 11 They were selected based on their age at onset (older than 55 years) and known APOE genotype (16—with ∊3/∊4 and 30—with ∊3/∊3). The control group consisted of 20 healthy individuals (normal control [NC]), regardless of their APOE genotypes. They had no signs of central nervous system disease, cognitive impairment, and depression.
Laboratory parameters were tested, and computed tomography and/or magnetic resonance imaging of the brain were performed to rule out other etiology of the parkinsonism and/or cognitive impairment.
Cognitive assessment was performed for all participants. For all 46 patients with LOPD, it was conducted during their best motor state, with the use of the following: (1) Mini-Mental State Examination (MMSE), Mini-Mental Parkinson (MMP), and Dementia Rating Scale (DRS)—for evaluation of global cognitive functioning; (2) Digit Span Backward, Trail Making Test A (TMT-A), Trail Making Test B, Modified Card Sorting Test (MCST), Stroop test, and Verbal Fluency letter “m” (VF-“m”)—for attention and executive functions; (3) Digit Span Forward—for short-term memory and Free and Cued Selective Reminding Test (FCSRT)—for episodic memory; (4) Boston Naming Test (BNT)—15 items and Verbal Fluency “animals” (VF-“an”)—for language abilities; and (5) clock drawing test (CDT)—for constructive praxis.
Assessment of the motor symptoms was performed for all 46 patients with LOPD, during their worst motor state, by Part III of Unified Parkinson’s Disease Rating Scale (UPDRS). The UPDRS total scores were used to compare both LOPD groups, for the purpose of their cognitive assessment. Separately, the UPDRS results of the patients in the early stage of the disease were compared, based on their APOE genotypes (13 patients with ∊3/∊4 genotype and 20 patients with ∊3/∊3 genotype, with disease duration <5 years).
“Neuropsychiatric inventory” (NPI) was applied on patients with LOPD as it is a widely used tool for the assessment of 10 behavioral disturbances: delusions, hallucinations, depression/dysphoria, anxiety, agitation/aggression, elation/euphoria, disinhibition, irritability/lability, apathy/indifference, and aberrant motor activity. When observed, they were assessed by severity, frequency, and level of distress. Information was obtained from the patient and/or caregiver, familiar with the patient's behavior.
The APOE genotyping was performed at the Molecular Medicine Centre, Medical University, Sofia. Polymerase chain reaction and restriction fragment length polymorphism analyses were used on DNA extracted from white blood cells, according to the method of Hixson and Powers. 12
Statistical analysis was performed with Statistical Package of IBM/SPSS Statistics 13.0.1. For demographic data and cognitive evaluation, analysis of variance (with post hoc analysis) was used. Data from motor and neuropsychiatric assessment were analyzed by independent samples t test, independent samples test (*, Mann-Whitney test), or chi-square and Fisher’s exact mean (**).
Results
Based on their genotypes, patients with LOPD were separated into 2 groups: the first—consisting of 16 patients carrying 1 ∊4 and 1 ∊3 allele (∊3/∊4, ∊4 carriers) and the second—consisting of 30 patients homozygous for the ∊3 allele (∊3/∊3, ∊4 noncarriers). Almost a third of them had positive familial history of parkinsonism and/or dementia (5 patients with APOE ∊3/∊4 genotype and 9 patients with APOE ∊3/∊3 genotype). The control group (NC) consisted of 20 healthy individuals.
Demographic characteristics of the 2 LOPD groups and NC are presented in Table 1. For the cognitive evaluation, the 3 groups were matched by age, sex, and years of education. In all the groups, male patients were almost twice more than female patients. Both LOPD groups were additionally matched by disease duration, total UPDRS part III score, and the type of prescribed antiparkinsonian medication. The average daily doses could not be accurately calculated, due to fluctuations in their administration. Subsequent analysis of the mean age at onset did not reveal significant APOE genotype-related differences between the LOPD groups.
Table 1.
Demographic Characteristics.a
| Cognitive/NPI Evaluation | LOPD ∊3/∊4 (n = 16) | LOPD ∊3/∊3 (n = 30) | NC (n = 20) | P Value |
|---|---|---|---|---|
| Age | 69.25 (6.6) | 69.74 (8.8) | 69.52 (7.3) | .835 |
| Sex, m/f | 11/5 | 21/9 | 14/6 | .657 |
| Education, years | 12.3 (3.7) | 13.9 (4.0) | 12.8 (3.2) | .183 |
| Age at onset | 63.31 (6.4) | 63.32 (8.7) | – | .995 |
| Disease duration, years | 5.69 (4.0) | 6.0 (4.1) | – | .816 |
| UPDRS part III | 43.8 (13.3) | 39.54 (14.7) | – | .086 |
| l-Dopab | 15 | 14 | – | .516 |
| Dopa agonistb | 17 | 13 | – | .106 |
| MAO-B inhibb | 16 | 13 | – | .342 |
| Amantadineb | 14 | 14 | – | .944 |
| Motor Evaluation | LOPD ∊3/∊4 (n = 13) | LOPD ∊3/∊3 (n = 20) | NC (n = 20) | P Value |
| Age | 66.87 (7.6) | 67.63 (8.9) | – | .933 |
| Sex m/f | 9/4 | 14/6 | – | .657 |
| Education, years | 12.1 (3.4) | 13.7 (3.8) | – | .183 |
| Disease duration, years | 2.75 (1.1) | 2.74 (1.3) | – | .984 |
| UPDRS part III | 36.8 (10.70) | 29.3 (9.59) | – | .036 |
Abbreviations: LOPD ∊3/∊4, late-onset Parkinson’s disease group with APOE ∊4/∊3 genotype; LOPD ∊3/∊3, Late-onset Parkinson’s disease group with APOE ∊3/∊3 genotype; NC, normal control; UPDRS, Unified Parkinson’s Disease Rating Scale; MAO-B inhib, monoamine oxidase B inhibitor; n, number of patients; APOE, apolipoprotein E; dopa, dopamine; SD, standard deviation; m/f, male/female; NPI, neuropsychiatric inventory.
a Data are presented as mean (SD).
b Data are presented as or mean rank.
The motor evaluation of patients with LOPD in the early stage (disease duration <5 years) revealed significantly higher total UPDRS part III scores for the ∊4 carriers (Table 1). With all other conditions similar (mean age, sex, years of education, and disease duration), these patients showed more severely affected speech (P = .030), hand movements (P = .002), rapid alternating movements (P = .032), and postural stability (P = .045).
Both LOPD groups expressed significant differences in almost all cognitive domains, compared to NC (Table 2). Significantly higher percentage of LOPD ∊4 carriers showed cognitive impairment below the applied cutoff scores for dementia (MMSE, P = .002; MMP, P = .013; and DRS, P = .001) when compared to LOPD ∊4 noncarriers. Further assessment revealed that the same group had significantly greater impairment on tasks related to executive functions (VF-“m,” P = .036), attention (TMT-A, P = .009), short-term/working memory (DSpF, P = .001; FCSRT/immediate recall, P = .005), language abilities (BNT, P = .000; VF-“an,” P = .000), and constructive praxis (CDT, P = .005). In addition, the LOPD ∊4 carriers had significantly higher NPI scores for depression (P = .032) and showed a tendency for the expression of delusions (P = .014) and euphoria (P = .044; Table 3).
Table 2.
Cognitive Functioning.a
| Cognitive Evaluation | LOPD ∊3/∊4 (n = 16) | LOPD ∊3/∊3 (n = 30) | NC (n = 20) | P Value |
|---|---|---|---|---|
| MMSE cutoff score ≤ 23 | 41.2% | 10.6% | – | .002 |
| MMP cutoff score ≤ 23 | 38.9% | 12.6% | – | .013 |
| DRS cutoff score ≤ 124 | 38.9% | 8.5% | – | .001 |
| FCSRT—immediate recall | 9 (4.6)b,c | 13.8 (3.03)d | 13 (1.9) | .005e |
| FCSRT—free recall | 22.4 (7.8)c | 21.0 (8.4)c | 31.9 (3.2) | – |
| FCSRT—total recall | 39.7 (7.6)c | 39.9 (9.3)c | 45.9 (1.3) | – |
| DSpF | 3.9 (0.6)b,c | 4.9 (1.1)c,d | 6.0 (0.9) | .001e |
| VF-“m”/60 s | 5.9 (4.6)b,c | 8.2 (3.6)c,d | 13.8 (3.5) | .036e |
| DSpB | 3.3 (0.9)c | 3.4 (0.8)c | 5.0 (0.9) | – |
| TMT-A, s | 121.6 (58.5)b,c | 87.7 (32.9)c,d | 46.3 (11.6) | .009e |
| TMT-B, s | 286.7 (153.9)c | 210.2 (94.8)c | 111.2 (25.1) | – |
| TMT-B errors | 1.8 (2.0) | 1.6 (1.7) | 1.3 (1.4) | – |
| MCST/6 categ | 1.3 (2.2)b,c | 3.3 (2.4)c,d | 6.0 (0.0) | .014e |
| MCST-TE | 8.7 (6.7)c | 8.2 (6.9)c | 2.5 (1.2) | – |
| Stroop-3 | 21.2 (12.5)c | 27.3 (16.1)c | 36.0 (5.2) | – |
| Stroop-3—errorsf | 53.10c | 50.35c | 20 | – |
| BNTf/15 | 23b,c | 48d | 45 | .000e |
| VF-“an”/60 s | 10 (6.7)b,c | 17.0 (5.2)c,d | 22.4 (4.1) | .000e |
| CDTf | 4.5b,c | 13d | 18 | .005e |
Abbreviations: LOPD ∊3/∊4, late-onset Parkinson’s disease group with APOE ∊3/∊4 genotype; LOPD ∊3/∊3, late-onset Parkinson’s disease group with APOE ∊3/∊3 genotype; NC, normal control; n, number of participants; MMSE, Mini-Mental State Examination; MMPE, Mini-Mental Parkinson’s Examination; DRS, Dementia Rating Scale; FCSRT, Free and Cued Selective Reminding Test; VF, Verbal Fluency; VF-“an”, Verbal Fluency “animals”; TMT-A/B, Trail Making Test A/B; DSpF/B, Digit Span Forward/Backward; MCST, Modified Card Sorting Test; MCST-TE, MCST Total Error; BNT, Boston Naming Test; CDT, clock drawing test; APOE, apolipoprotein E; DSpB, Digit Span Backward; SD, standard deviation.
a Data are presented as mean (SD).
b Significant difference compared to the LOPD ∊3/∊3 group.
c Significant difference compared to the NC group.
d Significant difference compared to the LOPD ∊3/∊4 group.
e Significant difference between the LOPD ∊3/∊4 group and the LOPD ∊3/∊3 group.
f Data are presented as mean rank.
Table 3.
Neuropsychiatric Evaluation.a
| NPI | LOPD ∊3/∊4 (n = 16) | LOPD ∊3/∊3 (n = 30) | P Value |
|---|---|---|---|
| Delusionsb | 4 (25%) | 0/0% | .021 |
| Hallucinationsc | 2/23 | 6/24 | .675 |
| Agitation/aggressionc | 4/24 | 2/21 | .283 |
| Depression/dysphoria | 13/8.74 (4.6) | 16/5.3 (5.9) | .032 |
| Anxietyc | 10/25 | 17/20 | .198 |
| Elation/euphoriab | 4 (25%) | 0/0% | .021 |
| Apathy/indifferencec | 10/24 | 14/22 | .508 |
| Disinhibitionb | 0/0% | 0/0% | – |
| Irritability/labilityc | 2/22 | 4/24 | .641 |
| Abberant motor behaviorc | 2/24 | 2/23 | .508 |
| Total score/120c | 16/27 | 30/20 | .092 |
Abbreviations: NPI, neuropsychiatric inventory; LOPD ∊3/∊4, late-onset Parkinson’s disease group with APOE genotype ∊4/∊3; LOPD ∊3/∊3, late-onset Parkinson’s disease group with APOE genotype ∊3/∊3; n, number of the patients, expressing the symptom; APOE, apolipoprotein E; SD, standard deviation.
a Data are presented as n/mean (SD).
b Data are presented as n/frequency.
c Data are presented as n/mean rank.
Discussion
To date, the role of APOE ∊4 allele in PD is still controversial. Studies on normal aging and patients with AD suggested regional-specific functions of the ∊4 allele in the brain. A study reported that thinner entorhinal cortex is observed in children and adolescent, carrying the ∊4 allele. 13 Although varying degrees of cognitive dysfunction have been described in nondemented individuals with 1 or 2 ∊4 alleles, Savitz et al argued that APOE variants play no role in cognitive development. They concluded that the neuropsychological dysfunction reported in nondemented ∊4 carriers is most likely to be the result of incipient AD. 14 In addition, Caselli et al suggested the existence of pre-MCI state in APOE ∊4 homozygotes with higher rates of cognitive decline in their 60s 15 ; and a magnetic resonance imaging-based study found that nondemented older adults, carriers of the ∊4 allele, express small measurable endophenotypes of brain structure and function that are similar to individuals with AD. 16 Also, APOE was identified as an important molecular link between central mechanisms in PD and AD, by activation of extracellular signaling pathways. 17 However, in clearly defined cases other authors failed to confirm association of dementia with PD and APOE polymorphisms. 18
Some authors reported increased ∊4 allele frequency in patients with PD having cognitive decline and positive familial history 19 and in patients with PD having coexisting Alzheimer pathology. 20 Our previous research found higher frequency of APOE ∊3/4 genotype in patients with LOPD (21%), compared to controls (10%; P = .044; unpublished data). Pathologic evaluation was not possible, but due to the selection procedure, relatively high proportion (almost 50%) of the patients had positive familial history of parkinsonism and/or dementia. The familial history could be related to the APOE genotype frequencies in case of familial aggregation of ∊4 allele, which increases the chance to select an APOE ∊4 allele carrier.
In the present study, the aim was to explore the association of ∊4 allele with a wide range of clinical characteristics of patients with LOPD. It was found that the mean age at onset was similar for ∊4 carriers—63.31 (6.4) years and ∊4 noncarriers—63.32 (8.7) years (Table 1). It did not reveal a major modifying role of ∊4 allele on age at onset in the current cohort, although other authors reported significantly earlier age at PD onset for ∊4 carriers. In a study conducted by Zareparsi et al, 21 the age at onset in the presence of ∊4 allele was 52.7 (9.8) years, compared to ∊3/∊3—56.1 (11.1) years. These results were confirmed by another study with age at onset 59.3 (10) years for ∊4 carriers, compared to 64.3 (8.4) years for noncarriers. 22 However, in both studies, younger patients (<55 years) were also included, in contrast to this study.
After application of previously suggested dementia cutoff scores, 23 -25 the participating patients with LOPD who carried ∊4 allele showed greater degree of cognitive impairment, compared to LOPD ∊4 noncarriers with similar disease duration (Table 2). The result is consistent with the findings of other authors, 22 although further assessment revealed some differences in the cognitive profile of the participating patients with LOPD. Both LOPD groups, in the current study, showed similar results on free and total recall of the episodic memory tasks (FCSRT), but in contrast it was found that working memory (immediate recall—FCSRT, Digit Span Forward) was more affected in the presence of ∊4 allele. However, it has to be considered that both studies were based on relatively small sample sizes. Also, the results may not be fully comparable, as the participating LOPD ∊4 noncarrier group did not include other APOE genotypes different than ∊3/∊3 and the participating LOPD ∊4 carriers had no earlier disease onset.
Further assessment revealed that the participating LOPD ∊4 carriers needed significantly longer time to perform TMT-A. As they were in comparable motor state with ∊4 noncarriers, the result suggested more prominent attention deficit. In addition, they expressed more severe frontal lobe dysfunction with affection of some aspects of the executive functions. They were characterized by poorer abilities of creating and maintaining of strategies for retrieval of information and conceptualization (VF-m, MCST). In contrast to LOPD ∊4 noncarriers, impaired language abilities (object naming, VF) and constructive praxis (CDT) were also presented. Although it could be secondary effect to more prominent executive dysfunction or higher percentage of “demented” (under the cutoff scores for dementia), more diffuse pathologic process, with additional involvement of semantic fields and visuospatial functions, could not be excluded.
Another finding in this study was that in the presence of ∊4 allele, patients with LOPD showed a tendency for higher expression of depression and few of them had delusions and euphoria. According to already available data, up to 40% of the patients with PD have depression. Involvement of dopaminergic (frontal) and noradrenergic systems has been proposed in its pathophysiology. 26 Some authors suggest a role of depression as a risk factor for psychosis in PD. 27 Variety of factors, both intrinsic and extrinsic, could contribute to their occurrence. Previous studies have suggested that dopaminergic medications are the main factor for developing psychosis, while other authors fail to confirm such a relationship. 28 In the present study, the APOE ∊4 carriers tended to receive more medications (dopamine agonists, monoamine oxidase B inhibitors) that could be involved in some of the psychopathology reflected in the NPI scores (Table 3). Imbalance of other neurotransmitters, such as serotonin, acetylcholine, and their interaction with the dopaminergic systems, may also be implicated. Despite the largely unknown genetic basis on the neuropsychiatric symptoms and the mechanisms of their influence in PD, data collected in this study suggest that ∊4 allele could contribute to the development of certain neuropsychiatric features, probably by a variety of mechanisms.
Regarding the severity of PD, for motor evaluation, only patients in the first stage of the disease (<5 years of disease duration) were selected. The evaluation of motor symptoms showed higher mean total UPDRS score and revealed greater degree of motor impairment for LOPD ∊4 carriers. Affection of speech, more prominent upper limbs bradykinesia, and postural instability were the significant differences. Although motor symptoms in PD are classically referred as dopaminergic, for some of them (speech, postural control), nondopaminergic mechanisms (adrenergic, cholinergic) could be of relevance. The presented results suggested a possible modifying role of the ∊4 allele in the impairment of dopaminergic and nondopaminergic transmitter systems.
In conclusion, this study explored the role of APOE ∊4 allele for a wide range of clinical characteristics in LOPD. In its presence, LOPD had aggravated clinical features—cognitive, neuropsychiatric, and motor. The results suggested an effect of ∊4 allele on different neurotransmitter systems. Although the main pathogenic mechanisms are still unclear, our data support the hypothesis that the ∊4 allele could act as a disease-modifying factor in LOPD. Confirmation of the results in larger samples is needed.
Footnotes
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was partly funded by Project No. 25/2012, Medical University, Sofia, Bulgaria.
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