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ORIGINAL ARTICLE
DOI: 10.24412/2707-6180-2021-63-123-128 УДК 616.858 МРНТИ 76.29.51
ASSOCIATION OF EDUCATION WITH COGNITIVE FUNCTION IN NEWLY
DIAGNOSED PARKINSON'S DISEASE
OH-DAE KWON1, MIN-JAE LEE1, HYE-GUK RYU2
'School of Medicine, Catholic University of Daegu, Daegu, Korea 2Pohang University of Science and Technology, Pohang, Korea
Oh-Dae Kwon - https://orcid.org/0000-0002-7465-2904 Min-Jae Lee - https://orcid.org/0000-0001-7884-2927 Hye-Guk Ryu - https://orcid.org/0000-0002-5901-1316
Citation/
библиографиялыщ сттеме/ библиографическая ссылка:
Oh-Dae Kwon, Min-Jae Lee, Hye-Guk Ryu Association of Education with Cognitive function in newly diagnosed Parkinson's disease. West Kazakhstan Medical Journal. 2021;63(3):123-128. doi: 10.24412/27076180-2021-63-123-128
О-Дэ Квон, Мин-Джэ Ли, Хе-Гук Рю. Паркинсон ауруынын, алFашrçы кезендершдеп БЫм жэне таным. West Kazakhstan Medical Journal. 2021;63(3):123-128. doi: 10.24412/27076180-2021-63-123-128
О-Дэ Квон, Мин-Джэ Ли, Хе-Гук Рю. Связь образованности и когнитивных функций на ранних стадиях болезни Паркинсона. West Kazakhstan Medical Journal. 2021;63(3):123-128. doi: 10.24412/2707-6180-2021-63-123-128
Association of Education with Cognitive function in newly diagnosed Parkinson's disease
Oh-Dae Kwon1, Min-Jae Lee1, Hye-Guk Rytf
'School of Medicine, Catholic University of Daegu, Daegu, Korea
2Pohang University of Science and Technology, Pohang, Korea
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Low education is known to be a risk factor for Alzheimer's disease (AD). Since many patients with PD show pathological findings similar to AD in addition to Lewy body, we reasoned that low education might also be associated with decreased cognition of PD
Methods. We studied 154 unrelated PD patients recruited consecutively from May 2003 until March 2008 in the outpatient Movement Disorder Clinic of the Daegu Catholic University Medical Center. The diagnosis was made through manifestations of two or more cardinal features of PD: initially unilateral resting tremor, bradykinesia or rigidity, levodopa-responsiveness, and absence of clinical features of atypical PD. The 150 controls were without a diagnosis of a neurodegenerative disorder, who were the spouses or other caregivers of the patients. Cognitive function was assessed using a standardized cognitive function test, Seoul Neuropsychological Screening battery. Results. The number of women was higher in PD patients, contrasting with Controls (p=0.000). The mean score of the Korean-mini mental state examination (K-MMSE) of PD was lower than that of controls (p=0.008). Patients with lower education related with higher age (p=0.030), higher women proportion (p=0.000), lower alcohol drinking (p=0.028), older age at onset (p=0.024), higher Unified Parkinson Disease Rating Scale part III score (p=0.050), lower K-MMSE (p=0.000), higher Geriatric Depression Scale (GDS) score (p=0.020). K-MMSE score of PD patients is strongly related to education level after adjusting age, sex, and GDS (p=0.000). Lower education (p=0.000) and higher GDS (p=0.007) has an association with lower K-MMSE in PD by univariate regression analysis.
Conclusion. As we hypothesized, newly diagnosed PD with low education showed lower cognitive performance. PD itself was seemed to be a risk factor for lower cognition as well as depression.
Keywords: Parkinson disease, Cognition, Education, Mini-mental state examination
Паркинсон ауруынын алFашк;ы кезевдервдеп БШм жэне таным
О-Дэ Квон1, Мин-Джэ Ли1, Хе-Гук Рю2 ■Тэгу католик университета, Тэгу, Корея
2Пхохан гылым жэне технологиялар университета, Пхохан, Корея Паркинсон ауруы (ПА) - ец кеп таралган екiншi нейродегенеративта ауру. БЫмнщ темен децгеш Альцгеймер (АА) ауруыныц цауш факторы екеш белгш. Кептеген ПА пациенттершде Леви тауьщтарынан бас;а, АА-га :р;сас патологияльщ белгшер анык;талгандык;тан, бiз темен бЫм децгеш ПА-да танымды; ;абшеттщ темендеуiмен де байланысты болуы мумжн деп болжады;. Эдктерь Бiз 2003 жылдыц мамырынан 2008 жылдыц наурызына дейн Тэгу Католик университетшщ медициналы; орталыгыныц моторлы; б^зылулардыц
е
Oh Dae Kwon
e-mail: dolbaeke@cu.ac.kr
Received/ Келт tyctí/ Поступила: 02.04.2021
Accepted/
Басылымра к,абылданды/ Принята к публикации: 01.09.2021
ISSN 2707-6180 (Print) © 2021 The Authors Published by West Kazakhstan Marat Ospanov Medical University
амбулаторияльщ клиникасында ЖYЙелi турде ;абылданган ПА бар 154 пациент зерттедж. Диагноз екi немесе одан да кеп ПА негiзгi белгшершщ кeрiнiсi негiзiнде жасалды, олар: бастащыда бiр жа;ты тынышты; треморы, брадикинезия немесе ;атшлы;, леводопага реакция жэне атиптi ПА клиникалы; белгшершщ болмауы. Ба;ылау тобыныц 150 адамында нейродегенеративт бузылыс диагнозы цойылмаган, олар ерльзайыптылар немесе пациенттерге KYтiм жасайтын бас;а адамдар болган. Когнитивтi функция стандартталган когнитивтi тест, нейропсихологиялы; скринингтщ Сеул батареясы ар;ылы багаланды.
Нэтижелерi. ПА бар эйелдердщ саны ба;ылау тобымен салыстырганда жогары болды (р = 0,000). Корей психикалы; жагдайыныц мини-тестшщ орташа балы (K-MMSE) ба;ылау тобына Караганда темен болды (р = 0,008). Теменп бiлiм децгейт пациенттер жасы улкен (р = 0,030), эйелдердщ улеа жогары (р = 0,000), алкогольдi аз тутыну (р = 0,028), аурудын басталуындагы жасы улкен (р = 0,024), Паркинсон ауруынын бiрынFай рейтинг шкаласы бойынша жогары балл, III бeлiм (р = 0,050), k-MMSE (р = 0,000), депрессиянын гериатриялы; шкаласы (GDS) бойынша жогары балл (р = 0.020). ПА пациенттершщ k-MMSE багалауы жасына, жынысына жэне GDS (р = 0,000) тузетшгеннен кейн бшм децгейне байланысты. Темен бiлiм децгеш (р = 0,000) жэне GDS шкаласы бойынша жогары балл (р = 0,007) бiр eлшемдi регрессиялы; талдау нэтижелерi бойынша ПА-да теменп K-MMSE-мен байланысты.
^орытынды. Бiз болжаганымыздай, алгаш аныщталган ПБ-мен темен бшм децгеш бар нау;астарда танымды; ;абшеттердщ темен децгейi бащалады. ПМУ eзi танымды; ;абшеттщ тeмендеуi, сондай-а; депрессия ушш круши фактор екенi белгш болды.
Негiзгi свздер: Паркинсон ауруы, таным, бiлiм, психикалыц жагдайды цысцаша зерттеу
Связь образованности и когнитивных функций на ранних стадиях болезни Паркинсона
О-Дэ Квон1, Мин-Джэ Ли1, Хе-Гук Рю2
'Католический университет Тэгу, Тэгу, Корея
2Пхоханский университет науки и технологий, Пхохан, Корея
Болезнь Паркинсона (БП) - второе по распространенности нейродегенеративное заболевание. Известно, что низкий уровень образованности является фактором риска болезни Альцгеймера (БА). Поскольку у многих пациентов с БП, помимо телец Леви, обнаруживаются патологические признаки, похожие на БА, мы предположили, что низкий уровень образованности также может быть связан со снижением познавательной способности при БП.
Методы. Мы изучили 154 неродственных пациентов с БП, поступивших последовательно с мая 2003 года по март 2008 гг, в амбулаторной клинике двигательных расстройств Медицинского центра католического университета Тэгу. Диагноз был поставлен на основании проявления двух или более основных признаков БП: изначально одностороннего тремора в покое, брадикинезии или ригидности, реакции на леводопа и отсутствия клинических признаков атипичной БП. У 150 человек контрольной группы диагноз нейродегенеративное расстройство не был поставлен, они были супругами или другими лицами, ухаживающими за пациентами. Когнитивная функция оценивалась с помощью стандартизированного теста когнитивной функции, сеульской батареи нейропсихологического скрининга. Результаты. Число женщин с БП было выше по сравнению с контрольной группой (р = 0,000). Средний балл корейского мини-теста психического состояния (K-MMSE) БП был ниже чем у контрольной группы (р = 0,008). Пациенты с более низким уровнем образованности связаны с более старшим возрастом (р = 0,030), более высокой долей женщин (р = 0,000), меньшим употреблением алкоголя (р = 0,028), более старшим возрастом в начале заболевания (р = 0,024), более высоким уровнем баллов по унифицированной рейтинговой шкале болезни Паркинсона, часть III (р = 0,050), более низким K-MMSE (р = 0,000), более высокими баллами по Гериатрической шкале депрессии (GDS) (р = 0,020). Оценка K-MMSE пациентов с БП сильно зависит от уровня образованности после корректировки возраста, пола и GDS (р = 0,000). Низкий уровень образования (р = 0,000) и более высокие баллы по шкале GDS (р = 0,007) имеют связь с более низким K-MMSE при БП по результатам одномерного регрессионного анализа.
Заключение. Как мы и предполагали, у больных с низким уровнем образованности впервые выявленной БП отмечается более низкий уровень когнитивных способностей. Оказалось, что сама по себе БП является фактором риска снижения
познавательной способности, а также депрессии.
Ключевые слова: болезнь Паркинсона, познание, образованность, краткое обследование психического состояния
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is primarily a motor disorder [1], but there are many non-motor symptoms, including cognitive disorders [1, 2]. The rate of mild cognitive impairment in newly diagnosed PD is two times of normal controls [2, 3]. Moreover, 20-57% of newly diagnosed PD developed mild cognitive impairment within five years of diagnosis [4-6]. Dementia prevalence of a meta-analysis showed that 40% of PD developed dementia [7]. The pathophysiology of cognitive dysfunction is not clearly understood. Dopaminergic neuronal loss and deficit of dopaminergic stimulation upon basal ganglia and the whole brain were suspected as the cause of cognitive dysfunction. However, dopaminergic therapy did not significantly improve PD's cognitive function and sometimes worsened behavioral symptoms and cognitive symptoms [8]. Therefore, another explanation for the cognitive decline is needed. Many PD patients have cholinergic deficits due to the cholinergic pathway's degeneration, including nucleus basalis of Meynert, similar to that of AD [9]. Choline acetyltransferase activity is also decreased in the cerebral cortex of PD, and reductions of Chloineacetyl transferase in the temporal neocortex are related to cognitive dysfunction [10]. Concurrent AD upon PD surely affects PD's cognitive decline [11].
Education and nurture positively affect brain development, including synaptic density and cell density of the brain. Development in an enriched environment increases total brain weight [12] and cortical thickness [13]. Low education is an important risk factor for AD [14, 15], and the prevalence of dementia is high in illiterate people [16]. There is a significant correlation between cerebral atrophy and educational level [17].
The reason we thought that lower education affects negatively the cognitive function of PD are as follows. First, there are concurrent AD pathologies in some patients with PD, and lower education is a risk factor for AD. Second, both AD and dementia in PD show cholinergic dysfunction. Third, education itself affects brain development. We hypothesized that lower education is related to lower cognitive performance in newly diagnosed PD and evaluated it by comparing neuropsychological performance between PD and normal controls and three educational groups in PD.
Methods
Subjects
This study was conducted in Daegu Catholic University Medical Center in southeast Korea. The 154 patients with PD were recruited from the patients who visited the outpatient Movement Disorders Clinic in the Department of Neurology, Daegu Catholic University Medical Center between May 2003 and March 2008. They
are newly diagnosed and drug naïve. Age- and education-matched 150 controls were selected from the caregivers of the patients. Each person in the control group was examined by a neurologist and not diagnosed with any neurodegenerative disease. The protocol was approved by the ethics committee of Daegu Catholic University Medical Center.
Diagnosis
A neurologist with a specialty in neurodegenerative diseases evaluated all the patients and controls. All patients were diagnosed with PD based on previously published diagnostic criteria, including having at least two cardinal signs, rest tremor, rigidity, bradykinesia, and postural instabilities, of PD and levodopa-responsiveness [18]. Patients with other causes of parkinsonism such as progressive supranuclear palsy, primary dementia, cerebellar dysfunction, or drug-induced parkinsonism were excluded by neurological examination and thorough history followed by follow-up examination for at least one year, laboratory findings, and brain magnetic resonance imaging. Participants also were excluded if they had a family history of parkinsonism.
Neuropsychological tests
We performed a standardized neuropsychological battery, the Seoul Neuropsychological Screening Battery (SNSB) [19], in all subjects. The battery contains tests for attention, language, praxis, four elements of Gerstmann syndrome, visuoconstructive function, verbal and visual memory, and frontal/executive function. Among these tests, the components that could be scored were: digit span (forward and backward); the Korean version of the Boston Naming Test; written calculations (three items each for addition, subtraction, multiplication, and division; one point for each correct item); the Rey-Osterrieth Complex Figure Test (RCFT: copying, immediate and 20-minute delayed recall as well as recognition); the Seoul Verbal Learning Test (SVLT: three learning-free recall trials of 12 words, 20-minute delayed recall trial for these 12 items and a recognition test); the phonemic and semantic Controlled Oral Word Association Test (COWAT); the Stroop Test (word and color reading of 112 items in two minutes); and Barthel-ADL which was considered normal when perfect score was performed. Instrumental ADL was also done with a cut-off point of less than eight. Cognitive function was also assessed using the Korean version of the mini-mental state examination (K-MMSE) and clinical dementia rating (CDR) scale. The geriatric depression scale (GDS) was also performed.
Statistical analysis
For comparison of the PD group and Control group, an Independent sample T-test was done. The comparison of three educational groups in PD was made by ANOVA test.
ANCOVA analysis for the association between education level and K-MMSE after adjusting age, sex, GDS among the three educational groups of PD was also done. Lastly, we adjust the Univariate Regression analysis to find out any relations between educational level and covariates. SPSS for Windows (version 17.0 SPSS Inc.) was used for all statistical analyses, and p values <0.05 were regarded as statistically significant.
Results
The number of women was higher in PD patients, contrasting to that of Caucasians (Table 1). The mean score of K-MMSE of PD was lower than that of controls (Table 1) by independent sample T-test. Patients with lower education related with higher age, higher women proportion, lower alcohol drinking, older age at onset, higher Unified Parkinson Disease Rating Scale part III score, lower K-MMSE, higher GDS score (Table 2) by ANOVA test. THE mean K-MMSE score of PD patients is strongly related to education level after adjusting age, sex, and GDS(F=5.154, P=0.000) by ANCOVA test. Lower education and higher GDS have an association with lower
K-MMSE in PD by univariate regression analysis (Table 3).
Discussion of results
Many patients with PD develop dementia in the late stage [7]. Moreover, many patients with PD show a cognitive decline in the early stage of PD [2, 3]. There is no conclusive evidence about the pathology of cognitive decline of this neurodegenerative disease. Some patients with PD show pathologic findings similar to those of AD [11]. Therefore, we thought the cognitive decline in PD might share the pathogenesis of AD as well as the risk factors of cognitive decline. We focused on the education level as a risk factor of cognitive decline of PD. To know the relationship between education level and cognitive decline, we compared the cognitive function between newly diagnosed PD and normal controls. We also compared cognitive functions among three educational groups in the patients.
The number of women was higher in the PD group than the control group, and it was contrasting to the previous studies, which showed male preponderance in prevalence
Table 1. General Characteristics of patients with Parkinson's disease and Controls
Characteristic PD Controls P Value
Number 154 150
Men/women 47/107 82/68 0.000*
Age, mean±SD (yrs) 71.38 ± 7.93 71.79 ± 4.14 0.571
Education, mean±SD (yrs) 5.76 ± 4.75 5.43 ± 2.87 0.459
K-MMSE 24.68± 4.05 25.79 ± 3.26 0.008*
* Independent sample T-test
Table 2. Clinical & neuropsychological characteristics among the education groups.
Education group (Total n =154) P LSD
0-5 yrs(n=66) 6-12 yrs(n=74) >12 yrs (n=14)
Age, mean (SD) yrs 73.03(6.62) 70.66(8.24) 67.43(10.29) 0.030* 1=2, 1>3, 2=3
Education, mean(SD) yrs 1.39(1.36) 7.78(2.28) 15.64(1.39) 0.000* 1<2<3
Men:Women (% women) 6:60(90.9%) 29:45 (60.8%%) 12:2 (14.3%%) 0.000* 1>2>3
Current alcohol drinking 22 (33.3%) 28 (37.8) 10 (71.4%%) 0.028* 1=2, 1<3, 2<3
Current smoking 14 (21.2%%) 26 (35.1%%) 7 (50.0%%) 0.051 1=2, 1<3, 2=3
Family History
Dementia 4(6.1%%) 6(8.1%%) 1 (7.1%%) 0.897 1=2=3
Stroke 10 (15.2%%) 18 (24.3%%) 3 (22.4%%) 0.403 1=2=3
Current illness
Hypertension 27 (40.9%%) 37 (50.0%%) 8 (57.1%%) 0.406 1=2=3
Diabetes mellitus 16 (24.2%%) 19 (25.7%%) 4 (28.6%%) 0.941 1=2=3
Age at onset of PD, mean (SD) 69.27(7.05) 65.68(10.19) 63.79(9.99) 0.024* 1>2, 1>3, 2=3
Hoehn-Yahr Stage, mean (SD) 2.29(0.65) 2.22(0.63) 2.21(0.43) 0.777 1=2=3
UPDRS III score, mean (SD) 25.85(8.20) 21.00(9.11) 20.17(6.71) 0.050* 1>2, 1>3, 2=3
Neuropsychological tests
K-MMSE, mean (SD) 21.94(3.49) 26.53(3.28) 27.79(1.97) 0.000* 1<2, 1<3, 2=3
GDS, mean (SD) 18.18(7.59) 16.17(6.87) 11.92(6.80) 0.020* 1=2, 1>3, 2=3
n;number, SD;standard deviation, K-MMSE:Korean version of mini-mental state examinationUPDRS: Unified Parkinson Disease Rating Scale, P values are by 1-way ANOVA.
Table 3. Uni-variate associations between covariates and K-MMSE score.
Exp(B) Confidence Interval P
Lower Upper
Age, mean (SD) yrs 2.421 0.651 9.008 0.187
Education, mean(SD) yrs 5.161 3.638 6.684 0.000*
Men:Women -1.009 -3.284 1.266 0.378
Current alcohol drinking 0.623 -1.102 2.349 0.472
Current smoking -0.922 -3.287 1.443 0.438
Family History
Dementia 0.031 -2.387 2.448 0.980
Stroke -0.348 -1.889 1.194 0.653
Current illness
Hypertension -0.854 -2.187 0.48 0.205
Diabetes mellitus -0.68 -2.168 0.808 0.363
Age at onset of PD, mean (SD) -0.047 -0.135 0.041 0.288
Hoehn-Yahr Stage, mean (SD) 0.265 -1.568 2.097 0.773
UPDRS III score, mean (SD) -0.029 -0.148 0.09 0.627
Neuropsychological tests
GDS, mean (SD) -0.134 -0.231 -0.038 0.007*
P value by univariate logistic regression anlaysis.
[20] and incidence [21]. Contrary to the early report only mentioning PD as a motor illness [1], we found significant cognitive impairment in the drug naïve PD patients. As we expected, the K-MMSE of PD was lower than that of controls. The newly diagnosed PD group's K-MMSE scores are strongly related to educational level after adjusting age, sex, and GDS. PD with lower education showed higher age, women proportion, lower alcohol drinking, higher age at onset, higher UPDRS III score, lower K-MMSE, higher GDS score. Lower education has an association with lower K-MMSE in PD and higher GDS also.
Because low education is a risk factor of AD, there were many patients with low education, even to the illiterate level, in our patient group that we focused on the relationship between educational level and cognition in the PD. For the effect of education on cognitive function, it is well known that early life education has a positive effect on late-life cognitive function [12, 22]. Furthermore, good education may protect late-life brain volume from atrophy
[23]. The brain's mechanism of education is explained by increased synaptic density and the brain's cell density [12]. An early study suggested that relatively many patients with PD will develop cognitive decline early in the disease
[24]. Our study is done with patients without previous PD medication, and the cognitive result was similar to it. We also thought PD's cognitive function is poor than normal controls, and the results of our study verified it.
This study has several advantages. We gathered consecutive patients with newly diagnosed PD, and none of them were on medication for the illness. Therefore, we can assess the pure disease effect on cognition. Moreover, we divided the education group into three, and it could give more information than the coefficient analysis itself.
This study also has several limitations. It is a cross-sectional study, and it is needed to follow up with the groups to know which educational group develops more AD or other types of dementia. Larger numbers of patients should be studied for more reliable results. There would be a selection bias because we gathered patients from only one university hospital in southeast Korea. Furthermore, the control group was mostly from the spouse or their children. Therefore, the control group could have shared genetic susceptibility or environmental risk factors of PD with the patients.
For the pathology of cognitive dysfunction in PD, there are several theories of pathogenesis. Firstly, AD pathology was mentioned because some PD patients showed abnormal proteins such as senile plaque and neurofibrillary tangle similar to those of AD [11,25]. However, the AD pathology is not explaining the entire aspect of cognitive decline in PD. One of our previous studies showed a very characteristic pattern of cognitive decline of PD by neuropsychological tests. Typically, memory decline is the most characteristic cognitive feature in AD. However, the PD patients showed a decline in memory and frontal executive function. The frontal executive function was more impaired between the two cognitive domains, and memory was relatively less impaired [26]. A study done in northern Europe showed that the PD group was more impaired in all neuropsychological tests than controls. The largest difference was for verbal memory, and one-fifth of the patients with PD were diagnosed with mild cognitive impairment [3]. Secondly, they think alpha-synucleinopathy, which develops the Lewy body, may result in PD's cognitive decline [27]. Moreover, many studies using levodopa to improve PD's cognitive decline were failed or with little effect [8]. Recently, a report
mentioned that striatal dopamine depletion might be related to mild cognitive impairment in de novo PD [28 ]. However, there is a controversy about the exact pathology of cognitive decline of PD until now.
The present study also showed the impaired cognitive function of the patients with PD compared to controls. We focused on the possible relationship between education level and cognitive function even though we did not administer all cognitive domain tests to the patients. However, the PD group had complete SNSB tests, and the result showed typical cognitive patterns.
In conclusion, we found that newly diagnosed PD with low education showed impaired cognitive performance and depressive mood. Therefore PD itself was seemed to be a risk factor of lower cognition as well as depression.
Acknowledgments
We wish to express our gratitude to Ms. SY Choi, Mrs. JY Kim for the excellent neuropsychological tests administered to the patients and controls. We also thank Mr. HG Ryu for data processing and statistical support.
References:
1. Charcot J. On Parkinson's disease. In Lectures on disease of the nervous system delivered at the Salpetriere. London: New Sydenham Society; 1877;129-56.
2. Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident cohort of Parkinson's patients in the UK. The CamPaIGN study. Brain. 2004;127(Pt 3):550-60.
3. Aarsland D, Bronnick K, Larsen JP, Tysnes OB, Alves G, Norwegian ParkWest Study G. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology. 2009;72(13):1121—6.
4. Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. Evolution of cognitive dysfunction in an incident Parkinson's disease cohort. Brain. 2007;130(Pt7):1787-98.
5. Janvin CC, Larsen JP, Salmon DP, Galasko D, Hugdahl K, Aarsland D. Cognitive profiles of individual patients with Parkinson's disease and dementia: comparison with dementia with lewy bodies and Alzheimer's disease. Movement disorders : official journal of the Movement Disorder Society. 2006;21(3):337-42.
6. Caviness JN, Hentz JG, Evidente VG, Driver-Dunckley E, Samanta J, Mahant P, et al. Both early and late cognitive dysfunction affects the electroencephalogram in Parkinson's disease. Parkinsonism & related disorders. 2007;13(6):348-54.
7. Cummings JL. The dementias of Parkinson's disease: prevalence, characteristics, neurobiology, and comparison with dementia of the Alzheimer type. European neurology. 1988;28 Suppl 1:15-23.
8. Emre M. Dementia associated with Parkinson's disease. Lancet neurology. 2003;2(4):229-37.
9. Schrag A, Quinn N. Disorders of the basal ganglia and their modern management. J R Coll Physicians Lond. 1999;33(4):323-7.
10. Perry EK, Curtis M, Dick DJ, Candy JM, Atack JR, Bloxham CA, et al. Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1985;48(5):413-21.
11. Boller F, Mizutani T, Roessmann U, Gambetti P. Parkinson disease, dementia, and Alzheimer disease: clinicopathological correlations. Ann Neurol. 1980;7(4):329-35.
12. Krech D, Rosenzweig MR, Bennett EL. Effects of environmental complexity and training on brain chemistry. J Comp Physiol Psychol. 1960;53:509-19.
13. Diamond MC. Enriching Heredity. The Impact of the Environment on the Anatomy of the Brain. New York: Free Press; 1988.
14. Katzman R. Education and the prevalence of dementia and Alzheimer's disease. Neurology. 1993;43(1):13-20.
15. Schmand B, Smit J, Lindeboom J, Smits C, Hooijer C, Jonker C, et al. Low education is a genuine risk factor for accelerated
memory decline and dementia. Journal of clinical epidemiology. 1997;50(9):1025-33.
16. Zhang MY, Katzman R, Salmon D, Jin H, Cai GJ, Wang ZY, et al. The prevalence of dementia and Alzheimer's disease in Shanghai, China: impact of age, gender, and education. Annals of Neurology. 1990;27(4):428-37.
17. Eisenberg DP, London ED, Matochik JA, Derbyshire S, Cohen LJ, Steinfeld M, et al. Education-associated cortical glucose metabolism during sustained attention. Neuroreport. 2005;16(13):1473-6.
18. Samii A, Nutt JG, Ransom BR. Parkinson's disease. Lancet. 2004;363(9423):1783-93.
19. Kang Y, Na DL. Seoul Neuropsychological Screening Battery; in Kang Y, Na DL (eds): Seoul Neuropsychological Screening Battery. Incheon: Human Brain Research & Consulting Co.; 2003.
20. Rosati G, Granieri E, Pinna L, Aiello I, Tola R, De Bastiani P, et al. The risk of Parkinson disease in Mediterranean people. Neurology. 1980;30(3):250-5.
21. Mayeux R, Marder K, Cote LJ, Denaro J, Hemenegildo N, Mejia H, et al. The frequency of idiopathic Parkinson's disease by age, ethnic group, and sex in northern Manhattan, 1988-1993. Am J Epidemiol. 1995;142(8):820-7.
22. Kwon OD, Cho SS, Seo SW, Na DL. Effect of illiteracy on neuropsychological tests and glucose metabolism of brain in later life. Journal of neuroimaging : official journal of the American Society of Neuroimaging. 2012;22(3):292-8.
23. Kwon OD, Yoon, U.C., Na, D.L. Effect of Illiteracy on Cognition and Cerebral Morphology in Later Life. Dement Neurocogn Disord. 2015;14(4):149-57.
24. Kandiah N, Narasimhalu K, Lau PN, Seah SH, Au WL, Tan LC. Cognitive decline in early Parkinson's disease. Movement disorders: official journal of the Movement Disorder Society. 2009;24(4):605-8.
25. Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW. Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch Neurol. 2002;59(1):102-12.
26. Kim JH, Jin, Y.S., Chang, M.S., Choi, S.Y., Kwon, O.D. Neuropsychological Characteristics of Mild Cognitive Impairment in Parkinson Disease and Subcortical Vascular Mild Cognitive Impairment. J Korean Neurol Assoc. 2011;29(3):177-83.
27. Hurtig HI, Trojanowski JQ, Galvin J, Ewbank D, Schmidt ML, Lee VM, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. Neurology. 2000;54(10):1916-21.
28. Chung SJ, Yoo HS, Oh JS, Kim JS, Ye BS, Sohn YH, et al. Effect of striatal dopamine depletion on cognition in de novo Parkinson's disease. Parkinsonism & related disorders. 2018;51:43-8.
