Gender Difference in Behavioral and Psychological Symptoms of Alzheimer's Disease
Behavioral and psychological symptoms of dementia (BPSD) are important clinical manifestations of Alzheimer's Disease (AD), which may occur at the early stage or throughout the entire course of dementia. They can predict the progression of dementia and serve as the major causes for long-term hospitalization and reduction in caregiver's life quality. Current studies on gender difference of AD are only limited to the epidemiological aspect, but rarely on the clinical and neuropathology aspect. The present study discussed gender differences in BPSD of AD patients and whether white matter hyperintensity was significant associated with BPSD. We divided a total of 76 patients diagnosed with Alzheimer's disease according to DSM-IV-TR into groups with male and female dementia. Then we examined whether there were differences in BPSD, cognitive function and cerebral white matter hyperintensity (WMH) between groups. Our results showed a significant gender differences in delusion, anxiety, sleep behavior disorder, verbal ability and attention (p < 0.05). The results of Regression Analysis showed that only WMH score entered the equation at last (t = 2.451, p = 0.020), while the other variables were removed from the equation, such as Gender (t = -0.315, p = 0.755), Course of disease (t = -0.679, p = 0.503), CDR (t = 0.809, p = 0.425). The result of this study indicated that certain gender differences exist in behavioral and psychological symptoms of Alzheimer's disease. At the same time, cerebral white matter lesions were independently associated with BPSD in Alzheimer's disease patients.
Alzheimer's disease, Behavioral and psychological symptoms of dementia (BPSD), Gender differences, White matter hyperintensity (WMH)
Alzheimer's Disease is a neurodegenerative disease featured by occult onset and progressive cognitive impairment. It is the leading cause of dementia, comprising up to 60%-3/4/201980% of cases [1,2]. Behavioral and psychological symptoms of dementia are important clinical manifestations of Alzheimer's Disease, which may occur at the early stage or throughout the entire course of dementia. They can predict the progression of dementia and serve as the major causes for long-term hospitalization and reduction in caregiver's life quality [3,4]. Current studies on the gender difference of AD are only limited to the epidemiological aspect, but rarely on the clinical and neuropathological aspect . The present study discussed gender differences in BPSD of AD patients and whether white matter hyperintensity was significant associated with BPSD.
The present study was performed in Affiliated Brain Hospital of Guangzhou Medical University from December 2012 to February 2015 (N = 76 patients). The study protocol, informed consents were approved by the Institutional Review Board of Affiliated Brain Hospital of Guangzhou Medical University.
76 Alzheimer's disease patients with BPSD as the main complaints were recruited in the study. The inclusion criteria were as follows: (1) The patients was diagnosed with Alzheimer's disease based on the criteria of the fourth revised edition of the Diagnostic and Statistic Manual of Mental (DSM-IV-TR); (2) Also based on the criteria for AD proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA); (3) Present BPSD already affecting the social functions of the patients; (4) The patients or relatives having signed the informed consent. Patients meeting any of the following criteria were excluded from the study: patients accompanying other mental disorders, such as schizophrenia, schizoaffective disorders, delusional disorder, affective disorder and alcohol or substance dependence.
The psychiatrist investigated the patients' medical history and collected baseline data and results of physical examination, neurological examination, psychiatric examination and clinical diagnosis before the inclusion. The "different genders" in our study only refer to the biological based dichotomized distinction of males vs. females.
Neuropsychiatric Inventory (NPI)
This tool was developed to assess the BPSD of dementia patients. It measures the severity and frequency of patients' abnormal behaviors in a total of twelve fields as well as the stress of caregivers, which includes Delusion, Hallucination, Agitation/Aggression, Depression, Anxiety, Euphoria/Elation, Apathy/Indifference, Disinhibition, Irritability/Lability, Aberrant Motor Behavior, Sleep/Nighttime Behavior and Appetite/Eating Changes. Higher scores indicate more severe problem behaviors.
Clinical Dementia Rating Scale (CDR)
This scale was used to determine the severity of cognitive impairment. The CDR scores range from 0.5 to 3. (CDR = 0 Healthy, 0.5 point for Questionable dementia, 1 point for Mild dementia, 2 points for Moderate dementia, 3 points for Severe dementia).
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)
ADAS-cog is the most widely used measure of cognitive performance in AD clinical trials. It includes 12 components (Word recall, Naming objects and fingers, Commands, Constructional praxis, Ideational praxis, Orientation, Word recognition, Remembering test instruction, Ability of spoken language, Word finding, Comprehension, Attention). A total ADAS-cog score ranges from 0 (best cognitive performance) to 70 (worst performance).
Detection of White Matter Hyperintensity (WMH) on MRI
A total of 37 patients diagnosed with AD were recruited to the further study. Patients were divided into two groups, namely, none to mild WMH group (0-2 points, n = 14) and moderate to severe WMH group (3-6 points, n = 23) by magnetic resonance imaging (MRI) scans. WMH was quantified using the Fazekas scale according to T2 and FLAIR (fluid-attenuated inversion recovery) - weighted images.
Fazekas scores were used to evaluate WMH on the T2 and FLAIR-weighted images on a 0-6 score scale. Hyperintensity around the ventricles and deep WMH were assessed on the FLAIR images. The total score was the sum of the two subscores. Scoring criteria for periventricular (PV) -WMH were as follows: 0 point, no lesions; 1 point, cap-like or pencil-like thin slice lesions; 2 points, lesion presenting as a smooth halo; 3 points, irregular periventricular hyperintensity, extending into the deep white matter. Deep subcortical (DW) WMH: 0 point, no lesions; 1 point, spot-like lesions; 2 points, initial signs of lesions merging; 3 points, extensive lesions merging . WMH grading: 0 point, no WMH; 1-2 points, mild; 3-4 points, moderate; 5-6 points, severe.
The image data were processed by medical imaging specialist, who was blinded to the clinical data of the subjects, so as to avoid bias.
Measurement data were expressed as Mean ± S.D deviation. Intergroup comparisons of measurement data were conducted by performing an independent t-test, and categorical variables were assessed by Chi-square test. Then Multiple Linear Stepwise Regression Analysis was used to evaluate the relationship between several factors and behavioral symptoms of dementia, with adjustment for other potential confounding factors. A p-value of less than 0.05 was considered statistically significant. All of the statistical analyses were conducted using SPSS software package, version 22.0.
Comparison of baseline information and NPI scores of associated BPSD in AD patients of different gender
A total of 76 patients of AD were included. There were 27 males and 49 females, who were aged 74.44 ± 9.88 and 75.06 ± 9.70 years old, respectively. There were no significant difference regarding age, years of education and course of disease between the males and females group (Table 1).
Statistical analysis showed that the scores of delusion, anxiety, and sleep behavior disorder were significantly higher in females than in males group (p < 0.05). The scores of the remaining 10 BPSD items were not significantly different (Table 1).
Comparison of baseline information and ADAS-cog scores in AD patients of different gender
Thirty two AD patients received ADAS-cog assessment, with 11 males and 21 females. Statistical analysis indicated that the scores of verbal ability attention and ADAS-cog total score were significantly higher in males than in females. There were no significant differences in cognitive assessment on the remaining 10 items (Table 2).
BPSD and WMH in AD patients
Score of periventricular hyperintensity (PV) WMH, deep subcortical (DW) WMH and total score of WMH were 2.00 ± 1.00, 1.07 ± 0.96, 3.07 ± 1.75 in the male group and 1.95 ± 0.90, 0.86 ± 0.71, 2.82 ± 1.26 in the female group. Independent samples t-test was conducted to compare the means of two groups, which found no significant difference (p > 0.05).
Our preliminary study showed that WMH of AD patients might be related with BPSD . Depending on the Fazekas score, the patients were divided into two groups, namely, none to mild WMH group (0-2 points, n = 14) and moderate to severe WMH group (3-6 points, n = 23). NPI, CDR and ADAS-cog scores were compared between the two groups. The results showed that the NPI and CDR score were significantly different between the two groups, with the score being higher in the moderate to severe WMH group than in the none to mild WMH group (P < 0.05). No other significant differences were observed in the ADAS-cog scores of the remaining items (p > 0.05). It was thus inferred that severe WMH predicted more common BPSD (Table 3).
Multiple linear stepwise regression analysis of NPI total scores
Furthermore we performed Multiple Linear Stepwise Regression Analysis. To examine the relationship between WMH, CDR, gender, course of disease and NPI total scores. The results showed that only WMH score entered the regression equation at last (t = 2.451, p = 0.020), while the other variables were removed from the equation, such as Gender (t = -0.315, p = 0.755), Course of disease (t = -0.679, p = 0.503), CDR (t = 0.809, p = 0.425). The result implied that only WMH score was independently associated with NPI total score. The important information of regression equation was in (Table 4).
There is a new dementia patient every three seconds in the world. The economic and care burden of Alzheimer's disease has been increasing, and attention to AD is urgent and profound. A recent epidemiological study has shown that females are more likely to evolve into AD, while males are faced with a higher risk of vascular dementia . Like age, gender is an important biological variable in the development and progression of AD. However, the existing studies seem to arrive at conflicting conclusions on the gender difference of BPSD in patients with AD .
The present study showed that delusion, anxiety and sleep behavior disorder were more frequent in females than in males AD patients. It inferred that the gender differences in etiology perhaps have significant effects on these symptoms of AD patients. Tatruru, et al. reported similar findings as ours, that is, males were less likely to suffer from delusional idea, hallucination, anxiety and emotional impairment . Lowheim, et al. reported higher prevalence of aggressiveness in males, but more prevalent depressive symptoms in females . Lee, et al. studied dementia patients from Korea, and found no significant gender difference in BPSD . Delusion occurs more frequently in dementia patients, and the common types of delusion are delusion of being stolen, persecutory delusion, and delusion of jealousy. Studies have shown that polymorphism of the dopamine D2 receptor (DRD2) gene is associated with delusional symptom in dementia patients. DRD2-141C Ins/Ins genotype is related to various subtypes of delusion, including delusion of jealousy . The prevalence of anxiety symptoms is 8%-71% in dementia patients . It remains unclear whether anxiety reflects the degree of psychopathological symptoms of cognitive decline or whether the cognitive decline is caused by biological changes in the emotion-related neural circuit . Sleep disorder may promote beta amyloid protein deposition in the brain and hence increase the risk of AD. Besides, degenerative change at the key sites of sleep regulatory pathway in AD is an important etiology of sleep disorder [16,17].
Our results also indicated gender differences in the scores of verbal ability, attention and ADAS-cog total score in AD patients, with females outperforming the males. Cognitive and non-cognitive disorders (mainly BPSD) constitute the clinical manifestations of dementia, and there may be gender differences in the prevalence, clinical manifestations, disease progression and prognosis. The identified risk factors for evolving into dementia in males are smoking, coronary heart disease, and cerebral trauma (with disturbance of consciousness); for female patients, the risk factors are longevity, female hormones, diabetes, overweight and hypertension. The shared risk factors are elderly age, family history of dementia, ApoE-ε4 carrier and low educational level .
Some studies have revealed gender differences in nucleus basalis of Meynert (NBM) existed. Cholinergic neurons in the frontal cortex are more active in females, while those in the hippocampus are more active in males . The above evidences have implied the neurobiological basis for gender differences in BPSD in AD patients, and further studies are needed in this respect.
The etiology of BPSD is very complex and implicates neurobiological and social psychological factors. Our previous small sample-study has indicated that WMH severity may influence BPSD in patients with AD . WMH, a radiological term that refers to white matter lesions of the brain, is also known as leukoaraiosis, which is considered relevant to the ischemic injury. As we know, course of disease, the severity of dementia and gender were also related to BPSD . After regression analysis of all the aforementioned variables, our study showed that only WMH score still had significant impact on NPI total score. This result reminded us to pay attention to white matter lesion of Alzheimer's disease, especially for those patients with BPSD. Cerebral white matter is important constituent part of central nervous system, which is the area of nerve fibers aggregation. Several studies also support our opinions [19-21], while some studies reported the converse . White matter lesions in AD usually occurs in periventricular and subcortical white matter. Periventricular white matter lesions may be related to cerebrospinal fluid circulation disorder, whereas subcortical white matter lesions are mainly caused by arteriolar sclerosis and tissue hypoxia. One study suggested that amyloid accumulation was associated with impaired structural integrity in WMHs putatively adding to effects of ischemia .
The present study had certain limitations, such as the sample size was small, and we used MRI technology for a rough qualitative study of cerebral white matter lesions, but to further clarify the topic, the sample size should be increased in the future. Voxel-based morphometry (VBM) may be used for localization and quantitative study of white matter lesions.
Overall, our study confirmed that certain gender differences exist in behavioral and psychological symptoms of Alzheimer disease, such as delusion, anxiety and sleep behavior disorder, and cerebral white matter lesions were independently associated with behavioral and psychological symptoms of Alzheimer disease.
The authors would like to acknowledge and thank Dr. Sun Bing, Dr. Chen Jianping, Dr. Huang Ruoyan, Dr. Han Haiyin, Dr. Zou Canfang, Dr. Liu Wentao, Dr. Luo Xiong, Dr. Wang Xiaoli and Ms. Zhou Yinlin.
The study was funded by National key clinical specialty construction project: Guangzhou Psychiatric Hospital (Department of Medical Administration, Ministry of Health of the PRC.2011.NO: 873 ): 201201006 and funded by Guangzhou Municipal Psychiatric Disease Clinical Transformation Laboratory (No: 201805010009). Key Laboratory for Innovation platform Plan, Science and Technology Program of Guangzhou, China. Guangzhou municipal key discipline in medicine (2017-2019).
- Alzheimer's Disease International (2015) World Alzheimer Report.
- Alzheimer's Association (2015) Alzheimer's disease facts and figures. Alzheimers Dement 11: 332-384.
- Stella F, Radanovic M, Balthazar ML, et al. (2014) Neuropsychiatric symptoms in the predromal stages of dementia. Curr Opin Psychiatry 27: 230-235.
- Shin IS, Carter M, Masterman D, et al. (2005) Neuropsychiatric symptoms and quality of life in Alzheimer disease. Am J Geriatr Psychiatry 13: 469-474.
- Ferretti MT, Lulita MF, Cavedo E, et al. (2018) Sex differences in Alzheimer disease-the gateway to precision medicine. Nat Rev Neurol 14: 457-469.
- Fazekas F, Chawluk JB, Alavi A, et al. (1987) MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol 149: 351-356.
- Mu N, Pan JY, Wu HW, et al. (2018) Research on white matter lesion and behavioral and psychological symptoms of patients with Alzheimer's Disease. J Pract Med 34: 1297-1300.
- Podcasy JL, Epperson CN (2016) Considering sex and gender in Alzheimer Disease and other dementias. Dialogues Clin Neurosci 18: 437-446.
- Lee J, Lee KJ, Kim H (2017) Gender differences in behavioral and psychological symptoms of patients with Alzheimer's disease. Asian J Psychiatr 26: 124-128.
- Tatsuru K, Maki K, Shoryoku H, et al. (2012) Gender difference in clinical manifestations and outcome among hospitalized patients with behavioral and psychological symptoms of dementia. J Clin Psychiatry 73: 1548-1554.
- Lovheim H, Sandman PO, Karlsson S, et al. (2009) Sex differences in the prevalence of behavioral and psychological symptoms of dementia. Int Psychogeriatr 21: 469-475.
- Lee JY, Im WY, Kim H, et al. (2014) Gender differences in behavioral psychological symptoms of dementia in patients with Alzheimer's disease. Korean J Psychosom Med 22: 71-78.
- Pai MC (2008) Delusions and visual hallucinations in dementia patients: Focus on personal history of the patients. Tohoku J Exp Med 216: 1-5.
- Seignourel PJ, Kunik ME, Snow L, et al. (2008) Anxiety in dementia: A critical review. Clin Psychol Rev 28: 1071-1082.
- Levenson RW, Sturm VE, Haase CM (2014) Emotional and behavioral symptoms in neurodegenerative disease: A model for studying the neural bases of psychopathology. Annu Rev Clin Psychol 10: 581-606.
- Mander B, Marks S, Vogel J, et al. (2015) β-amynoid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nature Neurosci 18: 1051-1057.
- Weldemichael D, Grossberg G (2010) Circadian rhythm disturbances in patients with Alzheimer's disease: A review. Int J Alzheimer Dis 102: 58-102.
- Giacobini E, Pepeu GC (2018) Sex and gender difference in the brain cholinergic system and in the response to therapy of Alzheimer Disease with cholinesterase inhibitors. Curr Alzheimer Res 15: 1077-1084.
- Beraw YA, Wells WM, Ellison JM, et al. (2010) Neuropsychiatric correlates of white matter hyperintensities in Alzheimer's disease. Int J Geriatr Psychiatry 25: 780-788.
- Kandiah N, Chander R, Zhang A, et al. (2014) Cerebral white matter disease is independently associated with BPSD in Alzheimer's disease. J Neurol Sci 337: 162-166.
- Moghekar A, Kraut M, Elkins W, et al. (2012) Cerebral white matter disease is associated with Alzheimer pathology in a prospective cohort. Alzheimers Dement 8: S71-S77.
- Staekenborg SS, Gillissen F, Romkes R, et al. (2008) Behavioural and psychological symptoms are not related to white matter hyperintensities and medial temporal lobe atrophy in Alzheimer's disease. Int J Geriatr Psychiatry 23: 387-392.
- Kalheim LF, Bjornerud A, Fladby T, et al. (2017) White matter hyperintensity microstructure in amyloid dysmetabolism. J Cereb Blood Flow Metab 37: 356-365.
PAN Jiyang, Department of Psychiatry, First Affiliated Hospital of Jinan University, China;
TANG Mouni, Department of Geriatric Psychiatry, Affiliated Brain Hospital of Guangzhou Medical University, China
© 2019 Nan MU, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.