Brain-wide activation involved in 15 mA transcranial alternating current stimulation in patients with first-episode major depressive disorder.

Background: Although 15 mA transcranial alternating current stimulation (tACS) has a therapeutic effect on depression, the activations of brain structures in humans accounting for this tACS configuration remain largely unknown. Aims: To investigate which intracranial brain structures are engaged in the tACS at 77.5 Hz and 15 mA, delivered via the forehead and the mastoid electrodes in the human brain. Methods: Actual human head models were built using the magnetic resonance imagings of eight outpatient volunteers with drug-naïve, first-episode major depressive disorder and then used to perform the electric field distributions with SimNIBS software. Results: The electric field distributions of the sagittal, coronal and axial planes showed that the bilateral frontal lobes, bilateral temporal lobes, hippocampus, cingulate, hypothalamus, thalamus, amygdala, cerebellum and brainstem were visibly stimulated by the 15 mA tACS procedure. Conclusions: Brain-wide activation, including the cortex, subcortical structures, cerebellum and brainstem, is involved in the 15 mA tACS intervention for first-episode major depressive disorder. Our results indicate that the simultaneous involvement of multiple brain regions is a possible mechanism for its effectiveness in reducing depressive symptoms.

Transcranial alternating current stimulation for treating depression: a randomized controlled trial.

Treatment of depression with antidepressants is partly effective. Transcranial alternating current stimulation can provide a non-pharmacological alternative for adult patients with major depressive disorder. However, no study has used the stimulation to treat first-episode and drug-naïve patients with major depressive disorder. We used a randomized, double-blind, sham-controlled design to examine the clinical efficacy and safety of the stimulation in treating first-episode drug-naïve patients in a Chinese Han population. From 4 June 2018 to 30 December 2019, 100 patients were recruited and randomly assigned to receive 20 daily 40-min, 77.5 Hz, 15 mA, one forehead and two mastoid sessions of active or sham stimulation (n = 50 for each group) in four consecutive weeks (Week 4), and were followed for additional 4-week efficacy/safety assessment without stimulation (Week 8). The primary outcome was a remission rate defined as the 17-item Hamilton Depression Rating Scale (HDRS-17) score ≤ 7 at Week 8. Secondary analyses were response rates (defined as a reduction of ≥ 50% in the HDRS-17), changes in depressive symptoms and severity from baseline to Week 4 and Week 8, and rates of adverse events. Data were analysed in an intention-to-treat sample. Forty-nine in the active and 46 in the sham completed the study. Twenty-seven of 50 (54%) in the active treatment group and 9 of 50 (18%) in the sham group achieved remission at the end of Week 8. The remission rate was significantly higher in the active group compared to that in the sham group with a risk ratio of 1.78 (95% confidence interval, 1.29, 2.47). Compared with the sham, the active group had a significantly higher remission rate at Week 4, response rates at Weeks 4 and 8, and a larger reduction in depressive symptoms from baseline to Weeks 4 and 8. Adverse events were similar between the groups. In conclusion, the stimulation on the frontal cortex and two mastoids significantly improved symptoms in first-episode drug-naïve patients with major depressive disorder and may be considered as a non-pharmacological intervention for them in an outpatient setting.

COVID-19 pandemic: study on simple, easy, and practical relaxation techniques while wearing medical protective equipment.

BACKGROUND: No studies have reported on how to relieve distress or relax in medical health workers while wearing medical protective equipment in coronavirus disease 2019 (COVID-19) pandemic. The study aimed to establish which relaxation technique, among six, is the most feasible in first-line medical health workers wearing medical protective equipment. METHODS: This was a two-step study collecting data with online surveys. Step 1: 15 first-line medical health workers were trained to use six different relaxation techniques and reported the two most feasible techniques while wearing medical protective equipment. Step 2: the most two feasible relaxation techniques revealed by step 1 were quantitatively tested in a sample of 65 medical health workers in terms of efficacy, no space limitation, no time limitation, no body position requirement, no environment limitation to be done, easiness to learn, simplicity, convenience, practicality, and acceptance. RESULTS: Kegel exercise and autogenic relaxation were the most feasible techniques according to step 1. In step 2, Kegel exercise outperformed autogenic relaxation on all the 10 dimensions among the 65 participants while wearing medical protective equipment (efficacy: 24 v. 15, no space limitation: 30 v. 4, no time limitation: 31 v. 4, no body position requirement: 26 v. 4, no environment limitation: 30 v. 11, easiness to learn: 28 v. 5, simplicity: 29 v. 7, convenience: 29 v. 4, practicality: 30 v. 14, acceptance: 32 v. 6). CONCLUSION: Kegel exercise seems a promising self-relaxation technique for first-line medical health workers while wearing medical protective equipment among COVID-19 pandemic.

The Relationship of Large-Artery Atherothrombotic Stroke with Plasma Trimethylamine N-Oxide Level and Blood Lipid-Related Indices: A Cross-Sectional Comparative Study.

OBJECTIVE: The role of trimethylamine N-oxide (TMAO) in cardiovascular diseases has been highlighted. Nevertheless, the associations of large-artery atherosclerotic (LAA) stroke with TMAO and blood lipid-related indices are little investigated. METHODS: A cross-sectional comparative study was performed on 50 patients with LAA stroke and 50 healthy controls. Basic demographic data, common vascular risk factors, and blood lipid-related indices were collected. Plasma TMAO was detected through liquid chromatography tandem mass spectrometry. Multivariable unconditional logistic regression analyses were run to assess the associations of LAA stroke with plasma TMAO level and blood lipid-related indices. The area under the curve (AUC) of the receiver operating characteristic (ROC) was computed to assess the diagnostic performance of plasma TMAO level and blood lipid-related indices for LAA stroke. RESULTS: Compared with healthy controls, the elevated plasma TMAO level (odds ratio [OR], 7.03; 95% confidence interval [CI], 2.86, 17.25; p < 0.01) and Apo-B (OR, 1.74; 95% CI, 1.06, 2.85; p = 0.03) were observed in LAA stroke patients, while lower Apo-A1 (OR, 0.56; 95% CI, 0.34, 0.91; p = 0.02), Apo-A1 to Apo-B ratio (OR, 0.29; 95% CI, 0.15, 0.56; p < 0.01), and HDL-C (OR, 0.56; 95% CI, 0.35, 0.91; p = 0.02) were found in LAA stroke patients after adjusted for age and gender. Moreover, plasma TMAO (AUC, 0.89; 95% CI, 0.83, 0.95), Apo-A1 (AUC, 0.81; 95% CI, 0.72, 0.89), Apo-B (AUC, 0.81; 95% CI, 0.73, 0.90), Apo-A1 to Apo-B ratio (AUC, 0.85; 95% CI, 0.78, 0.93), and HDL-C (AUC, 0.81; 95% CI, 0.72, 0.89) showed good diagnostic values for LAA stroke in adjusted models. CONCLUSIONS: The plasma TMAO level, Apo-A1, Apo-B, and HDL-C are important biomarkers for LAA stroke patients.

Post-COVID-19 Epidemic: Allostatic Load among Medical and Nonmedical Workers in China.

BACKGROUND: As the fight against the COVID-19 epidemic continues, medical workers may have allostatic load. OBJECTIVE: During the reopening of society, medical and nonmedical workers were compared in terms of allostatic load. METHODS: An online study was performed; 3,590 Chinese subjects were analyzed. Socio-demographic variables, allostatic load, stress, abnormal illness behavior, global well-being, mental status, and social support were assessed. RESULTS: There was no difference in allostatic load in medical workers compared to nonmedical workers (15.8 vs. 17.8%; p = 0.22). Multivariate conditional logistic regression revealed that anxiety (OR = 1.24; 95% CI 1.18-1.31; p < 0.01), depression (OR = 1.23; 95% CI 1.17-1.29; p < 0.01), somatization (OR = 1.20; 95% CI 1.14-1.25; p < 0.01), hostility (OR = 1.24; 95% CI 1.18-1.30; p < 0.01), and abnormal illness behavior (OR = 1.49; 95% CI 1.34-1.66; p < 0.01) were positively associated with allostatic load, while objective support (OR = 0.84; 95% CI 0.78-0.89; p < 0.01), subjective support (OR = 0.84; 95% CI 0.80-0.88; p < 0.01), utilization of support (OR = 0.80; 95% CI 0.72-0.88; p < 0.01), social support (OR = 0.90; 95% CI 0.87-0.93; p < 0.01), and global well-being (OR = 0.30; 95% CI 0.22-0.41; p < 0.01) were negatively associated. CONCLUSIONS: In the post-COVID-19 epidemic time, medical and nonmedical workers had similar allostatic load. Psychological distress and abnormal illness behavior were risk factors for it, while social support could relieve it.

Mental Health and Psychosocial Problems of Medical Health Workers during the COVID-19 Epidemic in China.

OBJECTIVE: We explored whether medical health workers had more psychosocial problems than nonmedical health workers during the COVID-19 outbreak. METHODS: An online survey was run from February 19 to March 6, 2020; a total of 2,182 Chinese subjects participated. Mental health variables were assessed via the Insomnia Severity Index (ISI), the Symptom Check List-revised (SCL-90-R), and the Patient Health Questionnaire-4 (PHQ-4), which included a 2-item anxiety scale and a 2-item depression scale (PHQ-2). RESULTS: Compared with nonmedical health workers (n = 1,255), medical health workers (n = 927) had a higher prevalence of insomnia (38.4 vs. 30.5%, p < 0.01), anxiety (13.0 vs. 8.5%, p < 0.01), depression (12.2 vs. 9.5%; p< 0.04), somatization (1.6 vs. 0.4%; p < 0.01), and obsessive-compulsive symptoms (5.3 vs. 2.2%; p < 0.01). They also had higher total scores of ISI, GAD-2, PHQ-2, and SCL-90-R obsessive-compulsive symptoms (p ≤ 0.01). Among medical health workers, having organic disease was an independent factor for insomnia, anxiety, depression, somatization, and obsessive-compulsive symptoms (p < 0.05 or 0.01). Living in rural areas, being female, and being at risk of contact with COVID-19 patients were the most common risk factors for insomnia, anxiety, obsessive-compulsive symptoms, and depression (p < 0.01 or 0.05). Among nonmedical health workers, having organic disease was a risk factor for insomnia, depression, and obsessive-compulsive symptoms (p < 0.01 or 0.05). CONCLUSIONS: During the COVID-19 outbreak, medical health workers had psychosocial problems and risk factors for developing them. They were in need of attention and recovery programs.

The efficacy of transcranial alternating current stimulation for treating post-stroke depression: Study Protocol Clinical Trial (SPIRIT Compliant).

BACKGROUND: The treatment of post-stroke depression (PSD) with anti-depressant drugs is partly practical. Transcranial alternating current stimulation (tACS) offers the potential for a novel treatment modality for adult patients with PSD. In this study, we will assess the efficacy and safety of tACS for treating PSD and explore its effect on gamma and beta-oscillations involving in emotional regulation. METHODS: The prospective study is an 8-week, double-blind, randomized, placebo-controlled trial. Seventy eligible participants with mild to moderate PSD aged between 18 years and 70 years will be recruited and randomly assigned to either active tACS intervention group or sham group. Daily 40-minute, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4), and an additional 4-week observational period (week 8) will be followed up. The primary outcome is the proportion of participants having an improvement at week 8 according to the Hamilton Depression Rating Scale 17-Item (HAMD-17) score, including the proportion of participants having a decrease of ≥ 50% in HAMD-17 score or clinical recovery (HAMD-17 score ≤ 7). Secondary outcomes include neurological function, independence level, activities of daily living, disease severity, anxiety, and cognitive function. The exploratory outcomes are gamma and beta-oscillations assessed at baseline, week 4, and week 8. Data will be analyzed by logistical regression analyses and mixed-effects models. DISCUSSION: The study will be the first randomized controlled trial to evaluate the efficacy and safety of tACS at a 77.5-Hz frequency and 15-mA current in reducing depressive severity in patients with PSD. The results of the study will present a base for future studies on the tACS in PSD and its possible mechanism. TRIAL REGISTRATION NUMBER: NCT03903068, pre-results.

Protocol on transcranial alternating current stimulation for the treatment of major depressive disorder: a randomized controlled trial.

BACKGROUND: Transcranial alternating current stimulation (tACS) offers a new approach for adult patients with major depressive disorder (MDD). The study is to evaluate the efficacy and safety of tACS treating MDD. METHODS: This is an 8-week, double-blind, randomized, placebo-controlled study. Ninety-two drug-naive patients with MDD aged 18 to 65 years will receive 20 daily 40-min, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4), following a 4-week observation period (week 8). The primary outcome is the remission rate defined as the 17-item Hamilton depression rating scale (HDRS-17) score ≤7 at week 8. Secondary outcomes are the rates of response at weeks 4 and 8 and rate of remission at week 4 based on HDRS-17, the proportion of participants having improvement in the clinical global impression-improvement, the change in HDRS-17 score (range, 0-52, with higher scores indicating more depression) over the study, and variations of brain imaging and neurocognition from baseline to week 4. Safety will be assessed by vital signs at weeks 4 and 8, and adverse events will be collected during the entire study. DISCUSSION: The tACS applied in this trial may have treatment effects on MDD with minimal side effects. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800016479; http://www.chictr.org.cn/showproj.aspx?proj=22048.

Effect of Transcranial Alternating Current Stimulation for the Treatment of Chronic Insomnia: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Clinical Trial.

BACKGROUND: Not all adults with chronic insomnia respond to the recommended therapeutic options of cognitive behavioral therapy and approved hypnotic drugs. Transcranial alternating current stimulation (tACS) may offer a novel potential treatment modality for insomnia. OBJECTIVES: This study aimed to examine the efficacy and safety of tACS for treating adult patients with chronic insomnia. METHODS: Sixty-two participants with chronic primary insomnia received 20 daily 40-min, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas in the laboratory on weekdays for 4 consecutive weeks, followed by a 4-week follow-up period. The primary outcome was response rate measured by the Pittsburgh Sleep Quality Index (PSQI) at week 8. Secondary outcomes were remission rate, insomnia severity, sleep onset latency (SOL), total sleep time (TST), sleep efficiency, sleep quality, daily disturbances, and adverse events at the end of the 4-week intervention and at the 4-week follow-up. RESULTS: Of 62 randomized patients, 60 completed the trial. During the 4-week intervention, 1 subject per group withdrew due to loss of interest and time restriction, respectively. Based on PSQI, at 4-week follow-up, the active group had a higher response rate compared to the sham group (53.4% [16/30] vs. 16.7% [5/30], p = 0.009), but remission rates were not different between groups. At the end of the 4-week intervention, the active group had higher response and remission rates than the sham group (p < 0.001 and p = 0.026, respectively). During the trial, compared with the sham group, the active group showed a statistically significant decrease in PSQI total score, a shortened SOL, an increased TST, improved sleep efficiency, and improved sleep quality (p < 0.05 or p < 0.001). Post hoc analysis revealed that, in comparison with the sham group, the active group had improved symptoms, except for daily disturbances, at the end of the 4-week intervention, and significant improvements in all symptoms at the 4-week follow-up. No adverse events or serious adverse responses occurred during the study. CONCLUSION: The findings show that the tACS applied in the present study has potential as an effective and safe intervention for chronic insomnia within 8 weeks.

Diagnosis and treatment of dementia in neurology outpatient departments of general hospitals in China.

INTRODUCTION: The status of dementia diagnosis and treatment of neurology outpatients in general hospitals in China remains unclear. METHODS: From neurology outpatients at 36 randomly selected hospitals, we first collected baseline data concerning the number of dementia doctors, memory clinics, and patients diagnosed with dementia. In stage 2, we intervened based on drawbacks discovered in stage 1, implementing a dementia initiative program. In stage 3, we reinvestigated the outpatients to determine the effects of intervention. RESULTS: After intervention, all 36 hospitals had established memory clinics (205 dementia doctors) compared with only 6 (47 dementia doctors) before intervention. The percentage of patients diagnosed with dementia significantly increased from 0.10% (536 dementia patients of 553,986 outpatients) in stage 1 to 0.41% (2482 dementia patients of 599,214 outpatients) in stage 3. DISCUSSION: Proper diagnosis and treatment are unavailable to many dementia patients because of a lack of dementia doctors and memory clinics in China.

The Effects of Acupuncture at Real or Sham Acupoints on the Intrinsic Brain Activity in Mild Cognitive Impairment Patients.

Accumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. Acupuncture at different acupoints could exert different modulatory effects on the brain network. However, whether acupuncture at real or sham acupoints can produce different effects on the brain network in MCI or AD patients remains unclear. Using resting-state fMRI, we reported that acupuncture at Taixi (KI3) induced amplitude of low-frequency fluctuation (ALFF) change of different brain regions in MCI patients from those shown in the healthy controls. In MCI patients, acupuncture at KI3 increased or decreased ALFF in the different regions from those activated by acupuncture in the healthy controls. Acupuncture at the sham acupoint in MCI patients activated the different brain regions from those in healthy controls. Therefore, we concluded that acupuncture displays more significant effect on neuronal activities of the above brain regions in MCI patients than that in healthy controls. Acupuncture at KI3 exhibits different effects on the neuronal activities of the brain regions from acupuncture at sham acupoint, although the difference is only shown at several regions due to the close distance between the above points.

Thinner changes of the retinal nerve fiber layer in patients with mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia and patients often have visual disorders. Mild cognitive impairment (MCI) is characterized by a memory deficit when compared with those of a similar age and education level which could indicate an earlier onset of AD. The aim of this study is to measure the changes of the retinal nerve fiber layer (RNFL) thickness of AD and MCI patients in comparison with the normal age controls. METHODS: The RNFL thickness was assessed using optical coherence tomography (OCT) in patients with MCI, AD (mild, moderate and severe) and the age matched controls. RESULTS: The thickness of RNFL in the superior quadrant and total mean values are gradually and significantly decreased from MCI to severe AD when compared to that in the controls. There is also a significant reduction of the retinal nerve fiber layer in the inferior quadrant in severe AD patients. CONCLUSIONS: Our data indicate that the retinal nerve fiber layer degeneration is paralleled with dementia progression. Owing to its non-invasive and cost effective nature, monitoring RNFL thickness may have a value in assessing disease progression and the efficacy of any treatments.

Elevated plasma angiogenesis factors in Alzheimer's disease.

Evidence has shown that aberrant angiogenesis is an integral part of Alzheimer's disease (AD). Angiogenesis is a complex process requiring successive activation of a rather large series of factors. The aim of this study was to determine which angiogenesis molecule(s) abnormalities were changed in plasma of AD subjects and whether plasma levels of angiogenesis factors were associated with cognitive function and risk of AD. Discovery-phase antibody arrays were used to detect plasma concentrations of 55 angiogenesis-related factors. Enzyme-linked immunosorbent assays (ELISAs) in a large cohort were further performed to identify the association of plasma angiogenesis factors with AD. We found that plasma angiogenin (ANG) and tissue inhibitor of matrix metalloproteinase-4 (TIMP-4) levels were higher in patients with AD than those in normal subjects. Significantly higher ANG and TIMP-4 were observed in the severe AD group relative to the mild AD. There were different levels of plasma ANG and TIMP-4 compared with vascular dementia and other dementias. Age or gender had no major effects on levels of these proteins. Plasma ANG and TIMP-4 levels tended to be higher in ApoE ε4 carriers compared with non-carriers, but not significantly. A multiple regression analysis after adjusting for covariates revealed correlations between plasma ANG and TIMP-4 and the MMSE and CDR. Higher plasma ANG and TIMP-4 levels were associated with significant AD risk. These results demonstrate that plasma ANG and TIMP-4 may reflect the severity of cognitive function impairment, and higher levels were associated with risk of AD.

Neural dynamics of animacy processing in language comprehension: ERP evidence from the interpretation of classifier-noun combinations.

An event-related potential experiment was conducted to investigate the temporal neural dynamics of animacy processing in the interpretation of classifier-noun combinations. Participants read sentences that had a non-canonical structure, object noun +subject noun+verb+numeral-classifier+adjective. The object noun and its classifier were either (a) congruent, (b) incongruent, but matching in animacy, or (c) incongruent, mismatching in animacy. An N400 effect was observed for both incongruent conditions, but not for additional mismatch in animacy. When only data from participants who accepted the non-canonical structure were analyzed, the animacy mismatch elicited a P600 but still no N400. These findings suggest that animacy information is not used immediately for semantic integration of nouns and their classifiers, but is used in a later analysis reflected by P600. Thus, the temporal neural dynamics of animacy processing in sentence comprehension may be modulated by the relevance of animacy to thematic interpretation.

Frequency-dependent changes in the amplitude of low-frequency fluctuations in amnestic mild cognitive impairment: a resting-state fMRI study.

Here we utilized resting-state functional magnetic resonance imaging (R-fMRI) to measure the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) in 24 patients with amnestic mild cognitive impairment (aMCI) and 24 age- and sex-matched healthy controls. Two different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz) were analyzed. We showed that there were widespread differences in ALFF/fALFF between the two bands in many brain regions, predominantly including the medial prefrontal cortex (MPFC), posterior cingulate cortex/precuneus (PCC/PCu), basal ganglia, and hippocampus/parahippocampal gyrus (PHG). Compared to controls, the aMCI patients had decreased ALFF/fALFF values in the PCC/PCu, MPFC, hippocampus/PHG, basal ganglia, and prefrontal regions, and increased ALFF/fALFF values mainly in several occipital and temporal regions. Specifically, we observed that the ALFF/fALFF abnormalities in the PCC/PCu, PHG, and several occipital regions were greater in the slow-5 band than in the slow-4 band. Finally, our results of functional analysis were not significantly influenced by the gray matter loss in the MCI patients, suggesting that the results reflect functional differences between groups. Together, our data suggest that aMCI patients have widespread abnormalities in intrinsic brain activity, and the abnormalities depend on the studied frequency bands of R-fMRI data.

[Relationship between three neuropsychological tests and cerebral glucose metabolism in Alzheimer's disease].

OBJECTIVE: To study the relationship between the scores of 3 neuropsychological scales: MMSE, extended scale of dementia (ESD) and Blessed dementia scale (BDS) and cerebral glucose metabolism in Alzheimer's disease (AD) indicated by positron emission tomography (PET). METHODS: Brain scanning was performed with SIEMENS ECAT 47 PET scanner among 21 AD patients, aged 60 - 83 (10 mild, 6 moderate, and 5 severe), and 15 healthy persons, aged 57 - 73. The ratio of mean radioactivity of cerebral lobe to that of cerebellum as semi-quantitative parameters was used to evaluate the cerebral glucose metabolism. Cognitive function was assessed by three neuropsycholigical scales: MMSE, ESD and BDS. RESULTS: The average MMSE score was 13.3 +/- 6.3 (range 2 - 25), the average ESD score was 120.5 +/- 54.8 (range 28 - 200), and the average BDS score was 4.7 +/- 3.1 (range 0.5 - 10) in the AD patients. The decreases of glucose metabolism in parietal, frontal and temporal lobes were significantly positively correlated with MMSE and ESD scores, and negatively correlated with BDS scores in AD patients (P < 0.05). The correlations between MMSE and ESD (r = 0.886), MMSE and BDS (r = -0.763), and ESD and BDS (r = -0.773) were significant in AD patients (all P < 0.01). Taking the ratio of radioactivity of cerebral lobe to that of cerebellum as an independent variable X, the MMSE, ESD and BDS scorsas dependent variable Y, three regression equations were established as follows: Y = 40.11 * X- 25.32, Y = 309.19 * X- 180.9, Y = 19.97 - 16.53 * X. The independent variable entering the three regression equations was always the ratio of radioactivity of left parietal lobe to that of cerebellum. The ratio of radioactivity of left parietal lobe to that of cerebellum was a significant predictor for cognitive dysfunction measured by MMSE, ESD and BDS in AD patients (P < 0.01). CONCLUSION: MMSE, ESD and BDS scores correlate well with impaired cerebral glucose metabolism in AD. The function of left parietal lobe may play an important role in the progress of the disease. MMSE, ESD and BDS are good measures for cognitive dysfunction.