Increased risk of dementia in patients with nasopharyngeal cancer treated with radiation therapy: A nationwide population-based cohort study.

PURPOSE: We evaluated the risk of dementia in patients with nasopharyngeal cancer (NPC) after undergoing radiation therapy (RT). METHODS: Between January 1, 2000, and December 31, 2015, 594 patients newly diagnosed with NPC and treated with RT (NPC cohort) were identified from the Longitudinal Health Insurance Database (LHID) for this nationwide population-based matched cohort study. LHID is a subset of the National Health Insurance Research Database of Taiwan. We selected 2376 controls (non-NPC comparison cohort) using a four-fold propensity score-matched by sex, age, comorbidities, education level, tobacco abuse, and index date (the date when the patient received first RT). After adjusting for confounding factors, Fine and Gray's competing risk analysis compared dementia development between the NPC study cohort and non-NPC comparison cohort over the observation period from 2000 to 2015. RESULTS: Dementia development was 6.57% (39 of 594) and 4.42% (105 of 2376) in the NPC study cohort and non-NPC comparison cohort, respectively. Patients with NPC receiving RT were more likely to develop dementia than the comparison cohort, with a crude hazard ratio (HR) of 1.63 [95% confidence interval (CI) = 1.25-2.13, P < 0.001]. After adjusting for age, sex, education level, tobacco abuse, comorbidity, geographic area, urbanization level of the residence, and care level, the adjusted HR was 1.91 (95% CI = 1.42-2.51, P < 0.001). CONCLUSIONS: Patients with NPC receiving RT had a 1.91-fold higher risk of dementia than the non-NPC comparison controls.

Detection of cognitive impairment using self-rated AD8 and informant-reported AD8.

BACKGROUND/PURPOSE: Screening of dementia can help to initiate proper management of the disorder. The use of the Ascertain Dementia 8-item Questionnaire (AD8) in screening has been promoted in Taiwan recently. The purpose of this study was to compare the psychometric properties and appropriateness of informant-reported and self-rated AD8 in cognitive impairment screening in Taiwan. METHODS: The AD8 were administered to 153 participants and their informants recruited from two neurology out-patient clinics. The discriminative abilities for early cognitive impairment [Clinical Dementia Rating scale (CDR) 0.5 and 1] of informant-based and self-rating AD8 were determined and compared with their areas under the receiver operating curve. κ coefficients representing the agreement between self-rated and informant-reported AD8 scores were also calculated. RESULTS: Participants and their informants were aged 76.9 years and 56.0 years on average, respectively. Only informant-reported AD8 was significantly associated with CDR level (Spearman ρ=0.469, p<0.001) and Cognitive Abilities Screening Instrument score (Spearman ρ=-0.458, p<0.001). The item-by-item agreements between self-rated and informant-reported AD8 were poor (κ coefficients: -0.030 to 0.206). The area under the receiver-operator characteristic curve was 0.59 for self-rated AD8 scores, and 0.77 for informant-reported AD8 scores, indicating that the discriminating ability of AD8 scores between CDR 0 and CDR 0.5 or greater is better when reported by informant than when rated by self. CONCLUSION: Informant-rated AD8 gave more accurate screening results than self-reported AD8 in an out-patient clinic setting.

CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking.

α7 nicotinic acetylcholine receptor (α7nAChR, encoded by CHRNA7) is involved in dementia pathogenesis through cholinergic neurotransmission, neuroprotection and interactions with amyloid-ß. Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via α7nAChR in preclinical studies. No studies explored the gene-gene, gene-environment interactions between CHRNA7 polymorphism, apolipoprotein E (APOE) ε4 status and smoking on dementia risk. This case-control study recruited 254 late-onset Alzheimer's disease (LOAD) and 115 vascular dementia (VaD) cases (age ≥65) from the neurology clinics of three teaching hospitals in Taiwan during 2007-2010. Controls (N = 435) were recruited from health checkup programs and volunteers during the same period. Nine CHRNA7 haplotype-tagging single nucleotide polymorphisms representative for Taiwanese were genotyped. Among APOE ε4 non-carriers, CHRNA7 rs7179008 variant carriers had significantly decreased LOAD risk after correction for multiple tests (GG + AG vs. AA: adjusted odds ratio = 0.29, 95% confidence interval = 0.13-0.64, P = 0.002). Similar findings were observed for carriers of GT haplotype in CHRNA7 block4. A significant interaction was found between rs7179008, GT haplotype in block4 and APOE ε4 on LOAD risk. rs7179008 variant also reduced the detrimental effect of smoking on LOAD risk. No significant association was found between CHRNA7 and VaD. These findings help to understand dementia pathogenesis.

The impacts of acute carbon monoxide poisoning on the brain: Longitudinal clinical and 99mTc ethyl cysteinate brain SPECT characterization of patients with persistent and delayed neurological sequelae.

OBJECTIVE: Acute carbon monoxide (CO) poisoning poses a significant threat to the central nervous system. It can cause brain injury and diverse neurological deficits including persistent neurological sequelae (PNS) and delayed neurological sequelae (DNS). The study aimed to investigate the long-term impacts of acute CO poisoning on brain perfusion and neurological function, and to explore potential differences between PNS and DNS patients. METHODS: We evaluated brain perfusion using (99m)Tc ethyl cysteinate (ECD) brain single photon emission computed tomography (SPECT) and assessed clinical neurological symptoms and signs one month following acute poisoning. For DNS patients, ECD SPECT and clinical evaluation were performed when their delayed symptoms appeared. All patients had follow-up SPECT imaging, along with clinical assessments six months following poisoning. RESULTS: 12 PNS and 12 DNS patients were recruited between 2007 and 2010. Clinically, the main characteristic presentations were cognitive decline, emotional instability, and gait disturbance. SPECT imaging demonstrated consistent frontal hypoperfusion of varying severities in all patients, which decreased in severity at follow-up imaging. DNS patients usually had more severe symptoms and perfusion defects, along with worse clinical outcomes than the PNS group. CONCLUSION: These results suggest that acute CO poisoning might lead to long term brain injuries and neurological sequelae, particularly in DNS patients.

A potential protective effect in multilingual patients with semantic dementia: two case reports of patients speaking Taiwanese and Japanese.

PURPOSE: Several reports have suggested that multilingualism has a protective effect against semantic dementia. Here, we provide further evidence for this effect. CASE REPORTS FIRST: The patient was a 75-year-old right-handed Taiwanese woman who had retired after working as a tailor. She was able to speak Taiwanese, Japanese and Mandarin Chinese fluently until 5 years ago. She gradually developed symptoms of profound anomia and difficulty with word-finding. Her mother tongue was Taiwanese and she had learned Japanese as her first symbolized language. She had used Mandarin Chinese for most of her life, but depended on Japanese to read and write (such as reading a newspaper and keeping accounts). However, she could now speak only very simple Taiwanese and Japanese, and could recognize only simple Japanese characters. SECOND: The patient was a 62-year-old right-handed man who had worked as an ironworker. He could speak Taiwanese and Mandarin Chinese fluently until 5 years ago. His mother tongue was Taiwanese. After 5 years of language deterioration, he was unable to communicate with his family members or recognize any characters, including numbers. SPECT RESULTS: Brain perfusion ECD SPECT (Tc-99m-ethyl cysteinate dimer single-photon emission computed tomography) showed less perfusion in the multilingual patient (Case #1) than in the bilingual patient (Case #2). Neuropsychological tests also demonstrated a slower rate of degeneration in the multilingual patient. CONCLUSION: We speculate that reading and writing in Japanese had a greater impact on the semantic system in Case #1. Thus, this patient showed relatively less degeneration or functional inactivity, as shown by perfusion in the frontal lobe, and this might be due to the persistent activation involved in multilingualism.

Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease.

BACKGROUND: Interleukin 6 (IL-6) has been related to beta-amyloid aggregation and the appearance of hyperphosphorylated tau in Alzheimer's disease (AD) brain. However, previous studies relating IL-6 genetic polymorphisms to AD included few and unrepresentative single nucleotide polymorphisms (SNPs) and the results were inconsistent. METHODS: This is a case-control study. A total of 266 patients with AD, aged≧65, were recruited from three hospitals in Taiwan (2007-2010). Controls (n = 444) were recruited from routine health checkups and volunteers of the hospital during the same period of time. Three common IL-6 haplotype-tagging SNPs were selected to assess the association between IL-6 polymorphisms and the risk of late-onset AD (LOAD). RESULTS: Variant carriers of IL-6 rs1800796 and rs1524107 were significantly associated with a reduced risk of LOAD [(GG + GC vs. CC): adjusted odds ratio (AOR) = 0.64 and (CC + CT vs. TT): AOR = 0.60, respectively]. Haplotype CAT was associated with a decreased risk of LOAD (0 and 1 copy vs. 2 copies: AOR = 0.65, 95% CI = 0.44-0.95). These associations remained significant in ApoE e4 non-carriers only. Hypertension significantly modified the association between rs2069837 polymorphisms and the risk of LOAD (pinteraction = 0.03). CONCLUSIONS: IL-6 polymorphisms are associated with reduced risk of LOAD, especially in ApoE e4 non-carriers. This study identified genetic markers for predicting LOAD in ApoE e4 non-carriers.

Neurosarcoidosis affecting the spinal cord.

Sarcoidosis is a chronic inflammatory disease that involves multiple systems. Complications in the nervous system are rare, especially in Asia. This report describes an unusual case of neurosarcoidosis affecting the spinal cord and other systems in a 53-year-old Taiwanese women patient. The patient presented with subacute onset of right arm radicular pain followed by quadriparesis. Magnetic resonance imaging revealed a hyperintense lesion on T2WI in the cervical spinal cord. The patient also had a history of facial neuropathy, bilateral parotid enlargement, intrathoracic lymphadenopathy, hypercalcemia, nephrocalcinosis, and renal function impairment. Parotid gland biopsy showed granulomatous lesion with multinucleated giant cells. Sarcoidosis was diagnosed after other possibilities were excluded. Oral steroid treatment resulted in initial significant clinical improvement. Awareness of the systemic and neurological presentations of sarcoidosis can prompt the correct diagnosis and treatment.

Dynamic cerebral autoregulation in carotid stenosis before and after carotid stenting.

BACKGROUND: Impaired dynamic cerebral autoregulation (DCA) has been shown in patients with severe (> or =70%) internal carotid artery (ICA) stenosis, but DCA in moderate (50% to 69%) ICA stenosis, especially its response to carotid revascularization, has rarely been reported. Our study aimed to characterize DCA in severe and moderate ICA stenosis before and after carotid stenting. METHODS: This study included 21 patients with ICA stenosis > or =50% who received carotid stenting. Data of arterial blood pressure and cerebral blood flow velocity of the middle cerebral artery, measured by transcranial Doppler, were collected for 10 minutes < or =24 hours before and after stenting. The DCA index, represented as aMx, was assessed by calculating the Pearson product-moment correlation coefficient of spontaneous arterial blood pressure and cerebral blood flow velocity fluctuations. The relationship between aMx and stenotic severity and also alternations of aMx before and after stenting were assessed. RESULTS: Carotid stenting was effective to improve the DCA in the stenting side but not in the contralateral nonstenting side. In considering individual ICAs, the average aMx (mean +/- SD) increased significantly from ICA stenosis <50% (0.117 +/- 0.091) to 50% to 69% (0.349 +/- 0.144), 70% to 99% (0.456 +/- 0.147), and total occlusion (0.557 +/- 0.210; P < .05, P < .01, and P < .01, compared with 50% to 69%, 70% to 99%, or total occlusion with <50% stenosis). The correlation between the degree of ICA stenosis and the aMx was also significant (r = 0.693, P < .005). The aMx improved significantly in the stented side after carotid stenting in both moderate and severe ICA stenosis, and this finding was not affected by age, sex, risk factors, or clinical symptoms. CONCLUSIONS: In addition to patients with severe carotid stenosis, patients with moderate carotid stenosis may also have impaired DCA that can be restored after carotid stenting.

Midlife risk factors for subtypes of dementia: a nested case-control study in Taiwan.

OBJECTIVE: To identify the midlife risk factors for subtypes of dementia newly developed later in life. METHODS: A nested case-control study was conducted on 157 demented cases and 628 comparison cases selected from 40,636 men and women who were enrolled from 1982 to 1992. Four comparison cases were frequency-matched on age, time at enrollment (within 6 months), gender, and residential township. Midlife risk factors included vascular risk factors (body mass index [BMI], total cholesterol, total triglycerides, blood glucose, cerebrovascular accident [CVA] history, diabetes mellitus history, and hypertension history), cigarette smoking, and alcohol consumption. Dementia assessments were ascertained through the computerized data linkage from National Health Insurance Database from 2000 to 2002 and clinically confirmed by neurologists or psychiatrists. Conditional logistic regression analysis was used to estimate the matched odds ratio (OR) and its 95% confidence intervals (CI) for each risk factor. RESULTS: A J-shaped relationship was observed between BMI (kg/m(2)) and dementia. The multivariate-adjusted ORs (95% CI) of developing dementia were 1.84 (1.02-3.33), 1.87 (1.08-3.23) and 2.44 (1.39-4.28), respectively, for BMIs of <20.5, 23.0-25.4, >or=25.5 compared with a BMI of 20.5-22.9 as the referent group (OR = 1.0). Similar findings were observed for Alzheimer disease (AD) and vascular dementia (VaD). The association between obesity (BMI >or=25.5) and both AD and VaD was statistically significant among cigarette smokers but not among nonsmokers. Additionally, history of CVA was a significant risk factor for VaD, but not for AD. CONCLUSION: Being underweight, being overweight, and a cerebrovascular accident in midlife may increase the risk of dementia in late life.

Underrecognition and undertreatment of atherothrombotic diseases: REACH Registry Taiwan baseline data.

BACKGROUND/PURPOSE: Atherothrombosis is a generalized disease affecting different vascular beds, making it the leading cause of death worldwide. To evaluate the long-term risk of atherothrombotic risk factors and determine the predictors for atherothrombotic events, an international, prospective, observational study was initiated, in which Taiwan was involved. METHODS: The REduction of Atherothrombosis for Continued Health (REACH) Registry recruited outpatients with either symptomatic atherothrombotic diseases or multiple risk factors. Baseline data were collected using a universal standard case report form. All subjects were followed to document future outcomes. In this paper, we analyzed the baseline data of the participants from Taiwan. RESULTS: In the REACH Registry, a total of 67,888 subjects from 44 countries were recruited. Among the 1062 Taiwanese participants, 971 were symptomatic subjects and 91 subjects were with risk factors only (RFO). In comparison with the global participants, the Taiwan patients were younger, with a higher prevalence of males, lower prevalence of hypertension, obesity, hypercholesterolemia, former smokers, and a greater prevalence of non-smokers. The baseline prevalence rates were: hypertension, 46.5%; fasting hyperglycemia, 38.4%; hypercholesterolemia, 45.8%; and hypertriglyceridemia, 42.8%. All these prevalence were higher than the global data, indicating an undertreatment status for the Taiwanese patients. Only 29 (2.7%) peripheral arterial disease (PAD) subjects were recruited in Taiwan, suggesting under recognition of this disease. The RFO Taiwanese patients had fewer former smokers and more non-smokers than the symptomatic patients, suggesting that smoking may be an important factor contributing to atherothrombotic diseases. CONCLUSION: In Taiwan, atherothrombotic outpatients were generally undertreated and PAD was underdiagnosed.

Impaired cerebral autoregulation in a case of severe acute encephalitis.

The status of cerebral autoregulation (CA) is an important prognostic factor for acute head trauma, but the role of CA in patients with acute encephalitis has not been previously discussed. We present the case of a 30-year-old woman with severe acute encephalitis who underwent craniectomy for intractable increased intracranial pressure (ICP). Preoperatively, adjustments of blood pressure (BP) with simultaneous recording of changes in cerebral blood flow velocity with transcranial Doppler indicated increased ICP and impaired CA. Postoperatively, ICP declined remarkably but CA remained impaired when the relationship between spontaneous fluctuation of mean BP and ICP was analyzed. Increased ICP recurred again within 24 hours of the decompression surgery and caused death of the patient. We propose that evaluating the status of CA could be of prognostic importance in patients with severe encephalitis.

Feasibility of endovascular recanalization for symptomatic cervical internal carotid artery occlusion.

OBJECTIVES: This study sought to report technical details and clinical results of the first series of endovascular recanalization for cervical internal carotid artery (ICA) occlusion. BACKGROUND: Cervical ICA occlusion is associated with impaired cerebral perfusion, which may lead to ischemic cerebral symptoms and hemodynamic infarcts. Neither surgical nor endovascular revascularization has been shown to benefit this population. METHODS: Endovascular recanalization was attempted in 30 patients with ICA occlusions (27 men; age 72.1 +/- 8.0 years, range 48 to 85 years). Recurrent neurologic deficit or cerebral ischemia by perfusion study, after known ICA occlusion, was noted in all patients. Strategies and devices for coronary occlusion intervention were applied, including microcatheter-supported tapered-tip stiff coronary guidewires. Contralateral ICA stenosis was found in 9 patients (30%). All patients underwent independent neurologic and duplex ultrasound follow-up. RESULTS: The overall technical success rate was 73% (22 of 30). No neck hematoma, intracranial hemorrhage, or hyperperfusion was noted. One (3.3%) fatal brainstem infarction occurred 1 day after a successful ICA procedure, with angiographically proven acute basilar artery occlusion and patent ICA stent. Baseline ophthalmic artery flow was reversed in 15 of the 22 successfully recanalized patients, and was normalized in 12 after the procedure. There was no new cerebral ischemic event or neurologic death for a mean follow-up of 16.1 +/- 18.5 months. CONCLUSIONS: Endovascular recanalization for cervical ICA occlusion is feasible with acceptable midterm clinical results.

Novel mutation of neurofibromatosis type 1 in a patient with cerebral vasculopathy and fatal ischemic stroke.

Vascular lesions are infrequently recognized as manifestations of neurofibromatosis 1 (NF1), but they can produce serious complications and contribute to mortality at younger ages. Here we report the case of a young female patient with NF1 who suffered from a fatal middle cerebral artery (MCA) infarct. In addition to the MCA infarct, head MRI also disclosed old infarcts at bilateral cerebella and multiple intracranial arterial steno-occlusions. Stroke related to NF1 cerebral vasculopathy was highly suggested after other diseases were excluded. Additionally, genetic analysis of the patient identified a novel mutation at the splicing donor site, c. 2,409+2T>G that resulted in a splicing aberration.

Validity and reliability of a Taiwan Chinese version of the community screening instrument for dementia.

OBJECTIVE: The Community Screening Instrument for Dementia (CSI-D) has been reported to be sensitive. The authors examined the reliability and validity of a Chinese (Taiwanese) version of the CSI-D for elderly patients. METHODS: Four groups were tested with the CSI-D: 31 with mild or moderate dementia; 32 non-dementia, depressed subjects; and 34 low-education, and 30 high-education normal-comparison subjects. Patients with dementia or depression were selected from outpatients of two hospitals. Testing was carried out in either the community or outpatient setting. RESULTS: The internal consistency, interrater reliability, and test-retest reliability of the CSI-D were good. The CSI-D was highly correlated with scores on the Mini-Mental State Examination and 10-word-list-learning task. Correlation with the Montgomery-Asberg Depression Rating Scale was not significant. Receiver Operating Characteristic analysis suggested that the CSI-D was a good instrument in differentiating dementia from depression and normal subjects with low education. It had good sensitivity and specificity. Education was related to the cognitive scores but not related to informant scores. The combination of an informant interview with a cognitive test enhanced the performance of the CSI-D. CONCLUSIONS: The Taiwan Chinese version of the CSI-D is psychometrically sound, brief, easy to complete, and therefore suitable as a screening instrument for dementia in Taiwan. The study reinforces earlier suggestions that the informant interview yields improved validity for detecting dementia.

Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

The phenotype and genotype of cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) in Caucasians have been well characterized, but CADASIL is less recognized in Asian populations. Here we investigated the first known Taiwanese family affected by CADASIL and identified an uncommon NOTCH3 mutation. The family had clinical manifestations in affected members including recurrent strokes, early dementia, and depression, but not migraine. A skin biopsy in the proband patient showed characteristic pathological findings of CADASIL on electron microscopy. Afterward, genetic analysis found an Arg332Cys mutation at exon 6 of NOTCH3. Neuropsychological evaluation showed vascular dementia in two of four affected people. Head MRI showed multiple infarcts in bilateral basal ganglia, thalami, periventricular white matter, external capsules, and brainstem, but involvement of the anterior temporal pole was found only in two people with milder symptoms. To our knowledge, the Arg332Cys NOTCH3 mutation at exon 6, which was identified in the studied family, has not been reported in Asian populations. Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL.

Carotid atherosclerosis, intima media thickness and risk factors--an analysis of 1781 asymptomatic subjects in Taiwan.

The aim of this study was to investigate the association of intima media thickness (IMT) and plaque with risk factors for atherosclerosis in asymptomatic subjects in Taiwan. Between 1998 and 2001, the study recruited 1781 asymptomatic subjects (1131 men and 650 women [mean age, 49 years; range 18-85 years]). These were examined by B-mode ultrasound to measure the IMT at the far wall of the common carotid artery (CCA) and the extent of plaque formation. A wide range of vascular risk factors including age, gender, smoking, body mass index, blood chemistry, and previous history were surveyed. The mean (+/-S.D.) IMT observed was 0.68 (+/-0.12) and 0.66 (+/-0.11) mm for men and women, respectively, (P=0.0008). The mean (S.D.) IMT of the CCA was 0.66 (+/-0.12) mm on the right side and 0.68 (+/-0.12) mm on the left side (P=0.0004). IMT increased with aging, according to the equation IMT=(0.005xage in years)+0.403 [corrected]. Higher IMT was associated with male gender, and IMT was greater in the left CCA. About 36.9% of subjects had carotid plaques. The percentage of plaque increased with aging. The plaque prevalence was positively associated with IMT. The value of IMT over the cut point of 0.68 mm correlated with obviously increased risk of carotid atherosclerosis. Age, systolic blood pressure and fasting blood sugar were independent risk factors related to both carotid atherosclerosis and thick IMT.

Biological gradient between long-term arsenic exposure and carotid atherosclerosis.

BACKGROUND: Long-term exposure to ingested arsenic has been documented to induce peripheral vascular disease, ischemic heart disease, and cerebral infarction in a dose-response relationship. This study further examined the biological gradient between ingested inorganic arsenic and carotid atherosclerosis. METHODS AND RESULTS: We studied 199 male and 264 female adult residents from the southwestern area of endemic arseniasis in Taiwan. The extent of carotid atherosclerosis was assessed by duplex ultrasonography. Diabetes mellitus was determined by oral glucose tolerance test, hypertension by mercury sphygmomanometers, and serum lipid profiles by autoanalyzers. Information regarding the consumption of high-arsenic artesian well water, cigarette smoking, and alcohol consumption was obtained through standardized questionnaire interviews. Logistic regression analysis was used to estimate the odds ratio and its 95% CI of carotid atherosclerosis for various risk factors. Three indices of long-term exposure to ingested arsenic, including the duration of consuming artesian well water, the average arsenic concentration in consumed artesian well water, and cumulative arsenic exposure, were all significantly associated with prevalence of carotid atherosclerosis in a dose-response relationship. The biological gradient remained significant after adjustment for age, sex, hypertension, diabetes mellitus, cigarette smoking, alcohol consumption, waist-to-hip ratio, and serum levels of total cholesterol and LDL cholesterol. The multivariate-adjusted odds ratio was 3.1 (95% CI 1.3 to 7.4) for those who had a cumulative arsenic exposure of > or =20 mg/L-years compared with those without exposure to arsenic from drinking artesian well water. CONCLUSIONS: Carotid atherosclerosis is associated with ingested inorganic arsenic, showing a significant biological gradient.