Application of blood-based biomarkers of Alzheimer's disease in clinical practice: Recommendations from Taiwan Dementia Society.

Blood-based biomarkers (BBM) are potentially powerful tools that assist in the biological diagnosis of Alzheimer's disease (AD) in vivo with minimal invasiveness, relatively low cost, and good accessibility. This review summarizes current evidence for using BBMs in AD, focusing on amyloid, tau, and biomarkers for neurodegeneration. Blood-based phosphorylated tau and the Aß42/Aß40 ratio showed consistent concordance with brain pathology measured by CSF or PET in the research setting. In addition, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are neurodegenerative biomarkers that show the potential to assist in the differential diagnosis of AD. Other pathology-specific biomarkers, such as α-synuclein and TAR DNA-binding protein 43 (TDP-43), can potentially detect AD concurrent pathology. Based on current evidence, the working group from the Taiwan Dementia Society (TDS) achieved consensus recommendations on the appropriate use of BBMs for AD in clinical practice. BBMs may assist clinical diagnosis and prognosis in AD subjects with cognitive symptoms; however, the results should be interpreted by dementia specialists and combining biochemical, neuropsychological, and neuroimaging information. Further studies are needed to evaluate BBMs' real-world performance and potential impact on clinical decision-making.

Monogenic Causes in Familial Stroke Across Intracerebral Hemorrhage and Ischemic Stroke Subtypes Identified by Whole-Exome Sequencing.

Whole exome sequencing (WES) has been used to detect rare causative variants in neurological diseases. However, the efficacy of WES in genetic diagnosis of clinically heterogeneous familial stroke remains inconclusive. We prospectively searched for disease-causing variants in unrelated probands with defined familial stroke by candidate gene/hotspot screening and/or WES, depending on stroke subtypes and neuroimaging features at a referral center. The clinical significance of each variant was determined according to the American College of Medical Genetics guidelines. Among 161 probands (mean age at onset 53.2 ± 13.7 years; male 63.4%), 33 participants (20.5%) had been identified with 19 pathogenic/likely pathogenic variants (PVs; WES applied 152/161 = 94.4%). Across subtypes, the highest hit rate (HR) was intracerebral hemorrhage (ICH, 7/18 = 38.9%), particularly with the etiological subtype of structural vasculopathy (4/4 = 100%, PVs in ENG, KRIT1, PKD1, RNF213); followed by ischemic small vessel disease (SVD, 15/48 = 31.3%; PVs in NOTCH3, HTRA1, HBB). In contrast, large artery atherosclerosis (LAA, 4/44 = 9.1%) and cardioembolism (0/11 = 0%) had the lowest HR. NOTCH3 was the most common causative gene (16/161 = 9.9%), presenting with multiple subtypes of SVD (n = 13), ICH (n = 2), or LAA (n = 1). Importantly, we disclosed two previously unreported PVs, KRIT1 p.E379* in a familial cerebral cavernous malformation, and F2 p.F382L in a familial cerebral venous sinus thrombosis. The contribution of monogenic etiologies was particularly high in familial ICH and SVD subtypes in our Taiwanese cohort. Utilizing subtype-guided hotspot screening and/or subsequent WES, we unraveled monogenic causes in 20.5% familial stroke probands, including 1.2% novel PVs. Genetic diagnosis may enable early diagnosis, management and lifestyle modification. Among 161 familial stroke probands, 33 (20.5%) had been identified pathogenic or likely pathogenic monogenic variants related to stroke. The positive hit rate among all subtypes was high in intracerebral hemorrhage (ICH) and ischemic small vessel disease (SVD). Notably, two previously unreported variants, KRIT1 p.E379* in a familial cerebral cavernous malformation and F2 p.F382L in familial cerebral venous sinus thrombosis, were disclosed. CVT cerebral venous thrombosis; HTN Hypertensive subtype; LAA large artery atherosclerosis; SV structural vasculopathy; U Undetermined.

Health-related quality of life and mild behavioral impairment in older adults without dementia.

BACKGROUND: The Mild Behavioral Impairment Checklist (MBI-C) was developed to assess neuropsychiatric symptoms (NPS) and to identify mild behavioral impairment (MBI). This study validated the Taiwanese version of the MBI-C and examined its association of health-related quality of life (HR-QoL). METHODS: We recruited 242 older individuals without dementia (129 amnestic mild cognitive impairment, 113 cognitively normal). Their family completed the MBI-C, the Neuropsychiatric Inventory Questionnaire (NPI-Q), and instrumental activities of daily living scale. Participants completed the Geriatric Depression Scale (GDS-15), the Mini-Mental State Examination, the 12-item word recall test, the category verbal fluency test and the EuroQol 5 dimensions questionnaire (EQ-5D). Cronbach's α was used to evaluate the internal consistency of the MBI-C. Linear regression models were used to examined the association between MBI-C score and HR-QoL assessed using ED-5D. RESULTS: The prevalence of MBI was 12% of all participants. Cronbach's α of the MBI-C was 0.893. The optimal cut-off point of MBI-C was 7.5 for identifying MBI, with a sensitivity of 100% and specificity of 85%. The MBI-C total score (ß = -0.01, 95% confidence interval [CI] = -0.02 to -0.01, p < 0.001), MBI-C subdomain of decreased motivation (ß = -0.04, 95% CI = -0.05 to -0.02, p < 0.001) and emotional dysregulation (ß = -0.02, 95% CI = -0.04 to -0.004, p = 0.01) were factors related to EQ-5D index scores. CONCLUSION: Among older adults without dementia, the Taiwanese version of the MBI-C has good reliability and validity for detecting MBI. The total and subdomains of MBI-C were associated with decreased HR-QoL among individuals without dementia.

A national survey on health-related quality of life for people with dementia in residential long-term care institutions.

BACKGROUND: Health-related quality of life (HRQoL) is an essential outcome parameter in geriatric research; however, the available evidence is mixed regarding the factors associated with HRQoL among people with dementia. We aimed to identify factors that contribute to HRQoL among people with dementia in residential long-term care (LTC) institutions. METHODS: We randomly selected 299 of 1607 registered residential LTC institutions in Taiwan. A cross-sectional survey was conducted between 2019 and 2020, including items on demographic characteristics, comorbidities, the EuroQol-5 dimensions-5 levels (EQ-5D-5L; utility and visual analog scale [VAS] scores), the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating (CDR), behavioral and psychological symptoms of dementia, activities of daily living (ADL), and instrumental ADL (IADL). RESULTS: In total, 1313 people with dementia from 267 institutions were enrolled (mean age, 76.4 ± 12.7 years). The mean EQ-5D-5L utility and VAS scores were 0.10 (standard deviation [SD] = 0.48) and 66.57 (SD = 20.67), respectively. In multivariate linear regression analysis, higher scores for ADL, IADL, and CDR sum of boxes were associated with higher utility scores. Higher VAS scores were associated with higher ADL and MMSE scores. Lower utility scores and VAS scores were associated with more frequent depressive symptoms. CONCLUSION: ADL, dementia severity, cognitive function, and depressive symptoms influenced the HRQoL of people with dementia in residential LTC institutions. Longitudinal studies should be conducted to better understand how HRQoL changes over time among people with disabilities.

Neuropsychiatric symptoms and mortality among patients with mild cognitive impairment and dementia due to Alzheimer's disease.

BACKGROUND: Neuropsychiatric symptoms (NPS) could increase mortality risk in people with dementia due to Alzheimer's disease (AD). However, whether NPS affects mortality risk in people with mild cognitive impairment (MCI) and whether any specific syndrome of NPS influences this risk are still unclear. METHODS: In total, 984 participants with dementia due to AD, 338 with MCI, and 365 controls were enrolled. Over a mean of 5-year follow-up, cause of death data were obtained from the Ministry of Health and Welfare in Taiwan. NPS were assessed using Neuropsychiatric Inventory Questionnaire (NPI-Q), and psychosis, mood, and frontal domain scores were determined. Survival analyses were conducted to determine the hazard ratio (HR) of death. RESULTS: In controlled analyses, HR of death for AD was 2.19 (95% confidence interval [CI] = 1.29-3.71) compared with the control group, whereas no statistical significance was noted for the MCI group. A high NPI-Q score (above the median score) increased mortality risk for both the MCI and AD groups, with HRs of 2.32 (95% CI = 1.07-5.03) and 2.60 (95% CI = 1.51-4.47), respectively. Among NPI-Q domain scores, only high mood domain, but not psychosis or frontal domain, scores increased death risk for both the MCI (HR = 2.89, 95% CI = 1.00-8.51) and AD (HR = 2.59, 95% CI = 1.47-4.55) groups. CONCLUSION: Mortality risk is high for patients with AD. Not only for AD, patients with MCI presenting with NPS, particularly mood symptoms, have high death risk.

Adult onset MELAS Syndrome Presenting as A Mimic of Herpes Simplex Encephalitis.

PURPOSE: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome primarily affects the young and may not be considered first in an older adult with infection-like encephalopathy. Here, we present the case of a patient who suffered from the acute onset of fever, delirium, and epilepsy, mimicking herpes simplex encephalitis (HSE). CASE REPORT: A 52-year-old woman with diabetes and end stage renal disease (ESRD) regularly took oral anti-diabetic drugs (OADs) and received hemodialysis. She presented with an acute onset of fever, delirium, and epilepsy, mimicking HSE. Further investigation showed a persistent elevated lactate level in the cerebrospinal fluid (CSF). A mitochondrial DNA analysis revealed a point mutation at nucleotide 3243. CONCLUSION: The clinical presentation and imaging studies of MELAS in adults are variable and may mimic those of HSE. Antiviral therapy should be administered until the diagnosis of MELAS is definitive. Infection and metformin may have also precipitated MELAS manifestation in this patient. Clinicians should avoid potential mitochondrial-toxic drugs in these patients.

Different Splice Isoforms of Peripheral Triggering Receptor Expressed on Myeloid Cells 2 mRNA Expressions are Associated With Cognitive Decline in Mild Dementia Due to Alzheimer's Disease and Reflect Central Neuroinflammation.

Triggering receptor expressed on myeloid cells 2 (TREM2) is upregulated in activated microglia and may be related to cognitive decline in patients with Alzheimer's disease (AD). There is conflicting evidence regarding the association of peripheral TREM2 mRNA expression/soluble TREM2 (the extracellular domain of TREM2) with cognitive function/neuroinflammation in patients with AD. Herein, we studied the TREM2 and TREM2alt mRNA expression and their association with the cognitive performance in subjects with mild dementia due to AD and healthy controls. In a subgroup of patients with AD, magnetic resonance spectroscopy was used to measure the myo-inositol level in the posterior cingulate cortex, a surrogate marker for neuroinflammation. The results showed that increased TREM2 and TREM2alt mRNA expression is associated with AD pathogenesis at the mild dementia stage, thereby serving as a potential biomarker for early symptomatic stage of AD. TREM2 may exert protective effects on both cognition and central neuroinflammation.

Predictors of live-in migrant caregiver employment for people with dementia in Taiwan.

BACKGROUND: With the increasing number of individuals with dementia, families have hired an increasing number of live-in migrant caregivers (LIMCs). Currently, limited evidence is available regarding the influence of long-term care resource utilization on the hiring of LIMCs for caring for individuals with dementia in Taiwan. METHODS: We recruited individuals with dementia who did not hire LIMCs and their primary family caregivers from nine hospitals in Taiwan as baseline. Multivariable logistic regression was used to evaluate the utilization of long-term care resources for individuals with dementia and other factors that may affect the decision to hire LIMCs. RESULTS: The users of non-long-term care resources had the highest likelihood of hiring LIMCs (odds ratio [OR] = 4.24, 95% CI, 2.30-7.84). Compared with spouses, nonimmediate family caregivers (OR = 3.40, 95% CI, 1.16-9.90) were significantly more likely to hire LIMCs. A higher likelihood of hiring LIMCs was observed for those with Lewy body dementia compared with other individuals (OR = 2.31, 95% CI, 1.03-5.14). Compared with individuals who did not hire LIMCs, those who hired LIMCs exhibited higher scores on the Neuropsychiatric Inventory (NPI) and higher severity of individual NPI items. CONCLUSION: Hiring LIMCs is strongly correlated with the utilization of non-long-term care resources and is influenced by the dynamics between individuals with dementia and their primary family caregivers. A higher likelihood of hiring LIMCs was observed for individuals with Lewy body dementia and individuals with elevated NPI scores compared with their counterparts. Given these observations, various support strategies and interventions should be tailored to the specific requirements of individuals with dementia and their families.

Serum brain-derived neurotrophic factor levels as a predictor for Alzheimer disease progression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of Alzheimer's disease (AD), and decreased peripheral levels of this protein are associated with an increased risk of developing the disease. This study focuses on whether serum BDNF levels could be used as a predictor of AD progression. METHODS: In this longitudinal observational study, we recruited cognition normal participants (N = 98) and AD (N = 442) from the Clinic at the Taipei Veterans General Hospital. We conducted a mini-mental status exam, a 12-item memory test, a categorical verbal fluency test, and a modified 15-item Boston naming test. A Serum BDNF level and apolipoprotein E ( APOE ) allele status were measured. The AD patients were followed prospectively. Based on the difference of MMSE scores, these patients were divided into fast decliners (decline ≥ 3/y) and slow decliners (MMSE decline < 3/y). Logistic regression was conducted to examine the impact of serum BDNF levels and other factor on the likelihood of AD patients being slow decliners. Pearson's correlation was used to estimate the relationship between serum BDNF levels and the score of neuropsychological tests. RESULTS: In a logistic regression model containing serum BDNF levels, age, sex, APOE4 carrier status, education levels, and baseline MMSE score, higher serum BDNF levels were associated with a slower rate of cognitive decline in the AD group. Serum BDNF levels positively correlated with the results of multiple neuropsychological tests. CONCLUSION: BDNF is a protective factor against AD progression and likely plays a role in establishing a link between AD pathology and clinical manifestations.

Endophenotypic effects of the SORL1 variant rs2298813 on regional brain volume in patients with late-onset Alzheimer's disease.

Introduction: Two common variants of sortilin-related receptor 1 gene (SORL1), rs2298813 and rs1784933, have been associated with late-onset Alzheimer's disease (AD) in the Han Chinese population in Taiwan. However, neuroimaging correlates of these two SORL1 variants remain unknown. We aimed to determine whether the two SORL1 polymorphisms were associated with any volumetric differences in brain regions in late-onset AD patients. Methods: We recruited 200 patients with late-onset AD from Taipei Veterans General Hospital. All patients received a structural magnetic resonance (MR) imaging brain scan and completed a battery of neurocognitive tests at enrollment. We followed up to assess changes in Mini-Mental State Examination (MMSE) scores in 155 patients (77.5%) at an interval of 2 years. Volumetric measures and cortical thickness of various brain regions were performed using FreeSurfer. Regression analysis controlled for apolipoprotein E status. Multiple comparisons were corrected for using the false discovery rate. Results: The homozygous major allele of rs2298813 was associated with larger volumes in the right putamen (p = 0.0442) and right pallidum (p = 0.0346). There was no link between the rs1784933 genotypes with any regional volume or thickness of the brain. In the rs2298813 homozygous major allele carriers, the right putaminal volume was associated with verbal fluency (p = 0.008), and both the right putaminal and pallidal volumes were predictive of clinical progression at follow-up (p = 0.020). In the minor allele carriers, neither of the nuclei was related to cognitive test performance or clinical progression. Conclusion: The major and minor alleles of rs2298813 had differential effects on the right lentiform nucleus volume and distinctively modulated the association between the regional volume and cognitive function in patients with AD.

Predictors of emergency department visit among people with dementia in Taiwan.

BACKGROUND: We aimed to identify predictors of emergency department (ED) visit by people with dementia (PWDs) and their caregivers with a one-year follow-up in a country with public health system. METHODS: Data were collected from a national dementia registration survey. Andersen's Behavioral Model of Health Services Use was used. Variables such as demographic data of PWDs and their caregivers, caregivers' monthly income, the relationship between PWD and caregivers, the severity of dementia (clinical dementia rating, CDR), physical comorbidities, cognitive function (mini-mental state examination, MMSE), and activities of daily living of PWDs, the caregiver burden, and neuropsychiatric symptoms (assessed by the Neuropsychiatric Inventory Questionnaire) were included in the analyses. RESULTS: A total of 1,227 PWDs-caregiver dyads completed the survey, and 405 (33%) of PWDs visited ED during the one-year follow-up. Multivariable logistic analyses revealed that older age of PWDs (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01-1.05), more severe dementia (CDR; OR = 1.42, 95% CI = 1.09-1.86), higher cognitive function (MMSE; OR = 1.04, 95% CI = 1.01-1.07), and having a female family caregiver (OR = 1.50, 95% CI = 1.13-2.01) were predictors of ED visit. CONCLUSION: Our study results provided information for healthcare providers and policy makers to target models of care that support PWD and their caregivers and reduce the need for ED visits.

Association between Alzheimer's disease genes and trajectories of cognitive function decline in Han Chinese in Taiwan.

Genetic background has been considered one of the important contributors to the rate of cognitive decline among patients with Alzheimer's disease (AD). We conducted a 4-year longitudinal follow-up study, recruited 255 AD and 44 mild cognitive impairment (MCI) patients, and used a data-driven trajectory analysis to examine the influence of selected AD risk genes on the age for and the rate of cognitive decline in Han Chinese population. Genotyping of selected single-nucleotide polymorphisms in the APOE, ABCA7, SORL1, BIN1, GAB2, and CD33 genes was conducted, and a Bayesian hierarchical model was fitted to analyze the trajectories of cognitive decline among different genotypes. After adjusting for sex and education years, the APOE ε4 allele was associated with an earlier mean change of -2.39 years in the age at midpoint of cognitive decline, the G allele in ABCA7 rs3764650 was associated with an earlier mean change of -1.75 years, and the T allele in SORL1 rs3737529 was associated with a later mean change of 2.6 years. Additionally, the rate of cognitive decline was associated with the APOE ε4 allele and SORL1 rs3737529. In summary, APOE and SORL1 might be the most important genetic factors related to cognitive decline in Han Chinese population.

Mutational analysis in familial Alzheimer's disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile.

Mutations in PSEN1, PSEN2, or APP genes are known to be causative for autosomal dominant Alzheimer's disease (ADAD). While more than 400 mutations were reported worldwide, predominantly PSEN1, over 40 mutations have been reported in Han Chinese and were associated with earlier onset and more affected family members. Between 2002 and 2018, 77 patients in the neurological clinic of Taipei Veterans General Hospital with a history suggestive of ADAD were referred for mutational analysis. We retrospectively collected demographics, initial symptoms, neurological features and inheritance. We identified 16 patients with PSEN1 and 1 with APP mutation. Among the mutations identified, PSEN1 p.Pro117Leu, p.Met146Ile, p.Gly206Asp, p.Gly209Glu, p.Glu280Lys and p.Leu286Val and APP p.Asp678His were known pathogenic mutations; PSEN1 p.His131Arg and p.Arg157Ser were classified as likely pathogenic and variance of unknown significance respectively. The mean age at onset was 46.2 ± 6.2 years in patients with mutation found. PSEN1 p.Met146Ile, occurred in 56.2% (9/16) of patients with PSEN1 mutations, was the most frequent mutation in the cohort. The additional neurological features occurring in 9 PSEN1 p.Met146Ile index patients were similar with the literature. We found patients with genetic diagnoses were more likely to have positive family history, younger age at onset and less brain white matter hyperintensity.

Summative Effects of Vascular Risk Factors on the Progression of Alzheimer Disease.

OBJECTIVES: To investigate the summative effects of vascular risk factors (VRFs) on the progression of Alzheimer disease (AD). DESIGN: Longitudinal follow-up cohort study. SETTING: AD patients from two teaching hospitals in Taiwan with 3-year follow-ups. PARTICIPANTS: A total of 330 AD patients with a mean age of 80.7 years, a mean Mini-Mental State Examination (MMSE) score 18.7, and a mean Clinical Dementia Rating Sum of Boxes (CDRSB) score of 6.9. MEASUREMENTS: All patients completed a clinically functional assessment and a neuropsychological test battery at baseline and yearly follow-ups. The VRF burden was combined into a summative VRF index at baseline (ie, having one, two, or more VRFs); VRFs included coronary heart disease, cardiac arrhythmia, hypertension, cerebrovascular disease, diabetes mellitus, obesity, smoking, and physical inactivity. The generalized estimating equation (GEE) method was used to analyze the correlations between the VRFs and longitudinal MMSE and CDRSB changes. RESULTS: The results of the GEE adjusted for age, years of education, sex, disease duration, baseline MMSE score, time, apolipoprotein E (APOE) ε4 carrier status, use of medications (acetylcholinesterase inhibitors or N-methyl-D-aspartate receptor antagonists), and hospitalization rates and showed that patients with more than three VRFs had more rapid cognitive decline than patients without VRFs (MMSE, P = .02; CDRSB, P = .001) as well as patients with three or fewer VRFs (MMSE, P = .009; CDRSB, P = .02). Subsequent analyses of APOE ε4 carriers with more than three VRFs also showed their more rapid cognitive decline compared with patients without VRFs (MMSE, P = .02; CDRSB, P = .001) and patients with three or fewer VRFs (MMSE, P = .009; CDRSB, P = .02), but no significant difference was found in APOE ε4 noncarriers. CONCLUSION: Multiple VRFs have summative effects on the progression of AD, especially in APOE ε4 carriers. J Am Geriatr Soc 68:129-136, 2019.

Levels of plasma neurofilament light chain and cognitive function in patients with Alzheimer or Parkinson disease.

Plasma neurofilament light (NFL) has been proposed as a blood-based biomarker for neurodegeneration in Alzheimer's disease (AD) and parkinsonian disorders. However, the relationship between plasma NFL and cognitive decline in dementia due to Parkinson's disease (PD) remains to be elucidated. In this research, 119 AD, 56 mild cognitive impairment (MCI), 26 non-demented PD (PDND), and 23 Parkinson's disease dementia (PDD) patients, as well as 59 cognitively healthy controls (HC) were recruited. Each subject underwent a battery of neuropsychological testing. Plasma NFL levels were measured in duplicate using an NF-Light assay and transferred onto the Simoa platform with a home-brew kit. Plasma NFL was significantly increased in the AD group, compared with the control, MCI, PDND, and PDD groups. Plasma NFL was significantly higher in the PDD group, compared with the PDND group. High plasma NFL correlated with poor cognition in AD and PD, but not with motor symptoms in PD. Plasma NFL may represent a biomarker of cognitive decline in AD and PD, with more specificity for AD.