More than a piece of cake: Noun classifier processing in primary progressive aphasia.

INTRODUCTION: Clinical understanding of primary progressive aphasia (PPA) has been primarily derived from Indo-European languages. Generalizing certain linguistic findings across languages is unfitting due to contrasting linguistic structures. While PPA patients showed noun classes impairments, Chinese languages lack noun classes. Instead, Chinese languages are classifier language, and how PPA patients manipulate classifiers is unknown. METHODS: We included 74 native Chinese speakers (22 controls, 52 PPA). For classifier production task, participants were asked to produce the classifiers of high-frequency items. In a classifier recognition task, participants were asked to choose the correct classifier. RESULTS: Both semantic variant (sv) PPA and logopenic variant (lv) PPA scored significantly lower in classifier production task. In classifier recognition task, lvPPA patients outperformed svPPA patients. The classifier production scores were correlated to cortical volume over left temporal and visual association cortices. DISCUSSION: This study highlights noun classifiers as linguistic markers to discriminate PPA syndromes in Chinese speakers. HIGHLIGHTS: Noun classifier processing varies in the different primary progressive aphasia (PPA) variants. Specifically, semantic variant PPA (svPPA) and logopenic variant PPA (lvPPA) patients showed significantly lower ability in producing specific classifiers. Compared to lvPPA, svPPA patients were less able to choose the accurate classifiers when presented with choices. In svPPA, classifier production score was positively correlated with gray matter volume over bilateral temporal and left visual association cortices in svPPA. Conversely, classifier production performance was correlated with volumetric changes over left ventral temporal and bilateral frontal regions in lvPPA. Comparable performance of mass and count classifier were noted in Chinese PPA patients, suggesting a common cognitive process between mass and count classifiers in Chinese languages.

Application of transcranial brain stimulation in dementia.

The number of patients with dementia grows rapidly as the global population ages, which posits tremendous health-care burden to the society. Only cholinesterase inhibitors and a N-methyl-D-aspartate receptor antagonist have been approved for treating patients with Alzheimer's disease (AD), and their clinical effects remained limited. Medical devices serve as an alternative therapeutic approach to modulating neural activities and enhancing cognitive function. Four major brain stimulation technologies including deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial ultrasound stimulation (TUS) have been applied to AD in a clinical trial setting. DBS allows electrical stimulation at the specified nucleus but remains resource-demanding, and after all, an invasive surgery; whereas TMS and tDCS are widely available and affordable but less ideal with respect to localization. The unique physical property of TUS, on the other hand, allows both thermal and mechanical energy to be transduced and focused for neuromodulation. In the context of dementia, using focused ultrasound to induce blood-brain barrier opening for delivering drugs and metabolizing amyloid protein has drawn great attention in recent years. Furthermore, low-intensity pulsed ultrasound has demonstrated its neuroprotective effects in both in vitro and in vivo studies, leading to ongoing clinical trials for AD. The potential and limitation of transcranial brain stimulation for treating patients with dementia would be discussed in this review.

Ultrasound reduces inflammation by modulating M1/M2 polarization of microglia through STAT1/STAT6/PPARγ signaling pathways.

INTRODUCTION: Activated microglia can be polarized to the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. Low-intensity pulsed ultrasound (LIPUS) can attenuate pro-inflammatory responses in activated microglia. OBJECTIVE: This study aimed to investigate the effects of LIPUS on M1/M2 polarization of microglial cells and the regulatory mechanisms associated with signaling pathways. METHODS: BV-2 microglial cells were stimulated by lipopolysaccharide (LPS) to an M1 phenotype or by interleukin-4 (IL-4) to an M2 phenotype. Some microglial cells were exposed to LIPUS, while others were not. M1/M2 marker mRNA and protein expression were measured using real-time polymerase chain reaction and western blot, respectively. Immunofluorescence staining was performed to determine inducible nitric oxide synthase (iNOS)-/arginase-1 (Arg-1)- and CD68-/CD206-positive cells. RESULTS: LIPUS treatment significantly attenuated LPS-induced increases in inflammatory markers (iNOS, tumor necrosis factor-α, interleukin-1ß, and interleukin-6) as well as the expression of cell surface markers (CD86 and CD68) of M1-polarized microglia. In contrast, LIPUS treatment significantly enhanced the expression of M2-related markers (Arg-1, IL-10, and Ym1) and membrane protein (CD206). LIPUS treatment prevented M1 polarization of microglia and enhanced or sustained M2 polarization by regulating M1/M2 polarization through the signal transducer and activator of transcription 1/STAT6/peroxisome proliferator-activated receptor gamma pathways. CONCLUSIONS: Our findings suggest that LIPUS inhibits microglial polarization and switches microglia from the M1 to the M2 phenotype.

Risk of Subsequent Dementia or Alzheimer Disease Among Patients With Age-Related Macular Degeneration: A Systematic Review and Meta-analysis.

PURPOSE: Alzheimer disease (AD), a common form of dementia, shares several clinical and pathologic features with age-related macular degeneration (AMD). Epidemiologic reports on the association of AMD with subsequent dementia or AD are inconsistent. DESIGN: Systematic review and meta-analysis. METHODS: The Meta-analysis of Observational Studies in Epidemiology reporting guidelines were applied. The Newcastle-Ottawa Scale was used to evaluate the risk of bias in the included cohort studies that examined the association of AMD with subsequent dementia or AD. We estimated the pooled hazard ratios (HRs) of dementia or AD using random effects model meta-analysis and subgroup analysis on different follow-up periods, AMD subtype, gender, age, study design, and methods to ascertain dementia or AD. RESULTS: A total of 8 223 581 participants were included in 8 studies published during 2000-2021. The meta-analysis showed that AMD was significantly associated with subsequent dementia (pooled HR 1.22, 95% CI 1.01-1.47) or AD (pooled HR 1.21, 95% CI 1.03-1.43). Our secondary analysis revealed that the association was more noticeable in dry AMD than wet AMD. CONCLUSIONS: Patients with AMD have higher risks of developing dementia or AD, and therefore identifying related comorbidities and retinal biomarkers is much warranted for older adults with AMD in ophthalmologic practice.

Epidemiology of atypical parkinsonian syndromes.

Atypical parkinsonism or atypical parkinsonian syndromes (APS) refer to a group of neurodegenerative disorders which mimic typical Parkinson's disease but poorly respond to levodopa treatment and deteriorate faster. APS are very rare and among them, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) are the three relatively better characterized entities. The prevalence estimates of PSP, MSA, or CBD are mostly <10/105, and the incidence estimates are around 1/105 person-year; both estimates remain stable over the past few decades. The age at onset is relatively young for MSA at late 50s, followed by CBD at early 60s, and then PSP at late 60s. The gender difference is not significant in APS, although slight female predominance in CBD has been reported in literature. Little is known about genetic and environmental risk factors for PSP, MSA, and CBD; although the COQ2 mutation has been identified as a genetic risk for MSA, familial cases are extremely rare. Survival after symptom onset is generally within 10 years, but cases with longer disease duration do exist. Respiratory infection remains the major cause of death for APS, but cardiac arrest should be particularly considered in MSA. In addition to disease rarity, the phenotype-pathology discrepancy in APS makes the epidemiological studies even more challenging. Including biomarkers in future diagnostic criteria and establishing disease registry for collecting sufficient number of APS cases may increase the likelihood of finding modifiable risk factors for prevention and intervention.

Dysgraphia Phenotypes in Native Chinese Speakers With Primary Progressive Aphasia.

BACKGROUND AND OBJECTIVES: Most primary progressive aphasia (PPA) literature is based on English language users. Linguistic features that vary from English, such as logographic writing systems, are underinvestigated. The current study characterized the dysgraphia phenotypes of patients with PPA who write in Chinese and investigated their diagnostic utility in classifying PPA variants. METHODS: This study recruited 40 participants with PPA and 20 cognitively normal participants from San Francisco, Hong Kong, and Taiwan. We measured dictation accuracy using the Chinese Language Assessment for PPA (CLAP) 60-character orthographic dictation test and examined the occurrence of various writing errors across the study groups. We also performed voxel-based morphometry analysis to identify the gray matter regions correlated with dictation accuracy and prevalence of writing errors. RESULTS: All PPA groups produced significantly less accurate writing responses than the control group and no significant differences in dictation accuracy were noted among the PPA variants. With a cut score of 36 out of 60 in the CLAP orthographic dictation task, the test achieved sensitivity and specificity of 90% and 95% in identifying Chinese participants with PPA vs controls. In addition to a character frequency effect, dictation accuracy was affected by homophone density and the number of strokes in semantic variant PPA and logopenic variant PPA groups. Dictation accuracy was correlated with volumetric changes over left ventral temporal cortices, regions known to be critical for orthographic long-term memory. Individuals with semantic variant PPA frequently presented with phonologically plausible errors at lexical level, patients with logopenic variant PPA showed higher preponderance towards visual and stroke errors, and patients with nonfluent/agrammatic variant PPA commonly exhibited compound word and radical errors. The prevalence of phonologically plausible, visual, and compound word errors was negatively correlated with cortical volume over the bilateral temporal regions, left temporo-occipital area, and bilateral orbitofrontal gyri, respectively. DISCUSSION: The findings demonstrate the potential role of the orthographic dictation task as a screening tool and PPA classification indicator in Chinese language users. Each PPA variant had specific Chinese dysgraphia phenotypes that vary from those previously reported in English-speaking patients with PPA, highlighting the importance of language diversity in PPA.

Multimorbidity and Regional Volumes of the Default Mode Network in Brain Aging.

INTRODUCTION: The default mode network (DMN) is selectively vulnerable in brain aging. Little is known about the effect of multimorbidity as a whole onto the brain structural integrity. OBJECTIVE: We aimed to investigate the association between multimorbidity and the structural integrity of DMN. METHODS: We enrolled senior volunteers aged between 60 and 80 years in Hualien County during 2014-2018 and conducted in-person interview to collect information on chronic diseases. Fasting blood glucose and glycated hemoglobin (HbA1c) were tested. We assessed multimorbidity burden by the cumulative illness rating scale-geriatric (CIRS-G). MRI brain scans were standardized to measure the regional volume within the DMN. In a cross-sectional design, we employed stepwise regression models to evaluate the effects of age, sex, hyperglycemia, and multimorbidity on the DMN. RESULTS: A total of 170 volunteers were enrolled with a mean age of 66.9 years, female preponderance (71%), an average mini-mental state examination score of 27.6, a mean HbA1c of 6.0, and a mean CIRS-G total score (TS) of 7.2. We found that older age was associated with reduced volumes in the hippocampus, left rostral anterior cingulate cortex, right posterior cingulate, right isthmus, precuneus, and right supramarginal. Higher levels of HbA1c and fasting glucose were associated with a reduced volume in the hippocampus only. A higher CIRS-G-TS was associated with reduced volumes in the left posterior cingulate cortex and right supramarginal gyrus; while a higher CIRS-G severity index was associated with a smaller right precuneus and right supramarginal. CONCLUSIONS: In the DMN, hippocampal volume shows vulnerability to aging and hyperglycemia, whereas the posterior cingulate, supramarginal, and precuneus cortices may be the key sites to reflect the total effects of multimorbidity.

A Study of Seven Patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Eastern Taiwan: A Case Series with Literature Review.

PURPOSE: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common cause of heritable vascular dementia. Recognizing the disease before the full-blown clinical features is challenging, so our case series high light clinical characteristics, screening tools and diagnostic process of the patients with CADASIL. CASE REPORT: Our case series reports neurocognitive features, neuroimaging, and exemplary pedigrees of seven patients with genetically confirmed CADASIL, in which six patients presented with dementia and the other one presented with migraine. CONCLUSION: Our report is the single-center experience of our hospital in eastern Taiwan, where access to medical care and genetic test is relatively limited compared to other parts of Taiwan. We had also compared the utility of Davous' CADASIL criteria and the CADASIL scale, and both can be used as sensitive screening tools before genetic tests, especially in the area with limited medical access.

Psychometric properties of the dementia knowledge assessment scale-traditional Chinese among home care workers in Taiwan.

BACKGROUND: The Dementia Knowledge Assessment Scale (DKAS) is a reliable and valid measurement of dementia knowledge for diverse allied health professionals but its traditional Chinese version has not been formally validated yet. The purpose of this study was to translate the DKAS from English to traditional Chinese and evaluate its psychometric properties among home care workers in Taiwan. METHODS: The DKAS scale was translated into traditional Chinese through a forward translation and back translation process following the cross-cultural translation guideline. A total of 285 home care workers in eastern Taiwan were recruited using convenience sample. A total of 252 participants completed the questionnaires, giving a response rate of 88.4%. We tested the construct validity by confirmatory factor analysis (CFA) and evaluated the reliability by internal consistency. RESULTS: The results of the CFA supported the 25-item, four-factor model for the DKAS-TC. The DKAS-TC achieved a good overall Cronbach's alpha of .93 and McDonald's omega of 0.94 with acceptable subscales McDonald's omega ranged from .77 to .82. CONCLUSIONS: The DKAS-TC has adequate construct validity and reliability and can serve as an assessment tool to evaluate the knowledge level of home care workers in a dementia training program in Taiwan. The dementia knowledge level among home care workers in Taiwan was inadequate. There is a need for developing suitable dementia care training tailored to their learning needs and educational levels, and to improve their quality of care for those with dementia.

Impact of Comorbidity Burden on Cognitive Decline: A Prospective Cohort Study of Older Adults with Dementia.

INTRODUCTION: The lack of longitudinal data of comorbidity burden makes the association between comorbidity and cognitive decline inconclusive. We aimed to measure comorbidity and assess its effects on cognitive decline in mild to moderate dementia. METHODS: This was a prospective cohort study. The participants were enrolled from the Hualien Tzu Chi Hospital between January 2015 and December 2018. We enrolled 175 older adults with mild to moderate dementia and conducted in-person interviews to follow-up comorbidity and cognitive function annually. The comorbidity burden indices included Cumulative Illness Rating Scale for Geriatrics (CIRS-G), Charlson Comorbidity Index (CCI), and Medication Regimen Complexity Index (MRCI), and cognitive function was measured by Mini-Mental State Examination (MMSE) and clock drawing test. We employed the generalized estimating equations to assess the longitudinal effect of time-varying comorbidity burden on cognitive decline after adjusting for age, sex, and education. RESULTS: Most patients were diagnosed with Alzheimer's disease (88.6%) and in the early stage of dementia (Clinical Dementia Rating [CDR] = 0.5, 57.1%; CDR = 1, 36.6%). Multimorbidity was common (median: 3), and the top 3 most common comorbidities were osteoarthritis (67.4%), hypertension (65.7%), and hyperlipidemia (36.6%). The severity index of CIRS-G was significantly associated with cognitive decline in MMSE after adjusting for age, sex, and education. CCI and MRCI scores were, however, not associated with cognitive function. CONCLUSION: The severity index of CIRS-G outperforms CCI and MRCI in reflecting the longitudinal effect of comorbidity burden on cognitive decline in mild to moderate dementia.

Uncertainty and health literacy in dementia care.

The number of dementia cases increases with age, and the prevalence of dementia at the age above 80 is approaching 20% in Taiwan. Dementia is not simply a neurological disorder, but also a long-term care issue in public health and a matter of social adaptation. Scientific discoveries about dementia diagnostics, therapeutics, and preventive strategy have become the focus of media attention, but always updated and overwhelmed, which appears to increase rather than decrease the uncertainty and complexity of health communication in dementia care. Health literacy is essential for patients to understand medical information, utilize medical resources, and make shared decisions; however, the capacity to handle health information is often compromised in older adults with cognitive decline. Both ends of the increased uncertainty in dementia science and the reduced capacity in older adults are major challenges in dementia care. Dementia literacy, defined as knowledge and beliefs regarding dementia that aid recognition, management, or prevention, plays a vital role in effective care risk assessment and communication. However, little is known about the current state of dementia literacy among older adults, people with dementia, and their caregivers, and how well the dementia care practice can be implemented at the individual level is questionable. Empowering caregivers with adequate dementia literacy and developing a risk communication model in practice will translate the power of knowledge to effective care strategies, thus ameliorating the caregiver burden and enhancing the life quality of people with dementia in the long run.

Cervical dystonia incidence and diagnostic delay in a multiethnic population.

BACKGROUND: Current cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized. OBJECTIVES: To determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization. METHODS: We identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration. RESULTS: CD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68). CONCLUSIONS: CD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society.

Diagnostic diversity among patients with cognitive complaints: A 3-year follow-up study in a memory clinic.

OBJECTIVES: To describe the distribution and estimate the mortality risks of degenerative dementias and nondegenerative conditions in a memory clinic. METHODS: We enrolled 727 consecutive patients with cognitive complaints who visited the memory clinic in Buddhist Tzu Chi General Hospital during 2013 to 2016. Three main diagnostic groups were defined: pure type dementia, in which only one type of dementia was diagnosed, such as Alzheimer disease (AD), vascular dementia (VaD), Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD); mixed type dementia; and nondegenerative conditions. We described the frequency of different diagnoses and employed Cox proportional hazards regression models to examine the mortality risks for each diagnostic group after adjusting for age, sex, education, and cognitive status. All patients alive on or after September 30, 2018, were censored in the analysis. RESULTS: Two-thirds of patients (n = 496, 68.2%) were diagnosed with degenerative dementias. Pure type to mixed type dementia ratio was about 2: 1. AD remained the most common pure dementia subtype, followed by VaD and PDD. Among all nondegenerative conditions, depression/anxiety and subjective cognitive decline were the most common diagnoses. During a mean follow-up of 3.4 years, 150 deaths were documented, and the mortality risk was 61 deaths/1000 person-years. Mortality risks were associated with age, sex, education, and cognitive function at diagnosis but did not differ by diagnostic group. CONCLUSIONS: Clinical diagnoses for patients with cognitive complaints are diverse, and nearly one-third are of nondegenerative conditions. Baseline cognitive function is a stronger predictor for survival than clinical diagnosis.

Cognitive Impairment and Glycemic Control in Elderly Patients Under Health-Care Case Management.

We aim to test whether the association between glucose control and cognitive function still holds true in elderly patients with diabetes mellitus (DM) and Alzheimer disease (AD) under health-care case management. We enrolled 100 patients with DM (mean age: 74.6 years; male: 49%) and 102 patients with AD (mean age: 77.9 years; male: 41.2%) consecutively from the Diabetes Shared Care Program and the memory clinic. These patients were followed up every 3 months with scheduled examinations. Most patients with AD were at early stage and DM was a common comorbidity (n = 42). In the DM group, there were 76 patients with subjective cognitive decline and 19 patients with mild cognitive impairment, but none sought further consultation. After adjusting for age, sex, education, and comorbidity, higher levels of glycated hemoglobin (HbA1C) were not associated with lower Mini-Mental State Examination (MMSE) scores in the DM group (coefficient: 0.03; 95% confidence interval [CI]: -0.44 to 0.50) and lower MMSE scores were not associated with higher HbA1C in the AD group either (coefficient: -0.05; 95% CI: -0.11 to 0.01). When additionally accounting for the variability of HbA1C in the DM group, higher standard deviation of HbA1C was associated with poor clock drawing test scores, but not MMSE. The coexistence of AD-DM was common, but the association between hyperglycemia and cognitive impairment was not seen in patients under regular health monitoring.

Medical Comorbidity in Alzheimer's Disease: A Nested Case-Control Study.

BACKGROUND: Little is known about the distribution of medical comorbidities in Alzheimer's disease (AD). OBJECTIVE: We aimed to describe the comorbidity pattern of AD in a nested case-control study. METHODS: Incident AD cases were identified by International Classification of Diseases codes in a random sample of 2 million individuals in Taiwan National Health Insurance program during 2001-2011. We further restricted cases to those treated with AD drugs of approved reimbursement. We sampled a set of age- and sex-matched control subjects (2:1 ratio) and employed conditional logistic regression to estimate the associations between pre-specified 14 comorbidities and AD. The clusters of multiple chronic diseases were then identified by exploratory factor analysis. RESULTS: A total of 2,618 AD cases were identified during 2001-2011 with a mean age of 76.1 years and female preponderance (59%). The most common 5 comorbidities in AD were hypertension (55.1%), osteoarthritis (38.2%), depression (32.3%), diabetes mellitus (DM) (25.7%), and cerebrovascular disease (CVD) (22.7%). After adjusting for age and sex, DM, osteoporosis, depression, and CVD were significantly associated with AD. The number of comorbidity was 3-fold greater in the AD group. The cluster of hypertension, DM, and hyperlipidemia was the most common combination in old age, whereas the cluster osteoarthritis and osteoporosis was the only multimorbidity pattern significantly associated with AD. CONCLUSION: Multimorbidity is common in AD. Depression, CVD, osteoporosis, and DM are associated with incident AD, supporting that their co-existence is a typical feature of AD at old age. Comorbidity care should be integrated into current management for patients with AD.

Dystonia and ataxia progression in spinocerebellar ataxias.

BACKGROUND: Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known. OBJECTIVES: To study clinical characteristics and ataxia progression in SCAs with and without dystonia. METHODS: We studied 334 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and compared the clinical characteristics of SCAs with and without dystonia. We repeatedly measured ataxia progression by the Scale for Assessment and Rating of Ataxia every 6 months for 2 years. Regression models were employed to study the association between dystonia and ataxia progression after adjusting for age, sex and pathological CAG repeats. We used logistic regression to analyze the impact of different repeat expansion genes on dystonia in SCAs. RESULTS: Dystonia was most commonly observed in SCA3, followed by SCA2, SCA1, and SCA6. Dystonia was associated with longer CAG repeats in SCA3. The CAG repeat number in TBP normal alleles appeared to modify the presence of dystonia in SCA1. The presence of dystonia was associated with higher SARA scores in SCA1, 2, and 3. Although relatively rare in SCA6, the presence of dystonia was associated with slower progression of ataxia. CONCLUSIONS: The presence of dystonia is associated with greater severity of ataxia in SCA1, 2, and 3, but predictive of a slower progression in SCA6. Complex genetic interactions among repeat expansion genes can lead to diverse clinical symptoms and progression in SCAs.

Alzheimer's disease and osteoporosis.

Alzheimer's disease (AD) and osteoporosis are both common degenerative diseases in the elderly population. The incidence of both diseases increases with age and will be posing enormous societal burden worldwide. It may appear that AD and osteoporosis are two distinct diseases although many risk factors are shared. Previous observational studies have shown that patients with osteoporosis have higher risks of developing AD than those who do not have osteoporosis. Although osteoporosis, falls, and fractures are more often seen in patients with AD than other older adults, the association between these two diseases may be due to a pathophysiological link rather than one condition causing the other. Several in vitro and in vivo studies lend support to this notion. Patients with AD have excessive amyloid plaques in the brain, and the pathology may extend to peripheral organs and cause skeletal amyloid deposition, which would enhance receptor activator nuclear factor-kappa B ligand signaling and lead to greater osteoclast activities. Patients with osteoporosis may have Vitamin D deficiency or lower levels of Vitamin D binding protein, which protects against amyloid aggregation, thus linking Vitamin D deficiency and AD or osteoporosis and AD. Osteoporosis coexisting with AD provides a window to examine the amyloid hypothesis from peripheral tissues. Future studies are warranted to clarify the role of genetic background regarding Vitamin D levels, exposure to sunlight, estrogen replacement therapy, and physical activity in patients with both chronic diseases.

The borderland between normal aging and dementia.

Alzheimer's disease (AD) has become a global health issue as the population ages. There is no effective treatment to protect against its occurrence or progression. Some argue that the lack of treatment response is due to delays in diagnosis. By the time a diagnosis of AD is made, neurodegenerative changes are at the stage where very few neurons can be salvaged by medication. The AD research community has developed the idea of mild cognitive impairment (MCI) in an attempt to find predementia patients who might benefit from potentially therapeutic drugs that have proven ineffective in the past. However, MCI is heterogeneous in terms of its underlying pathology and practicality for predicting dementia. This article first reviews the conceptual evolution of MCI as the borderland between normal aging and dementia, and then proposes that built environment and sociocultural context are two key elements in formulating a diagnosis of dementia. Dementia is more than a biomedical term. Cognitive impairment is considered a dynamic outcome of how an individual interacts with cognitive challenges. To focus on amyloid deposition as a single etiology for AD does not adequately capture the social implications and geriatric aspects of dementia. Moreover, MCI is nosologically questionable. Unlike a diagnosis of AD, for which a prototype has been well established, MCI is defined by operational criteria and there are no cases seen as typical MCI. Biofluid and imaging markers are under active development for early detection of amyloid deposition and neurofibrillary tangles in the brain, whereas vascular risks, chronic medical diseases, and polypharmacy continue to add to the complexity of dementia in old age. The paradigm of dementia care policy may shift to early diagnosis of AD pathology and comprehensive care for chronic diseases in the elderly population.