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.

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.

Long-term cognitive and multimodal imaging outcomes after carotid artery stenting vs intensive medication alone for severe asymptomatic carotid stenosis.

BACKGROUND: Severe carotid stenosis is associated with cognitive impairment, which may be attributed to asymptomatic microembolism and/or chronic hypoperfusion. We aim to evaluate the long-term cognitive and brain connectivity outcomes of carotid artery stenting (CAS) for asymptomatic ≥70% stenosis of the extracranial internal carotid artery (ICA). METHODS: We conducted a non-randomized controlled study to compare intensive medical therapy alone (Med) or in combination with carotid artery stenting for the composite vascular events, neuropsychological, and multimodal magnetic resonance perfusion imaging and diffusion tensor imaging outcomes. RESULTS: Sixty-nine patients were followed for a mean of 2.3 years (31 Med, 38 CAS) and 11 patients had composite vascular events of all-cause death, ischemic stroke, or myocardial infarction (6 Med vs 5 CAS). Forty-six asymptomatic subjects completed neuropsychological and multimodality imaging follow-ups (23 Med, 23 CAS). Compared to the Med group, the CAS group had a modest improvement of 12-item delayed verbal memory (8.9 ± 2.4 to 9.8 ± 2.7 vs 9.0 ± 2.1 to 8.9 ± 2.3, p = 0.04), but not in global cognition, attention or executive function, which was associated with increased structural connectivity of fractional anisotropy at the ipsilateral deep white matter. Importantly, the memory improvement was correlated with the perfusion increment at the ipsilateral middle cerebral artery territory. CONCLUSION: For asymptomatic extracranial carotid steno-occlusion, successful carotid revascularization in addition to intensive medical treatment may potentially benefit cognitive reserve and connectivity strength which are partly attributed to restoration of non-critical hypoperfusion.

Neuromagnetic evidence of abnormal automatic inhibitory function in subjective memory complaint.

Subjective memory complaint (SMC), a self-perceived worsening in memory capacity concurrent with normal performance on standardized cognitive assessments, is considered a risk factor for the development of Alzheimer's disease (AD). Deficient sensory gating (SG), referring to the lack of automatic inhibition of neural responses to the second identical stimulus, has been documented in prodromal and incident AD patients. However, it remains unknown whether the cognitively normal elderly with SMC demonstrate alterations of SG function compared with those without SMC. A total of 19 healthy controls (HC) and 16 SMC subjects were included in the present study. Neural responses to the auditory paired-stimulus paradigm were recorded by the magnetoencephalography and analyzed by the distributed source imaging method of minimum norm estimate. The SG of M50 and M100 components were measured using the amplitude ratio of the second response over the first response at the cortical level. Compared to HC, subjects with SMC showed significantly increased M50 SG ratios in the inferior parietal lobule (IPL). Furthermore, M50 SG ratios in the right IPL yielded an acceptable discriminative ability to distinguish SMC from HC. However, we did not find a significant association between SG ratios and cognitive function requiring inhibitory control either in the HC or SMC group. In conclusion, although SMC subjects have intact cognitive functioning revealed by objective neuropsychological tests, their deficits in automatic inhibitory function could be detected through neurophysiological recordings. Our results suggest that altered brain function occurs in SMC prior to the obvious decline of cognitive performance.

Upregulation of Cisd2 attenuates Alzheimer's-related neuronal loss in mice.

CDGSH iron-sulfur domain-containing protein 2 (Cisd2), a protein that declines in an age-dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid ß (Aß) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two-fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aß-mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild-type mice. These findings highlight Cisd2-based therapies as a potential disease-modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Large-Scale Structural Covariance Networks Predict Age in Middle-to-Late Adulthood: A Novel Brain Aging Biomarker.

The aging process is accompanied by changes in the brain's cortex at many levels. There is growing interest in summarizing these complex brain-aging profiles into a single, quantitative index that could serve as a biomarker both for characterizing individual brain health and for identifying neurodegenerative and neuropsychiatric diseases. Using a large-scale structural covariance network (SCN)-based framework with machine learning algorithms, we demonstrate this framework's ability to predict individual brain age in a large sample of middle-to-late age adults, and highlight its clinical specificity for several disease populations from a network perspective. A proposed estimator with 40 SCNs could predict individual brain age, balancing between model complexity and prediction accuracy. Notably, we found that the most significant SCN for predicting brain age included the caudate nucleus, putamen, hippocampus, amygdala, and cerebellar regions. Furthermore, our data indicate a larger brain age disparity in patients with schizophrenia and Alzheimer's disease than in healthy controls, while this metric did not differ significantly in patients with major depressive disorder. These findings provide empirical evidence supporting the estimation of brain age from a brain network perspective, and demonstrate the clinical feasibility of evaluating neurological diseases hypothesized to be associated with accelerated brain aging.

Discovery of a Metabolic Signature Predisposing High Risk Patients with Mild Cognitive Impairment to Converting to Alzheimer's Disease.

Assessing dementia conversion in patients with mild cognitive impairment (MCI) remains challenging owing to pathological heterogeneity. While many MCI patients ultimately proceed to Alzheimer's disease (AD), a subset of patients remain stable for various times. Our aim was to characterize the plasma metabolites of nineteen MCI patients proceeding to AD (P-MCI) and twenty-nine stable MCI (S-MCI) patients by untargeted metabolomics profiling. Alterations in the plasma metabolites between the P-MCI and S-MCI groups, as well as between the P-MCI and AD groups, were compared over the observation period. With the help of machine learning-based stratification, a 20-metabolite signature panel was identified that was associated with the presence and progression of AD. Furthermore, when the metabolic signature panel was used for classification of the three patient groups, this gave an accuracy of 73.5% using the panel. Moreover, when specifically classifying the P-MCI and S-MCI subjects, a fivefold cross-validation accuracy of 80.3% was obtained using the random forest model. Importantly, indole-3-propionic acid, a bacteria-generated metabolite from tryptophan, was identified as a predictor of AD progression, suggesting a role for gut microbiota in AD pathophysiology. Our study establishes a metabolite panel to assist in the stratification of MCI patients and to predict conversion to AD.

Effect of Times to Blood Processing on the Stability of Blood Proteins Associated with Dementia.

BACKGROUND: The stability of proteins in the collecting tubes after blood draw is critical to the measured concentrations of the proteins. Although the guidelines issued by the Clinical and Laboratory Standards Institute (CLSI) suggest centrifugation should take place within 2 h of drawing blood, it is very difficult to follow these guidelines in hospitals or clinics. It is necessary to study the effect of times to blood processing on the stability of the proteins of interest. METHODS: In this work, the plasma proteins of interest were those relevant to dementia, such as amyloid ß 1-40 (Aß1-40), Aß1-42, Tau protein (Tau), and α-synuclein. The times to blood processing after blood draw ranged from 0.5 to 8 h. The storage temperatures of blood were room temperature (approx. 25°C) and 30°C. After storage, blood samples were centrifuged at room temperature to obtain plasma samples. Ultrasensitive immunomagnetic reduction was applied to assay these proteins in the plasma. RESULTS: The levels of plasma Aß1-40, Tau, and α-synuclein did not significantly change until 8 h after blood draw when stored at room temperature. Plasma Aß1-42 levels did not change significantly after 8 h of storage at room temperature before blood processing. Higher storage temperatures, such as 30°C, for blood samples accelerated the significant variations in the measured concentrations of Aß1-40, Tau, and α-synuclein in plasma. CONCLUSION: According to these results, for clinical practice, it is suggested that blood samples be stored at room temperature for no longer than 4.5 h after blood draw until centrifugation for the assay of dementia biomarkers in plasma.

Changes in Plasma Amyloid and Tau in a Longitudinal Study of Normal Aging, Mild Cognitive Impairment, and Alzheimer's Disease.

BACKGROUND: Changes in cerebrospinal fluid, neuroimaging, and cognitive functions have been used as diagnostic biomarkers of Alzheimer's disease (AD). This study aimed to investigate the temporal trajectories of plasma biomarkers in subjects with mild cognitive impairment (MCI) and patients with AD relative to healthy controls (HCs). METHODS: In this longitudinal study, 82 participants (31 HCs, 33 MCI patients, and 18 AD patients) were enrolled. After 3 years, 7 HCs had transitioned to MCI and 10 subjects with MCI had converted to AD. We analyzed plasma amyloid beta (Aß) and tau proteins at baseline and annually to correlate with biochemical data and neuropsychological scores. RESULTS: Longitudinal data analysis showed an evolution of Aß-related biomarkers over time within patients, whereas tau-related biomarkers differed primarily across diagnostic classifications. An initial steady increase in Aß42 in the MCI stage was followed by a decrease just prior to clinical AD onset. Hyperphosphorylated tau protein levels correlated with cognitive decline in the MCI stage, but not in the AD stage. CONCLUSION: Plasma Aß and tau levels change in a dynamic, nonlinear, nonparallel manner over the AD continuum. Changes in plasma Aß concentration are time-dependent, whereas changes in hyperphosphorylated tau protein levels paralleled the clinical progression of MCI. It remains to be clarified whether diagnostic efficiency can be improved by combining multiple plasma markers or combining plasma markers with other diagnostic biomarkers.

Associations between low circulatory low-density lipoprotein cholesterol level and brain health in non-stroke non-demented subjects.

Low-density lipoprotein cholesterol (LDL-C) and hypertension have independent and synergistic effects on atherosclerotic cardiovascular disease. However, the role of circulatory LDL-C and its possible interactions with hypertension in brain health have been poorly investigated. The study aimed to investigate the relationship between the circulatory LDL-C level and (1) brain structures, grey-matter volume (GMV) and white matter hyperintensity (WMH) and (2) cognitive functions, and whether hypertension plays a role in these relationships. Subjects who were non-stroke and non-demented were prospectively recruited from the community-based I-Lan Longitudinal Aging Study. High-resolution 3T MRI was performed with GM and WMH segmentation. GMVs, total and regional including Alzheimer's disease-susceptible area, and WMH volumes were measured. Neurological tests including verbal memory, visuospatial, and verbal executive functions were assessed. Eight-hundred-and-two participants (59.2 ±â€¯5.7 years; 44% men) were included. Multivariate linear regression analyses showed that low circulatory LDL-C levels (<98 mg/dL) were significantly associated with reduced GMVs in frontal (standardized ß = -0.130; p = 0.003) and posterior cingulate (ß = -0.113; p = 0.032) regions in hypertensive but not normotensive subjects. In addition, low circulatory LDL-C levels, combined with hypertension, had the lowest posterior cingulate GMV (ß = -0.073; p = 0.021), highest periventricular WMH (ß = 0.089; p = 0.011) and lowest verbal memory test scores (ß = -0.088; p = 0.035) compared with neither low circulatory LDL-C level nor hypertension, and either hypertension or low circulatory LDL-C level. Age, sex, total intracranial volume, vascular risk factors, level of other circulatory lipids, and the taking of anti-hypertensive and lipid-lowering medications were adjusted. In conclusion, the role of circulatory LDL-C level and its interactive effect with hypertension on brain health are firstly demonstrated. A low circulatory LDL-C level was associated with reduced regional brain GMVs in hypertensive but not normotensive subjects. In addition, there seems a combined detrimental-effect of low circulatory LDL-C levels with hypertension on posterior cingulate GMV, WMH, and verbal memory.

Somatosensory gating is altered and associated with migraine chronification: A magnetoencephalographic study.

Background Brain excitability is changed in migraine but not fully characterized yet. This study explored if somatosensory gating is altered in migraine and linked to migraine chronification. Methods Paired electrical stimuli were delivered to the left index fingers of 21 patients with migraine without aura (MO), 22 patients with chronic migraine (CM), and 36 controls. The first and second responses to the paired stimuli were obtained from the contralateral primary (cSI), contralateral secondary (cSII) and ipsilateral secondary (iSII) somatosensory cortices to compute the gating ratios (second vs. first response strengths). Results The first and second cSI responses and gating ratios differed in all groups ( p < 0.05); the responses were typically smaller in the MO and CM groups. The cSI gating ratio increased as a continuum across controls (0.73 ± 0.04, p < 0.001), MO (0.83 ± 0.04) to CM (0.97 ± 0.06) and was higher in CM vs. controls ( p < 0.001). When MO and CM were combined, cSI gating ratio was associated with headache frequency (r = 0.418, p = 0.005). Paired responses and gating ratios of cSII and iSII did not differ among the groups. Conclusions Somatosensory gating is altered in migraine and associated with headache chronification. Further studies must clarify if this abnormal sensory modulation is a true gating deficit independent of low preexcitation level.

Diagnostic accuracy of Instrumental Activities of Daily Living for dementia in community-dwelling older adults.

BACKGROUND: many people living with dementia remain underdiagnosed and unrecognised. Screening strategies are important for early detection. OBJECTIVE: to examine whether the Lawton's Instrumental Activities of Daily Living (IADL) scale, compared with other cognitive screening tools-the Mini-Mental State Examination (MMSE), and the Ascertain Dementia 8-item Informant Questionnaire (AD8)-can identify older (≥ 65 years) adults with dementia. DESIGN: population-based cross-sectional observational study. SETTING: all 19 counties in Taiwan. PARTICIPANTS: community-dwelling older adults (n = 10,340; mean age 74.87 ± 6.03). METHODS: all participants underwent a structured in-person interview. Dementia was identified using National Institute on Aging-Alzheimer's Association core clinical criteria for all-cause dementia. Receiver operator characteristic curves were used to determine the discriminant abilities of the IADL scale, MMSE and AD8 to differentiate participants with and without dementia. RESULTS: we identified 917 (8.9%) participants with dementia, and 9,423 (91.1%) participants without. The discriminant abilities of the MMSE, AD8 and IADL scale (cutoff score: 6/7; area under curve = 0.925; sensitivity = 89%; specificity = 81%; positive likelihood ratio = 4.75; accuracy = 0.82) were comparable. Combining IADL with AD8 scores significantly improved overall accuracy: specificity = 93%; positive likelihood ratio = 11.74; accuracy = 0.92. CONCLUSIONS: our findings support using IADL scale to screen older community-dwelling residents for dementia: it has discriminant power comparable to that of the AD8 and MMSE. Combining the IADL and the AD8 improves specificity.

Altered insula-default mode network connectivity in fibromyalgia: a resting-state magnetoencephalographic study.

BACKGROUND: Fibromyalgia (FM) is a disabling chronic pain syndrome with unknown pathophysiology. Functional magnetic resonance imaging studies on FM have suggested altered brain connectivity between the insula and the default mode network (DMN). However, this connectivity change has not been characterized through direct neural signals for exploring the embedded spectrotemporal features and the pertinent clinical relevance. METHODS: We recorded the resting-state magnetoencephalographic activities of 28 patients with FM and 28 age- and sex-matched controls, and analyzed the source-based functional connectivity between the insula and the DMN at 1-40 Hz by using the minimum norm estimates and imaginary coherence methods. We also measured the connectivity between the DMN and the primary visual (V1) and somatosensory (S1) cortices as intrapatient negative controls. Connectivity measurement was further correlated with the clinical parameters of FM. RESULTS: Compared with the controls, patients with FM reported more tender points (15.2±2.0 vs. 5.9±3.7) and higher total tenderness score (TTS; 29.1±7.0 vs. 7.7±5.5; both p < 0.001); they also had decreased insula-DMN connectivity at the theta band (4-8 Hz; left, p = 0.007; right, p = 0.035), but displayed unchanged V1-DMN and S1-DMN connectivity (p > 0.05). When patients with FM and the controls were combined together, the insula-DMN theta connectivity was negatively correlated with the number of tender points (left insula, r = -0.428, p = 0.001; right insula, r = -0.4, p = 0.002) and TTS score (left insula, r = -0.429, p = 0.001; right insula, r = -0.389, p = 0.003). Furthermore, in patients with FM, the right insula-DMN connectivity at the beta band (13-25 Hz) was negatively correlated with the number of tender points (r = -0.532, p = 0.004) and TTS (r = -0.428, p = 0.023), and the bilateral insula-DMN connectivity at the delta band (1-4 Hz) was negatively correlated with FM Symptom Severity (left: r = -0.423, p = 0.025; right: r = -0.437, p = 0.020) and functional disability (Fibromyalgia Impact Questionnaire; left: r = -0.415, p = 0.028; right: r = -0.374, p = 0.050). CONCLUSIONS: We confirmed the frequency-specific reorganization of the insula-DMN connectivity in FM. The clinical relevance of this connectivity change may warrant future studies to elucidate its causal relationship and potential as a neurological signature for FM.

Strictly Lobar Cerebral Microbleeds Are Associated With Cognitive Impairment.

BACKGROUND AND PURPOSE: Different distributions of cerebral microbleeds (CMBs) are associated with distinct pathological mechanisms. Lobar CMBs are thought to be related to cerebral amyloid angiopathy, whereas deep or infratentorial CMBs are related to hypertensive vasculopathy. The present study aimed to evaluate the effects of CMBs and their locations on a variety of cognitive domains. METHODS: Study subjects were selected from the community-based I-Lan Longitudinal Aging Study. We assessed cognitive domains, including verbal memory, language, visuospatial executive function, and verbal executive function. CMBs were evaluated using 3T susceptibility-weighted magnetic resonance imaging. RESULTS: We studied 959 subjects (mean±SD, 62.5±8.6 years; 425 [44.3%] men). CMBs were found in 14.2% of the population. We classified subjects with CMBs into 2 different groups based on the locations of their CMBs: (1) deep or infratentorial (85 subjects, 8.8% of population) and (2) strictly lobar (49, 5.1%). Multivariate linear analysis showed that strictly lobar CMBs were significantly associated with deficits in global cognitive function (Mini-Mental State Examination) and visuospatial executive function, as determined by the copy test of the Taylor complex figure test and the clock drawing test. We adjusted our results for age, sex, years of education, cardiovascular risk factors, and other markers of cerebral small vessel disease, lacunes, and white matter hyperintensity. Deep or infratentorial CMBs were not associated with changes in cognitive function in our population. CONCLUSIONS: Strictly lobar, but not deep or infratentorial, CMBs are associated with changes in cognitive function, especially in visuospatial executive functions. Cerebral amyloid angiopathy may be the underlying pathology associated with CMB-related cognitive impairment.

Clinical Prediction Score for Successful Retrograde Procedure in Chronic Total Occlusion Percutaneous Coronary Intervention.

OBJECTIVE: To develop and validate a prediction score for a successful retrograde procedure in chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS: A total of 228 CTO lesions in 223 patients who underwent PCI by retrograde approach were analyzed. All subjects were randomly grouped to a derivation set and a validation set at a ratio of 2:1. A successful retrograde procedure was set as the end point. Each of the identified predictors for the end point by logistic regression was assigned 1 point and summed. RESULTS: Independent predictors of a successful retrograde procedure were Werner's score [odds ratio (OR) 4.841, 95% confidence interval (CI) 1.952-12.005, p = 0.001], diameter of distal CTO segment (OR 5.263, 95% CI 2.067-13.398, p < 0.001) and tortuous collateral (type b; OR 0.119, 95% CI 0.032-0.444, p = 0.002). The predictive model developed in the derivation set stratified the difficulty of achieving a successful retrograde procedure into 4 grades - very difficult (10.5%), difficult (23.7%), intermediate (50.7%) and easy (15.1%) - and was demonstrated significantly in the validation set: very difficult (15.8%), difficult (18.4%), intermediate (47.4%) and easy (18.4%). The area under the receiver-operating characteristic curve was 0.832 ± 0.042 for the derivation set and 0.912 ± 0.041 for the validation set with an almost equal performance. CONCLUSIONS: According to the experience of our center, this model performed excellently in predicting the difficulty in achieving a successful retrograde procedure.

Reduced cerebellar gray matter is a neural signature of physical frailty.

Physical frailty has been recognized as a clinical syndrome resulting from declines in various physiological systems; however, the role of the central nervous system in the pathophysiology of frailty remains unclear. The I-Lan Longitudinal Aging Study randomly sampled community-dwelling people aged 50 or older for a brain magnetic resonance imaging study. All participants were assessed for frailty status (robust, prefrail, and frail) based on the presence of five frailty components: slow walking speed, muscle weakness, low physical activity, exhaustion and weight loss (Fried criteria). Gray matter volume (GMV) changes associated with frailty status and individual frailty components were examined. Overall, 456 participants (64.0 ± 8.5 years, 47.6% women) were included in this study. The prefrail (n = 178, 39.0%) and frail (n = 19, 4.2%) subjects were grouped for analysis. The prefrail-frail group showed reduced GMV, compared to the robust group (n = 259, 56.8%), in the cerebellum, hippocampi, middle frontal gyri, and several other cerebral regions (corrected P < 0.05). Each frailty component was associated with GMV changes in functionally related brain areas. Hierarchical cluster analysis categorized these components into three subsets. Motor-related components, including weakness, low activity, and slowness, comprised one subset with a common cerebellar involvement. Exhaustion and weight loss were the other two subsets without cerebellar changes. To conclude, physical frailty is associated with a decreased reserve in specific brain regions, especially cerebellum. Further longitudinal studies are needed to explore if the cerebellum- and noncerebellum-based frailty components reflect a distinctive future risk for developing frailty.

Comparison of the efficacy of aroma-acupressure and aromatherapy for the treatment of dementia-associated agitation.

BACKGROUND: One of the most common symptoms observed in patients with dementia is agitation, and several non-pharmacological treatments have been used to control this symptom. However, because of limitations in research design, the benefit of non-pharmacological treatments has only been demonstrated in certain cases. The purpose of this study was to compare aroma-acupressure and aromatherapy with respect to their effects on agitation in patients with dementia. METHODS: In this experimental study, the participants were randomly assigned to three groups: 56 patients were included in the aroma-acupressure group, 73 patients in the aromatherapy group, and 57 patients in the control group who received daily routine as usual without intervention. The Cohen-Mansfield Agitation Inventory (CMAI) scale and the heart rate variability (HRV) index were used to assess differences in agitation. The CMAI was used in the pre-test, post-test and post-three-week test, and the HRV was used in the pre-test, the post-test and the post-three-week test as well as every week during the four-week interventions. RESULTS: The CMAI scores were significantly lower in the aroma-acupressure and aromatherapy groups compared with the control group in the post-test and post-three-week assessments. Sympathetic nervous activity was significantly lower in the fourth week in the aroma-acupressure group and in the second week in the aromatherapy group, whereas parasympathetic nervous activity increased from the second week to the fourth week in the aroma-acupressure group and in the fourth week in the aromatherapy group. CONCLUSIONS: Aroma-acupressure had a greater effect than aromatherapy on agitation in patients with dementia. However, agitation was improved in both of the groups, which allowed the patients with dementia to become more relaxed. Future studies should continue to assess the benefits of aroma-acupressure and aromatherapy for the treatment of agitation in dementia patients. TRIAL REGISTRATION: ChiCTR-TRC-14004810; Date of registration: 2014/6/12.

Temporo-frontal functional connectivity during auditory change detection is altered in Alzheimer's disease.

Cortico-cortical connections might be disturbed in patients with Alzheimer's disease (AD). This study aimed to investigate the alterations of functional connectivity in AD during auditory change detection processing by measuring the local neuronal activation and functional connectivity between cortical regions. Magnetoencephalographic responses to deviant and standard sounds were recorded in 16 AD patients, 18 young controls and 16 elderly controls. Larger source amplitudes and shorter peak latencies were found in the right temporal magnetic mismatch responses of young controls compared with elderly controls and AD patients. During deviant stimuli, the right theta temporal-frontal phase synchrony was significantly smaller in AD than in young controls and elderly controls. Moreover, the left temporal-frontal synchronization at theta and alpha bands was reduced in AD and elderly controls compared with young controls. In conclusion, the loss in temporo-frontal theta synchronization might be an electrophysiological hallmark of AD.

Callosal degeneration topographically correlated with cognitive function in amnestic mild cognitive impairment and Alzheimer's disease dementia.

Degeneration of the corpus callosum (CC) is evident in the pathogenesis of Alzheimer's disease (AD). However, the correlation of microstructural damage in the CC on the cognitive performance of patients with amnestic mild cognitive impairment (aMCI) and AD dementia is undetermined. We enrolled 26 normal controls, 24 patients with AD dementia, and 40 single-domain aMCI patients with at least grade 1 hippocampal atrophy and isolated memory impairment. Diffusion tensor imaging (DTI) with fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA), and radial diffusivity (DR) were measured. The entire CC was parcellated based on fiber trajectories to specific cortical Brodmann areas using a probabilistic tractography method. The relationship between the DTI measures in the subregions of the CC and cognitive performance was examined. Although the callosal degeneration in the patients with aMCI was less extended than in the patients with AD dementia, degeneration was already exhibited in several subregions of the CC at the aMCI stage. Scores of various neuropsychological tests were correlated to the severity of microstructural changes in the subregional CC connecting to functionally corresponding cortical regions. Our results confirm that CC degeneration is noticeable as early as the aMCI stage of AD and the disconnection of the CC subregional fibers to the corresponding Brodmann areas has an apparent impact on the related cognitive performance.

Confrontation naming errors in Alzheimer's disease.

BACKGROUND/AIMS: Impairment in visual interpretation, semantic conception, or word retrieval may contribute to the naming errors identified in the Boston Naming Test (BNT). We investigated the possible cognitive mechanism of the naming difficulty in Alzheimer's disease (AD) by analyzing the error patterns presented in the BNT. METHODS: The Chinese version of the 30-item BNT (BNT-30) was performed on 115 normal control (NC) subjects and 104 mild-to-moderate AD patients. Accurate rates after semantic and phonemic cues were analyzed. The frequencies of 7 types of error patterns in the AD patients and the NC subjects were compared. RESULTS: The accurate rate after semantic cues was significantly lower in the AD than in the NC groups, but phonemic cues were more helpful than semantic cues to achieve accurate naming in both groups. The AD patients made more errors in all error patterns. Particularly, the frequency of nonresponse errors (n = 806) in the AD group significantly exceeded that in the NC group (n = 382). However, the distribution of the error patterns did not differ between the two groups. CONCLUSION: Naming difficulties in AD might be attributed to progressive semantic knowledge degradation. The AD and the NC groups differ quantitatively but not qualitatively in the error patterns in confrontation naming.