Kok Pin Ng

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

Objective: To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). Methods: We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET. Results: Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. Conclusions: The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.

Anosognosia predicts default mode network hypometabolism and clinical progression to dementia

Objective To identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment. Methods We stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [18F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [18F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia. Results We found that participants with impaired awareness had lower [18F]fluorodeoxyglucose uptake and increased [18F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [18F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame. Conclusions Our results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.

Is ApoE ɛ 4 a good biomarker for amyloid pathology in late onset Alzheimer's disease?

Amyloid plaques are pathological hallmarks of Alzheimer’s Disease (AD) and biomarkers such as cerebrospinal fluid (CSF) β-amyloid 1–42 (Aβ1-42) and amyloid positron emission tomographic (PET) imaging are important in diagnosing amyloid pathology in vivo. ɛ4 allele of the Apolipoprotein E gene (ApoE ɛ 4), which is a major genetic risk factor for late onset AD, is an important genetic biomarker for AD pathophysiology. It has been shown that ApoE ɛ 4 is involved in Aβ deposition and formation of amyloid plaques. Studies have suggested the utility of peripheral blood ApoE ɛ 4 in AD diagnosis and risk assessment. However it is still a matter of debate whether ApoE ɛ 4 status would improve prediction of amyloid pathology and represent a cost-effective alternative to amyloid PET or CSF Aβ in resource-limited settings in late onset AD. Recent research suggest that the mean prevalence of PET amyloid-positivity is 95% in ApoE ɛ 4-positive AD patients. This short review aims to provide an updated information on the relationship between ApoE ɛ 4 and amyloid biomarkers.

Associations between lesions and domain-specific cognitive decline in poststroke dementia

Objective To investigate whether the effect of prestroke and stroke-related lesions on incident poststroke dementia (PSD) is mediated by a unique pattern of domain-specific cognitive impairment, and the relative strength of these anatomical–cognitive associations in predicting incident PSD. Methods In this incident case-control study (n = 150), we defined incident cases as acute stroke patients who developed PSD and controls as acute stroke patients who remained free from dementia at a 6 month follow-up, matched on age, prestroke cognitive status, and number of stroke-related lesions. MRI was performed at initial clinical presentation; neuropsychological assessments and clinical diagnosis of PSD was performed 6 months poststroke. Moderated mediation analysis evaluated the interactions among PSD, anatomical lesions, cognitive domains, and individual demographic and medical characteristics. Results Compared to stroke-related lesions, prestroke lesions were associated with the widest range of cognitive domain impairments and had stronger clinical utility in predicting incident PSD. Specifically, global cortical atrophy (GCA) and deep white matter hyperintensities (WMH) were indirectly associated with PSD by disrupting executive functions, memory, and language. Acute infarcts were indirectly associated with PSD by disrupting executive functions and language. The strongest mediator was executive dysfunction, increasing risk of PSD in patients with deep WMH, GCA, and large infarcts by more than 9 times, with sex and educational attainment moderating the magnitude of association. Periventricular WMH were directly associated with incident PSD but not mediated by deficits in cognitive domains. Conclusion We provide an anatomical–cognitive framework that can be applied to stratify patients at highest risk of PSD and to guide personalized interventions.

Cerebrospinal fluid phosphorylated tau, visinin-like protein-1, and chitinase-3-like protein 1 in mild cognitive impairment and Alzheimer’s disease

BackgroundVisinin-like protein-1 (VILIP-1) and chitinase-3-like protein 1 (CHI3L1 or YKL-40) in cerebrospinal fluid (CSF) are newly discovered markers indicating neuronal damage and microglial activation, respectively. Phosphorylated tau (p-tau) reflects the neuropathology of Alzheimer’s disease (AD) and is useful as diagnostic markers for AD. However, it is unknown whether these biomarkers have similar or complementary information in AD.MethodsWe stratified 121 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN), stable mild cognitive impairment (sMCI), progressive MCI (pMCI), and dementia due to AD. Analysis of covariance (ANOVA) and chi-square analyses, Spearman correlation, and logistic regression models were performed to test the demographic, associations between biomarkers, and diagnostic accuracies, respectively. Linear mixed-effects models were used to evaluate the effects of CSF amyloid-β (Aβ) on above biomarkers within diagnostic groups, the combination of diagnostic group and Aβ status as predictor, and CSF biomarkers as predictors of AD features, including cognition measured by Mini–Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI).ResultsP-tau, VILIP-1, and YKL-40 were all predictors of AD diagnosis, but combinations of biomarkers did not improve the diagnostic accuracy (AUC 0.924 for p-tau, VILIP-1, and YKL-40) compared to p-tau (AUC 0.922). P-tau and VILIP-1 were highly correlated (r = 0.639, p < 0.001) and strongly associated with Aβ pathology across clinical stages of AD, while YKL-40 was correlated with Aβ pathology in CN and AD groups. VILIP-1 was associated with acceleration of cognitive decline, hippocampal atrophy, and expansion of ventricles in longitudinal analyses. YKL-40 was associated with hippocampal atrophy at baseline and follow-up, while p-tau was only associated with worsening WMH at baseline.ConclusionsCSF levels of p-tau, VILIP-1, and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD. Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration. These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD.

Impact of the biological definition of Alzheimer’s disease using amyloid, tau and neurodegeneration (ATN): what about the role of vascular changes, inflammation, Lewy body pathology?

BackgroundThe NIA-AA research framework proposes a biological definition of Alzheimer’s disease, where asymptomatic persons with amyloid deposition would be considered as having this disease prior to symptoms.DiscussionNotwithstanding the fact that amyloid deposition in isolation is not associated with dementia, even the combined association of amyloid and tau pathology does not inevitably need to dementia over age 65. Other pathological factors may play a leading or an accelerating role in age-associated cognitive decline, including vascular small vessel disease, neuroinflammation and Lewy Body pathology.ConclusionResearch should aim at understanding the interaction between all these factors, rather than focusing on them individually. Hopefully this will lead to a personalized approach to the prevention of brain aging, based on individual biological, genetic and cognitive profiles.

Interaction between APOE-ɛ4 and HMGB1 is associated with widespread cortical thinning in mild cognitive impairment

Biomarkers which allow for identification of the underlying aetiology of mild cognitive impairment (MCI) are of prognostic importance. In addition to the amyloid-β and hyperphosphorylated tau pathology, genetic factors such as apolipoprotein E (APOE)-e4 and neuroinflammation may have additional roles in the pathogenesis of Alzheimer’s Disease (AD). In this study, we investigated the influence of APOE-ɛ4 status, neuroinflammation as measured by high mobility group box 1 protein (HMGB1), and their interaction effect on cortical thickness in MCI. We hypothesised that the interaction between APOE-ɛ4 and HMGB1 would result in a more widespread pattern of cortical thinning compared with either one factor alone. Fifty-two individuals (27 mild cognitive impairment (MCI) and 25 controls) were recruited from a tertiary neurological centre. MCI was clinically diagnosed using the National Institute on Aging and the Alzheimer’s Association workgroup (NIA-AA) criteria.1 They had a Clinical Dementia Rating (CDR) score of 0.5 and had no other disease that could account for their cognitive deficits. Subjects with active systemic inflammatory states including infections, recent surgery or acute strokes and those receiving anti-inflammatory or cancer treatment were excluded as they could affect the levels of high mobility group box 1 protein (HMGB1). This study was approved by the SingHealth Institutional Ethics Review Board and written informed consent was obtained for all. Blood samples were collected from all subjects. Genomic DNA was extracted from peripheral blood with QIAamp DNA Blood Maxi Kit (Qiagen, Hilden, Germany). Genotyping for apolipoprotein E (APOE) was performed as described previously.2 Subjects with at least a single copy of …

The influence of language and culture on cognitive assessment tools in the diagnosis of early cognitive impairment and dementia

ABSTRACT Introduction: Cognitive assessment tools measure cognitive impairment and complement biomarkers to link cognitive symptoms with pathophysiological processes underlying dementia. However, language and cultural differences in multilingual populations can influence the interpretation of cognitive assessment tools when applied in cross-cultural and multinational studies. Areas covered: This article examines the influence of culture and language on the interpretation of the Mini-Mental State Examination, Montreal Cognitive Assessment, and Alzheimer’s Disease Assessment Scale-cognitive subscale, which are more commonly used worldwide. It discusses how this impacted multinational studies. Lastly, it presents language-neutral tools such as the Visual Cognitive Assessment Test, which do not require translation when applied in multilingual populations. Expert commentary: Linguistic and cultural variation within tools due to translation and differences in administration introduce method bias and differential item functioning, which influence the interpretation of cognitive scores in multinational studies. The ultimate goal is to have a tool that accurately measures cognitive impairment, yet with minimal influence from linguistic, cultural, educational, and demographic differences, through concerted international efforts to harmonize the development and validation of tools. While recently developed visual-based language-neutral tools show promise in the early detection of cognitive impairment, further validation will be required for these tools to be applied internationally.

MILD COGNITIVE IMPAIRMENT ASSOCIATED WITH PARKINSON’S DISEASE (PD-MCI) AND MCI ASSOCIATED WITH ALZHEIMER’S DISEASE (AD-MCI) HAVE DISTINCT COGNITIVE PROFILES: A LONGITUDINAL STUDY

many significantly different features both under singleand dual-task walking scenarios. However, dual–task scenario provides better discrimination between MCI and HC subjects. The MCI people presented significantly higher swing time, stance time, stride time, CVof swing time, CVof stride time while having lower cadence and gait speed in comparison with the HCs. Conclusions:The inertial sensor based pervasive gait analysis method provides many assistive markers or indicators to help MCI diagnosis and facilitates the early detection of AD.

THE ROLE OF COMPREHENSIVE INVESTIGATION IN THE DIAGNOSTIC WORK-UP OF YOUNGER PATIENTS WITH COGNITIVE IMPAIRMENT

and adjusted for age. WM tracks that significantly correlated with EYO were further evaluated with pathological biomarkers (cerebrospinal fluid (CSF) amyloid and tau). Results:Significant changes in mean diffusivity and radial diffusivity were seen within parietal and frontal regions for MC CDR>0 compared to other groups (Fig1). Within the MC group, three WM tracks were significantly associated with EYO: forceps major (FMaj), cingulum, and posterior corpus callosum (PCC). Initial decline in WM for MC and NC occur around 10 years prior to EYO. A significant interaction was observed for mutation status and EYO in the cingulum. CSF amyloid correlated with average mean fractional anisotropy (FA; p1⁄40.02) but not with any specific WM track. CSF T-tau correlated with FA for the PCC (p1⁄40.04) and FMaj (p1⁄40.001). Conclusions: This data reveals that WM integrity in ADAD is most strongly affected in posterior/parietal white matter with more advanced disease. These changes suggest that structural decline may initiate just before EYO that associates with the underlying pathology.