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The emergence of sustained neuropsychiatric symptoms (NPS) among non-demented individuals in later life, defined as mild behavioral impairment (MBI), is linked to a higher risk of cognitive decline. However, the underlying pathophysiological mechanisms remain largely unexplored. A growing body of evidence has shown that MBI is associated with alterations in structural and functional neuroimaging studies, higher genetic predisposition to clinical diagnosis of Alzheimer's disease (AD), as well as amyloid and tau pathology assessed in the blood, cerebrospinal fluid, positron-emission tomography (PET) imaging and neuropathological examination. These findings shed more light on the MBI-related potential neurobiological mechanisms, paving the way for the development of targeted pharmacological approaches. In this review, we aim to discuss the available clinical evidence on the role of amyloid and tau pathology in MBI and the potential underlying pathophysiological mechanisms. Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, disruption of neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), abnormal neuroinflammatory responses including the kynurenine pathway, dysregulation of transforming growth factor beta (TGF-β1), epigenetic alterations including micro-RNA (miR)-451a and miR-455-3p, synaptic dysfunction, imbalance in neurotransmitters including acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA) and norepinephrine, as well as altered locus coeruleus (LC) integrity are some of the potential mechanisms connecting MBI with amyloid and tau pathology. The elucidation of the underlying neurobiology of MBI would facilitate the design and efficacy of relative clinical trials, especially towards amyloid- or tau-related pathways. In addition, we provide insights for future research into our deeper understanding of its underlying pathophysiology of MBI, and discuss relative therapeutic implications. [ABSTRACT FROM AUTHOR]

Mild Behavioral Impairment (MBI) leverages later-life emergent and persistent neuropsychiatric symptoms (NPS) to identify a high-risk group for incident dementia. Phosphorylated tau (p-tau) is a hallmark biological manifestation of Alzheimer disease (AD). We investigated associations between MBI and tau accumulation in early-stage AD cortical regions. In 442 Alzheimer's Disease Neuroimaging Initiative participants with normal cognition or mild cognitive impairment, MBI status was determined alongside corresponding p-tau and A β. Two meta-regions of interest were generated to represent Braak I and III neuropathological stages. Multivariable linear regression modelled the association between MBI as independent variable and tau tracer uptake as dependent variable. Among A β positive individuals, MBI was associated with tau uptake in Braak I (β =0.45(0.15), p<. 01) and Braak III (β =0.24(0.07), p<. 01) regions. In A β negative individuals, MBI was not associated with tau in the Braak I region (p=0.11) with a negative association in Braak III (p=. 01). These findings suggest MBI may be a sequela of neurodegeneration, and can be implemented as a cost-effective framework to help improve screening efficiency for AD. • MBI is associated with greater tau burden in early cortical regions affected by AD. • The study provides biomarker evidence in support of MBI and its clinical utility. • MBI provides an effective framework for detecting AD early in the disease course. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated resilience to AD-related neuropathology in a form of cognitive reserve (CR). In this study we investigated a relationship between CR and hypometabolic subtypes of AD, specifically the typical and the limbic-predominant subtypes. We analyzed data from 59 Aβ-positive cognitively normal (CN), 221 prodromal Alzheimer's disease (AD) and 174 AD dementia participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) from ADNI and ADNIGO/2 phases. For replication, we analyzed data from 5 Aβ-positive CN, 89 prodromal AD and 43 AD dementia participants from ADNI3. CR was estimated as standardized residuals in a model predicting cognition from temporoparietal grey matter volumes and covariates. Higher CR estimates predicted slower cognitive decline. Typical and limbic-predominant hypometabolic subtypes demonstrated similar baseline CR, but the results suggested a faster decline of CR in the typical subtype. These findings support the relationship between subtypes and CR, specifically longitudinal trajectories of CR. Results also underline the importance of longitudinal analyses in research on CR. • We compared cross-sectional and longitudinal CR between hypometabolic AD subtypes. • Typical and limbic-predominant subtypes demonstrated similar CR at baseline. • Typical hypometabolic subtype seemed to benefit more from higher CR. • Results suggested a faster longitudinal decline of CR in the typical subtype. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that the failure of the glymphatic system – the brain's waste clearance system, which is active during sleep – plays a key role in the pathophysiology of Alzheimer's Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD. Case report: This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5–6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD. Conclusion: The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that the failure of the glymphatic system – the brain’s waste clearance system, which is active during sleep – plays a key role in the pathophysiology of Alzheimer’s Disease (AD). Glymphatic function can be investigated using serial MRIs after intrathecal gadobutrol injection. This technique can reveal the health of the glymphatic system, but has not yet been used in participants with cognitive impairment due to AD. Case report: This report describes the sleep and gadobutrol tracer clearance patterns of four participants diagnosed with mild to moderate cognitive impairment with evidence of AD pathology (pathological levels of Ab and p-tau in cerebrospinal fluid). We performed polysomnography and MRI studies before tracer injection and MRI scans at 1.5-2 h, 5–6 h, and 48 h after injection. Despite participants reporting no sleep problems, polysomnography revealed that all participants had moderate to severe sleep disturbances, including reduced sleep efficiency during the study and obstructive sleep apnea. Severe side-effects related to tracer administration were observed, impeding the completion of the protocol in two participants. Participants who finished the protocol displayed delayed and persistent tracer enrichment in the cortex and white matter, even 48 h after injection. These outcomes have not been observed in previous studies in participants without AD. Conclusion: The findings suggest that brains with sleep impairment and AD pathology have poor glymphatic function, and therefore cannot clear the contrast tracer efficiently. This is likely to have caused the severe side effects in our participants, that have not been reported in healthy individuals. Our results may therefore represent the only available data acquired with this technique in participants with AD pathology. [ABSTRACT FROM AUTHOR]

Background: Evidence on the relative risk of death across all stages of Alzheimer's disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer's Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people. Methods: This was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing. Results: Aged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3–12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors. Conclusions: Relative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of Alzheimer's disease (AD) confirmed by biomarkers allows the patient to make important life decisions. However, doubt about the fleetness of symptoms progression and future cognitive decline remains. Neuropsychological measures were extensively studied in prediction of time to conversion to dementia for mild cognitive impairment (MCI) patients in the absence of biomarker information. Similar neuropsychological measures might also be useful to predict the progression to dementia in patients with MCI due to AD.Objective: To study the contribution of neuropsychological measures to predict time to conversion to dementia in patients with MCI due to AD.Methods: Patients with MCI due to AD were enrolled from a clinical cohort and the effect of neuropsychological performance on time to conversion to dementia was analyzed.Results: At baseline, converters scored lower than non-converters at measures of verbal initiative, non-verbal reasoning, and episodic memory. The test of non-verbal reasoning was the only statistically significant predictor in a multivariate Cox regression model. A decrease of one standard deviation was associated with 29% of increase in the risk of conversion to dementia. Approximately 50% of patients with more than one standard deviation below the mean in the z score of that test had converted to dementia after 3 years of follow-up.Conclusion: In MCI due to AD, lower performance in a test of non-verbal reasoning was associated with time to conversion to dementia. This test, that reveals little decline in the earlier phases of AD, appears to convey important information concerning conversion to dementia. [ABSTRACT FROM AUTHOR]

Background: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest.Objective: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study).Methods: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid β peptide 1-42 (Aβ42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated.Results: Prodromal AD was found in 55 aMCI patients defined by low Aβ42 in the cerebrospinal fluid (Aβ positive). Compared to the aMCI group with high Aβ42 levels (Aβ negative), Aβ positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03).Conclusion: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression. [ABSTRACT FROM AUTHOR]

Background: Dubois et al. proposed the criteria for prodromal Alzheimer's disease (AD) to detect dementia in its very early stage. Because detection requires magnetic resonance imaging and 18F‐fluorodeoxyglucose‐positron emission tomography (PET), the prevalence and prognosis have not been fully investigated. Methods: Our database included 346 healthy participants (Clinical Dementia Rating (CDR) 0), 119 with questionable dementia (CDR 0.5), and 32 dementia participants (CDR 1+) and was applied to investigate the prevalence of prodromal AD. Forty‐four CDR 0.5 participants (37%) were randomly selected to undergo 18F‐fluorodeoxyglucose‐PET. The same percentage was applied to select 128 CDR 0 and 12 CDR 1 + participants (total: n = 184) to calculate the prevalence. A neuroradiologist classified the PET images in a blinded manner based on the criteria of Silverman et al. Participants were considered to have prodromal AD if they exhibited ‘parietal/temporal +/− frontal hypometabolism’ (PET) with hippocampal atrophy (magnetic resonance imaging). Results: Eighteen CDR 0.5 participants (40.9%) met the criteria for prodromal AD, which was a prevalence rate of 9.8% among older adults aged ≥65 years. Thirteen prodromal AD participants (72%) converted to AD during the 5‐year follow‐up period. Discussion: The concept and criteria for prodromal AD are useful for predicting which subjects in a community will convert to AD. [ABSTRACT FROM AUTHOR]

Objectives: To investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer's disease (AD).Methods: Data were obtained from 177 patients with subjective complaints, mild cognitive impairment and AD from the Amsterdam Dementia Cohort. AD stages were based on diagnosis and cerebrospinal fluid biomarkers amyloid-β (Aβ) and total-tau (tau). General-linear-models were used to assess relationships between AD stages and total and regional CBF, correcting for age and sex.Results: Decreasing CBF was related to more advanced AD stages in all supratentorial regions (p for trend < 0.05). Post-hoc testing revealed that CBF was lower in AD compared to controls and stage-1 predementia patients (i.e. abnormal Aβ and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Aβ and tau) in temporal regions. CBF values of stage-2 predementia patients were numerically in between those of stage-1 predementia patients and AD.Conclusion: The continuing decrease of CBF along the continuum of AD indicates the potential of ASL-CBF as a measure for disease progression.Key Points: • Decreasing CBF relates to more advanced AD stages in all supratentorial regions. • The reduction of CBF does not reach a bottom level. • ASL-CBF has potential as a measure for disease progression in AD. [ABSTRACT FROM AUTHOR]

Background/Aims: To prospectively follow up a group of amnesic patients at risk for Alzheimer’s disease (AD), to characterize a group of patients whose features were intermediate between amnesic mild cognitive impairment (aMCI) and probable AD, prodromal AD (Prd-AD), and to investigate if these patients were at higher risk for AD conversion. Methods: A total of 109 subjects were assessed by neuropsychological evaluation and by 1H magnetic resonance spectroscopy (1H-MRS): 27 controls, and 16 aMCI, 34 probable AD and 32 Prd-AD patients. Results: Episodic memory and frontal test scores resulted lower in Prd-AD compared to aMCI patients. Prd-AD patients obtained significantly higher scores than AD ones in language, perception, praxis and frontal functions. Although Prd-AD and AD patients had distinct 1H-MRS features from aMCI ones, there were no 1H-MRS differences between Prd-AD and AD patients. The AD annual conversion rate after 1 year of follow-up for Prd-AD (57.1%) was higher than in aMCI patients (20%; p < 0.01). A logistic regression, in which all amnesic patients were treated as a single group, showed that the Visual Memory Test was a significant neuropsychological predictor for AD conversion. Conclusions: Prd-AD patients are a clinically distinguishable group, with distinct neuropsychological and 1H-MRS features and a higher conversion rate to probable AD than aMCI patients. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: The diagnosis of mild cognitive impairment (MCI) refers to cognitive impairment not meeting dementia criteria. A survey among members of the American Association of Neurology (AAN) showed that MCI was considered a useful diagnosis. Recently, research criteria have been proposed for the diagnosis of Alzheimer's disease (AD) in MCI based on AD biomarkers (prodromal AD/MCI due to AD). The aim of this study was to investigate the attitudes of clinicians in Europe on the clinical utility of MCI and prodromal AD/MCI due to AD criteria. We also investigated whether the prodromal AD/MCI due to AD criteria impacted management of MCI patients. Methods: An online survey was performed in 2015 among 102 members of the European Academy of Neurology (EAN) and the European Alzheimer's Disease Consortium (EADC). Questions were asked on how often criteria were used, how they were operationalized, how they changed patient management, and what were considered advantages and limitations of MCI and prodromal AD/MCI due to AD. The questionnaire consisted of 47 questions scored on a Likert scale. Results: Almost all respondents (92%) used the MCI diagnosis in clinical practice. Over 80% of the EAN/EADC respondents found a MCI diagnosis useful because it helped to label the cognitive problem, involve patients in planning for the future, and start risk reduction activities. These findings were similar to those reported in the AAN survey. Research criteria for prodromal AD/MCI due to AD were used by 68% of the EAN/EADC respondents. The most common reasons to use the criteria were increased certainty of diagnosis (86%), increased possibilities to provide counseling (51%), facilitation of follow-up planning (48%), start of medical intervention (49%), and response to patients' wish for a diagnosis (41%). Over 70% of the physicians considered that a diagnosis of prodromal AD/MCI due to AD had an added value over the MCI diagnosis. Conclusions: The diagnostic criteria of MCI and prodromal AD/MCI due to AD are commonly used among EAN/EADC members. The prodromal AD/MCI due to AD were considered clinically useful and impacted patient management and communication. [ABSTRACT FROM AUTHOR]