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Alzheimer's disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD ( APOE ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE ε4-carriers during a virtual navigation task. We report a selective impairment in APOE ε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations when no compensatory strategies were available, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ε4-carriers. Furthermore, posterior cingulate/retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Dementia, of which the most frequent form is Alzheimer's disease, is a chronic and terminal condition with multi-factorial causes and numerous consequences on a patient's life. Combining perspectives from different disciplines seems necessary for unraveling dementia's entangled issues. Current dementia management is a multidisciplinary effort; however, integrating different disciplines as a holistic treatment process is often hindered due to different responsibilities, various conceptual approaches, and distinctive research methods. With this paper, we raise some of the challenges that need to be addressed in order to initiate an interdisciplinary or even transdisciplinary research agenda. We also outline recommendations on how to integrate multiple disciplinary perspectives in dementia care and research. We see opportunities for young investigators to draw from different fields of research in dementia as their research focus is still developing. By establishing common objectives with investigators from other fields, we can pursue the goal of improving treatment and care as a team-meaning accomplishing different tasks but sharing a common purpose. It is necessary to address the communication between fields that limits the understanding of connections between cognitive symptoms, biological processes, treatment, lifestyle, and care giving in order to reach the aim of developing a holistic, person-centered, patient-first approach. Associating biomedical research to field experience from care professionals and the study of human science will promote a more independent, social, and sustainable lifestyle for people with dementia., Competing Interests: The authors have no conflict of interest to report., (© 2020 – IOS Press and the authors. All rights reserved.)

Early diagnosis of Alzheimer's disease (with the announcement of the diagnosis). The number of patients consulting to find out if they have Alzheimer's disease continues to grow. Reasons to consult most often include anxiety about being affected by this disease, confidence in medical and therapeutic advances relayed in the media and the desire to plan for the future, taking into account a possible deterioration. Advances in the knowledge of the natural history of the disease and the technical progress currently allow an early diagnosis, before the stage of dementia. Although the clinical use of biomarkers is justified in patients who have attended a Memory Clinic, ethical issues remain. The disclosure of the diagnosis of Alzheimer's disease to the person who is not yet suffering from dementia remains a sensitive subject. In this context, it seems appropriate at this stage to restrict the use of these methods to centers specializing in early diagnosis., Competing Interests: A. Ivanoiu déclare des liens ponctuels (essais cliniques, travaux scientifiques, conférences, prise en charge lors de congrès) avec GE Healthcare, Nutricia, Schwabe Pharma, AbbVie, Lilly, Roche et MSD. S. Engelborghs déclare des liens ponctuels (essais cliniques, travaux scientifiques, conférences) avec Janssen Pharmaceutica, ADx Neurosciences, Novartis et Nutricia. B. Hanseeuw déclare avoir été pris en charge lors de congrès par GE Healthcare.

Background: Cerebrospinal fluid (CSF) biomarkers are increasingly used to diagnose Alzheimer's disease (AD). However, important methodological and technical remain regarding measurement variability between kit providers and users. We compared the Lumipulse fully automated assays with the manual INNOTEST assays (both from Fujirebio Europe NV, Gent, Belgium) on a clinically representative sample of patients and controls., Methods: CSF samples of 156 patients were used to quantify Amyloïd Aβ 1-42 peptide (Aβ 1-42 ) and Total-Tau (T-Tau) protein by chemiluminescent enzyme-immunoassay (Lumipulse). Patients were divided into several subgroups: Alzheimer (AD = 44), mild-cognitive impairment (MCI = 23), other dementias (OD = 36), non-dementing neurological conditions (ND = 11), and controls (CTRL = 42). Clinical cut-offs were determined by comparing AD and CTRL with ROC curves for the two markers and their related ratio (T-Tau/Aβ 1-42 ). Subgroups of 58 (for phosphorylated-Tau) and 115 samples (for Aβ 1-42 and T-Tau) were used to evaluate the concordance of this analyzer with the INNOTEST assays., Results: Lumipulse and INNOTEST assays showed good concordance for all markers, but systematic bias was observed justifying the need to redefine new clinical cut-offs. To discriminate AD from CTRL subjects, T-Tau/Aβ 1-42 ratio was the best biomarker, with a cut-off value of 1.12 (sensitivity 81.8% and specificity 92.9%). Similar clinical performances were observed for the Lumipulse and Innotests assays on the subsample of 115 subjects., Conclusions: Our results demonstrate that the Lumipulse Aβ 1-42 and T-Tau assays show good analytical and clinical performances in the context of patient evaluation referred to a memory clinic. Automated analyzers should be preferred for the measurement of CSF AD biomarkers to reduce inter- and intra-laboratory variability.

Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-β proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-β accumulation, apolipoprotein ε4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-β and tau accumulation) before clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-β accumulation with PiB-positron emission tomography imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions before clinical impairment. SIGNIFICANCE STATEMENT The circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in vivo characterization of amyloid-β and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, before the clinical manifestations of Alzheimer's disease., (Copyright © 2019 the authors 0270-6474/19/390549-09$15.00/0.)

Background: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined., Objective: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults., Methods: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis., Results: rs3846455G was associated with greater PACC decline (β= -0.087/year, 95% CI -0.169 to -0.005, p = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= -57.3 mm3/year, 95% CI -102.8 to -11.9, p = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = -0.014, 95% CI -0.032 to -6.0×10-4, p = 0.039)., Conclusion: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

The ability to accurately judge memory efficiency (meta-memory monitoring) for newly learned (episodic) information, is decreased in older adults and even worse in Alzheimer's disease (AD), whereas no differences have been found for semantic meta-memory. The pathological substrates of this phenomenon are poorly understood. Here, we examine the association between meta-memory monitoring for episodic and semantic information to the two major proteinopathies in AD: amyloid (Aβ) and tau pathology in a group of cognitively unimpaired older adults. All participants underwent multi-tracer PET and meta-memory monitoring was assessed using a feeling-of-knowing (FOK) task for non-famous (episodic) and famous (semantic) face-name pairs. Whole brain voxel-wise correlations between meta-memory and PET data were conducted (controlling for memory), as well as confirmatory region-of-interest analyses. Participants had reduced episodic FOK compared to semantic FOK. Decreased episodic FOK was related to tauopathy in the medial temporal lobe regions, including the entorhinal cortex and temporal pole, whereas decreased semantic FOK was related to increased tau in regions associated with the semantic knowledge network. No association was found with Aβ-pathology. Alterations in the ability to accurately judge memory efficiency (in the absence of memory decline) may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Palliative care and Advance Care Planning (ACP) are increasingly recommended for an optimal management of late-stage dementia. In Belgium, euthanasia has been decriminalized in 2002 for patients who are "mentally competent" (interpreted as non-demented). It has been suggested that advance directives for euthanasia (ADE) should be made possible for dementia patients., Objective: This study presents the results of an internet survey among Belgian dementia specialists., Methods: In 2013, the Belgian Dementia Council (BeDeCo) organized a debate on end of life decisions in dementia. Participants were medical doctors who are specialists in the dementia field. After the debate, an anonymous internet survey was organized. The participation rate was 55%. The sample was representative of the BeDeCo members., Results: The results showed consensus in favor of palliative care and ACP, although ACP is not systematically addressed in practice. Few patients with dementia have requested euthanasia, but for those who did the participants had agreed to implement it for some patients. A majority of participants (94%) believe that most patients and their families are poorly informed about euthanasia. Although most participants (77%) said they approved the Law on euthanasia, 65% said they were against an extension of the Law to allow ADE for dementia., Conclusion: Palliative care and ACP are clearly accepted by professionals, although a gap between recommendation and practice remain. Euthanasia is a much more debated issue, even if a majority of professionals are, in principle, in favor of the current Law and seem to disapprove with a Law change allowing ADE for dementia. A better education for both health professionals and the lay public will be a key element in the future.

Loneliness is a perception of social and emotional isolation that increases in prevalence among older adults during the eighth decade of life. Loneliness has been associated with higher brain amyloid-β deposition, a biologic marker of Alzheimer's disease, in cognitively normal older adults, suggesting a link with preclinical Alzheimer's disease pathophysiology. This study examined whether greater loneliness was associated with tau pathology, the other defining feature of Alzheimer's disease, in 117 cognitively normal older adults. Using flortaucipir positron emission tomography, we measured tau pathology in the entorhinal cortex, a region of initial accumulation in aging adults with or without elevated amyloid-β, and in the inferior temporal cortex, a region of early accumulation typically associated with elevated amyloid-β and memory impairment. Loneliness was measured by self-report using the 3-item UCLA-loneliness scale. We found that higher tau pathology in the right entorhinal cortex was associated with greater loneliness, controlling for age, sex, and apolipoprotein E ε4, the Alzheimer's disease genetic risk marker. This association remained significant after further adjustment for socioeconomic status, social network, depression and anxiety scores, and memory performance. There was no association of inferior temporal cortical or left entorhinal tau pathology with loneliness. Exploratory whole-brain surface maps supported these findings and identified additional clusters correlating loneliness and tau in the right fusiform gyrus. These results provide further support for loneliness as a socioemotional symptom in preclinical Alzheimer's disease.

Background: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD)., Objective: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression., Methods: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available., Results: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment., Conclusion: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

Alzheimer's disease (AD) is a highly prevalent condition and its prevalence is expected to further increase due to the aging of the general population. It is obvious that the diagnosis of AD has implications for driving. Finally, driving discussions are also emotionally charged because driving is associated with independence and personal identity. However, it is not clear how to implement this in clinical practice and the Belgian law on driving is rather vague in its referral to neurodegenerative brain diseases in general nor does it provide clear-cut instructions for dementia or AD compared to for example driving for patients with epilepsy and as such does not prove to be very helpful. The present article reviews what is known from both literature and existing guidelines and proposes a consensus recommendation tailored to the Belgian situation agreed by both AD experts and the Belgian Road Safety Institute endorsed by the Belgian Medical Association. It is concluded that the decision about driving fitness should be considered as a dynamic process where the driving fitness is assessed and discussed early after diagnosis and closely monitored by the treating physician. The diagnosis of AD on itself definitely does not imply the immediate and full revocation of a driving license nor does it implicate a necessary referral for a formal on-road driving assessment. There is no evidence to recommend a reduced exposure or a mandatory co-pilot. A MMSE-based framework to trichotomise AD patients as safe, indeterminate or unsafe is presented. The final decision on driving fitness can only be made after careful history taking and clinical examination, neuropsychological, functional and behavioral evaluation and, only for selected cases, a formal assessment of driving performance.

Importance: The ability to explore associations between reports of subjective cognitive decline (SCD) and biomarkers of early Alzheimer disease (AD) pathophysiologic processes (accumulation of neocortical β-amyloid [Aβ] and tau) provides an important opportunity to understand the basis of SCD and AD risk., Objective: To examine associations between SCD and global Aβ and tau burdens in regions of interest in clinically healthy older adults., Design, Setting, and Participants: This imaging substudy of the Harvard Aging Brain Study included 133 clinically healthy older participants (Clinical Dementia Rating Scale global scores of 0) participating in the Harvard Aging Brain Study who underwent cross-sectional flortaucipir F 18 (previously known as AV 1451, T807) positron emission tomography (FTP-PET) imaging for tau and Pittsburgh compound B carbon 11-labeled PET (PiB-PET) imaging for Aβ. The following 2 regions for tau burden were identified: the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with AD-related pathologic mechanisms. Data were collected from June 11, 2012, through April 7, 2016., Main Outcomes and Measures: Subjective cognitive decline was measured using a previously published method of z-transforming subscales from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire. The Aβ level was measured according to a summary distribution volume ratio of frontal, lateral temporal and parietal, and retrosplenial PiB-PET tracer uptake. The FTP-PET measures were computed as standardized uptake value ratios. Linear regression models focused on main and interactive effects of Aβ, entorhinal cortical, and inferior temporal tau on SCD, controlling for age, sex, educational attainment, and Geriatric Depression Scale score., Results: Of the 133 participants, 75 (56.3%) were women and 58 (43.6%) were men; mean (SD) age was 76 (6.9) years (range, 55-90 years). Thirty-nine participants (29.3%) exhibited a high Aβ burden. Greater SCD was associated with increasing entorhinal cortical tau burden (β = 0.35; 95% CI, 0.19-.52; P < .001) and Aβ burden (β = 0.24; 95% CI, 0.08-.40; P = .005), but not inferior temporal tau burden (β = 0.10; 95% CI, -0.08 to 0.28; P = .27). This association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for Aβ burden (β = 0.36; 95% CI, 0.15-.58; P = .001), and no interaction influenced SCD (β = -0.36; 95% CI, -0.34 to 0.09; P = .25). An exploratory post hoc whole-brain analysis also indicated that SCD was predominantly associated with greater tau burden in the entorhinal cortex., Conclusions and Relevance: Subjective cognitive decline is indicative of accumulation of early tauopathy in the medial temporal lobe, specifically in the entorhinal cortex, and to a lesser extent, elevated global levels of Aβ. Our findings suggest multiple underlying pathways that motivate SCD that do not necessarily interact to influence SCD endorsement. As such, multiple biological factors must be considered when assessing SCD in clinically healthy older adults.

The biological mechanisms that link Beta-amyloid (Aβ) plaque deposition, neurodegeneration, and clinical decline in Alzheimer's disease (AD) dementia, have not been completely elucidated. Here we studied whether amyloid accumulation and neurodegeneration, independently or interactively, predict clinical decline over time in a group of memory impaired older individuals [diagnosed with either amnestic mild cognitive impairment (MCI), or mild AD dementia]. We found that baseline Aβ-associated cortical thinning across clusters encompassing lateral and medial temporal and parietal cortices was related to higher baseline Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Baseline Aβ-associated cortical thinning also predicted CDR-SB over time. Notably, the association between CDR-SB change and cortical thickness values from the right lateral temporo-parietal cortex and right precuneus was driven by individuals with high Aβ burden. In contrast, the association between cortical thickness in the medial temporal lobe (MTL) and clinical decline was similar for individuals with high or low Aβ burden. Furthermore, amyloid pathology was a stronger predictor for clinical decline than MTL thickness. While this study validates previous findings relating AD biomarkers of neurodegeneration to clinical impairment, here we show that regions outside the MTL may be more vulnerable and specific to AD dementia. Additionally, excluding mild AD individuals revealed that these relationships remained, suggesting that lower cortical thickness values in specific regions, vulnerable to amyloid pathology, predict clinical decline already at the prodromal stage.

Importance: Abnormal accumulation of tau and amyloid-β (Aβ) proteins in the human brain are 2 pathologic hallmarks of Alzheimer disease (AD). Because pathologic processes begin decades before the onset of the clinical manifestations, the study of the cortical distribution of early-stage pathologic alterations is critical in understanding the underpinnings of the disease., Objectives: To identify the in vivo brain spatial distributions of tau and Aβ deposits in a sample of cognitively normal participants in the Harvard Aging Brain Study, determine spatial patterns of pathologic alterations, and provide means for improved individual in vivo staging., Design, Setting, and Participants: Eighty-eight individuals from the general community underwent flortaucipir 18 T807 (18F-T807) and carbon 11-labeled Pittsburgh Compound B (11C-PiB) positron emission tomographic (PET) imaging. A voxel-level hierarchical clustering approach was used to obtain the main clustering partitions corresponding to the cortical distribution maps of 18F-T807 and 11C-PiB. Hierarchical relationships between areas of distinctive pathologic deposits were then studied. Using cerebellar gray reference, 18F-T807 data were expressed as standardized uptake value ratio, and 11C-PiB were given as distribution volume ratio., Main Outcomes and Measures: Main in vivo and hierarchically organized tau and Aβ deposits in the elderly brain., Results: Of the 88 study participants, 39 (44%) were men, with a mean (SD) age of 76.2 (6.2) years. The tau and Aβ maps both displayed optimal cortical partitions at 4 clusters. The tau deposits were grouped in the temporal lobe, distributed in heteromodal areas, medial and visual regions, and primary somatomotor cortex; the Aβ deposits were clustered in the heteromodal areas and rather patchy in distributed regions involving the primary cortices, medial structures, and temporal areas. Moreover, tau deposits in the temporal lobe and distributed heteromodal areas were tightly nested., Conclusions and Relevance: Tau and Aβ deposits in the elderly brain generally display well-defined hierarchical cortical relationships as well as overlaps between the principal clusters of both pathologic alterations in the heteromodal association regions. These findings represent systematic, large-scale mechanisms of early AD pathology.

Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimer's disease (AD). Previous findings in AD dementia patients suggest that anosognosia is due to both functional metabolic changes within cortical midline structures involved in self-referential processes, as well as functional disconnection between these regions. The present study aims to extend these findings by investigating the neural correlates of anosognosia in the prodromal stage of AD. Here, we used regional brain metabolism (resting state 18-F fluorodeoxyglucose positron emission tomography (FDG-PET)) to unravel the metabolic correlates of anosognosia in subjects with amnestic mild cognitive impairment (aMCI) and subsequently resting state functional magnetic resonance imaging (rs-fMRI) to investigate the intrinsic connectivity disruption between brain regions. Thirty-one subjects (mean age: 74.1; Clinical Dementia Rating (CDR) global score: 0.5) with aMCI, and 251 cognitively normal (CN) older adults (mean age: 73.3; CDR: 0) were included as a reference group for behavioral and FDG data. An anosognosia index was obtained by calculating a discrepancy score between subjective and objective memory scores. All subjects underwent FDG-PET for glucose metabolism measurement, and aMCI subjects underwent additional rs-fMRI for intrinsic connectivity measurement. Voxel-wise correlations between anosognosia and neuroimaging data were conducted in the aMCI subjects. Subjects with aMCI had significantly decreased memory awareness as compared to the CN older adults. Greater anosognosia in aMCI subjects was associated with reduced glucose metabolism in the posterior cingulate (PCC) cortices and hippocampus. Intrinsic connectivity analyses revealed a significant association between anosognosia and attenuated functional connectivity between the PCC seed region and orbitofrontal cortex (OFC) as well as bilateral inferior parietal lobes (IPL). These findings provide further evidence that implicates cortical midline structures and hippocampus in the awareness of memory deficits. Investigating neuroimaging changes that co-vary with memory awareness may improve our ability to identify the cause of anosognosia and ultimately increase our chances for its treatment.

Objective: To identify the functional and pathologic correlates underlying subjective memory complaints (SMCs) in cognitively normal older adults., Methods: Two hundred fifty-one older adults underwent resting-state fluorodeoxyglucose (FDG)-PET and Pittsburg compound B-PET β-amyloid (Aβ) imaging and filled out a questionnaire regarding SMCs. Participants were classified into 2 groups based on their Aβ burden. Age-adjusted voxel-wise correlations were used to examine SMCs, amyloid status (Aβ + vs Aβ - ), and the interaction between SMCs and Aβ status as predictors of metabolism. Region-of-interest (ROI) analyses were performed to confirm the whole-brain analyses and to test for additional covariates., Results: Greater SMCs correlated with decreased FDG metabolism in the bilateral precuneus, bilateral inferior parietal lobes, right inferior temporal lobe, right medial frontal gyrus, and right orbitofrontal gyrus. A significant interaction effect between SMCs and amyloid burden was found such that Aβ + individuals with increased complaints had decreased FDG metabolism in the bilateral medial temporal lobes. ROI analyses confirmed the voxel-wise analyses result in that decreased precuneus metabolism was associated with greater SMCs regardless of Aβ status, age, or thickness, whereas the relationship between hippocampal metabolism and SMCs was a function of Aβ, even after adjustment for age, hippocampal volume, or depressive symptoms., Conclusions: These data show the relevant role of posterior and anterior midline regions in SMCs in older individuals. Decreased hippocampal metabolism may be a specific marker of subclinical changes in cognition due to amyloid pathology. However, longitudinal studies are needed to determine whether our findings foreshadow clinical decline., (© 2017 American Academy of Neurology.)

While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the preclinical and prodromal stages of the disease. Paradoxically, very early in the Alzheimer's disease process, individuals may experience heightened awareness of memory changes before any objective cognitive deficits can be detected, here referred to as hypernosognosia. In contrast, awareness of memory dysfunction shown by individuals with mild cognitive impairment (MCI) is very variable, ranging from marked concern to severe lack of insight. This study aims at improving our mechanistic understanding of how alterations in memory self-awareness are related to pathological changes in clinically normal (CN) adults and MCI patients. 297 CN and MCI patients underwent PiB-PET (Positron Emission Tomography using Pittsburgh Compound B) in vivo amyloid imaging. Amyloid burden was estimated from Alzheimer's disease vulnerable regions, including the frontal, lateral parietal and lateral temporal, and retrosplenial cortex. Memory self-awareness was assessed using discrepancy scores between subjective and objective measures of memory function. A set of univariate analysis of variance were performed to assess the relationship between self-awareness of memory and amyloid pathology. Whereas CN individuals harboring amyloid pathology demonstrated hypernosognosia, MCI patients with increased amyloid pathology demonstrated anosognosia. In contrast, MCI patients with low amounts of amyloid were observed to have normal insight into their memory functions. Altered self-awareness of memory tracks with amyloid pathology. The findings of variability of awareness may have important implications for the reliability of self-report of dysfunction across the spectrum of preclinical and prodromal Alzheimer's disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Relatively few studies have investigated relationships between performance on clinical memory measures and indexes of underlying neuropathology related to Alzheimer's disease (AD). This study investigated predictive relationships between Free and Cued Selective Reminding Test (FCSRT) cue efficiency (CE) and free-recall (FR) measures and brain amyloid levels, hippocampal volume (HV), and regional cortical thickness., Methods: Thirty-one older controls without memory complaints and 60 patients presenting memory complaints underwent the FCSRT, amyloid imaging using [F18]-flutemetamol positron emission tomography, and surface-based morphometry (SBM) using brain magnetic resonance imaging. Three groups were considered: patients with high (Aβ+P) and low (Aβ- P) amyloid load and controls with low amyloid load (Aβ- C)., Results: Aβ+P showed lower CE than both Aβ- groups, but the Aβ- groups did not differ significantly. In contrast, FR discriminated all groups. SBM analyses revealed that CE indexes were correlated with the cortical thickness of a wider set of left-lateralized temporal and parietal regions than FR. Regression analyses demonstrated that amyloid load and left HV independently predicted FCSRT scores. Moreover, CE indexes were predicted by the cortical thickness of some regions involved in early AD, such as the entorhinal cortex., Conclusions: Compared to FR measures, CE indexes appear to be more specific for differentiating persons on the basis of amyloid load. Both CE and FR performance were predicted independently by brain amyloid load and reduced left HV. However, CE performance was also predicted by the cortical thickness of regions known to be atrophic early in AD. (JINS, 2016, 22, 991-1004).

Importance: A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear., Objective: To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline)., Design, Setting, and Participants: This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aβ (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aβ-/ND-), 1 (Aβ+/ND-), and 2 (Aβ+/ND+) and SNAP (Aβ-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016., Main Outcomes and Measures: Evidence of amyloid-independent tau deposition and/or cognitive decline., Results: Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aβ- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, β = -0.005 [SE, 0.036]; parahippocampal gyrus, β = -0.001 [SE, 0.027]; and inferior temporal lobe, β = -0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, β = -0.125 [SE, 0.041]; parahippocampal gyrus, β = -0.074 [SE, 0.030]; and inferior temporal lobe, β = -0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, β = -0.239 [SE, 0.042]; stage 1, β = -0.242 [SE, 0.051]; and SNAP, β = -0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (β = -0.082 [SE, 0.037]; P = .03)., Conclusions and Relevance: In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ- CN individuals., Competing Interests: Potential Conflicts of Interest E. Mormino received funding from NIH grant F32AG044054 and P01 AG036694. K. Papp received funding from NIH grant P01 AG036694 and the Charles King Trust Foundation. D. Rentz received research support from the NIH grants P01 AG036694, R01 MH090291, U01 AG024904, R01 AG027435, R01 AG037497 and P50 AG005134, Alzheimer Association grant IIRG-08-90934 and Fidelity Biosciences. She has also served as a paid consultant for Eli Lilly, Janssen Pharmaceuticals and Neurotrack. These relationships are not related to the content in the manuscript. A. Schultz has no conflicts to report. M. LaPoint has no conflicts to report. R. Amariglio received funding from the Alzheimer’s Association NIRG-12-243012 and NIH P01AG036694, RO1-AG027435. B. Hanseeuw received support from the Belgian American Education Foundation (BAEF). G. Marshall received research support from NIH grants K23AG033634, P50AG005134, P01AG036694, R01AG027435, and U01AG024904, he received salary support from Eisai Inc. and Eli Lilly and Company, and he served as a paid consultant for Halloran/GliaCure. These relationships are not related to the content in the manuscript. T. Hedden received funding from NIH grants K01 AG040197, P01 AG036694, and R01 AG034556. K. Johnson has served as paid consultant for Bayer, GE Healthcare, Janssen Alzheimer’s Immunotherapy, Siemens Medical Solutions, Genzyme, Novartis, Biogen, Roche, ISIS Pharma, AZTherapy, GEHC, Lundberg, and Abbvie. He is a site coinvestigator for Lilly/Avid, Pfizer, Janssen Immunotherapy, and Navidea. He has spoken at symposia sponsored by Janssen Alzheimer’s Immunotherapy and Pfizer. These relationships are not related to the content in the manuscript. K. Johnson receives funding from NIH grants R01EB014894, R21 AG038994, R01 AG026484, R01 AG034556, P50 AG00513421, U19 AG10483, P01 AG036694, R13 AG042201174210, R01 AG027435, and R01 AG037497 and the Alzheimer’s Association grant ZEN-10-174210. R. Sperling has served as a paid consultant for Abbvie, Biogen, Bracket, Genentech, Lundbeck, Roche, and Sanofi. She has served as a co-investigator for Avid, Eli Lilly, and Janssen Alzheimer Immunotherapy clinical trials. She has spoken at symposia sponsored by Eli Lilly, Biogen, and Janssen. R. Sperling receives research support from Janssen Pharmaceuticals, and Eli Lilly and Co. These relationships are not related to the content in the manuscript. She also receives research support from the following grants: P01 AG036694, U01 AG032438, U01 AG024904, R01 AG037497, R01 AG034556, K24 AG035007, P50 AG005134, U19 AG010483, R01 AG027435, Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer’s Association.

Background: Patients with mild cognitive impairment (MCI) are at risk for Alzheimer's dementia but the presence of amyloid (Aβ) strongly increases this risk. In clinical settings, when Aβ status is not available, different neurodegenerative markers are used to characterize MCI. The accuracy of these markers to discriminate between Aβ-and Aβ+ MCI is not yet determined., Objective: To compare different markers of neurodegeneration in Aβ-and Aβ+ MCI, with an Aβ-elderly control (EC) group., Methods: Patients with MCI (n = 39) and EC (n = 28) underwent MRI, 18F-FDG PET, and Aβ PET (18F-flutemetamol). We compared FDG and MRI biomarker values in cortical and hippocampal regions of interest, and using voxel-wise surface maps. We computed ROC curves discriminating between the three groups for each biomarker., Results: All biomarker values were reduced in Aβ+ MCI compared to EC (p < 0.001). Aβ-MCI had low cortical metabolism (p = 0.002), but hippocampal volume, cortical thickness, and hippocampal metabolism were not significantly different between Aβ-MCI and EC (p > 0.40). Cortical metabolism best discriminated between MCI and EC (AUC = 0.92/0.86, Aβ+/Aβ-) while hippocampal volume best discriminated between Aβ-MCI and Aβ+ MCI (AUC = 0.79)., Conclusions: Cortical hypometabolism was observed in both Aβ-MCI and Aβ+ MCI whereas hippocampal atrophy was mostly found in Aβ+ MCI. For MCI patients without available Aβ information, hippocampal atrophy is thus more informative about Aβ status than cortical hypometabolism.

We present the effects of Targretin® (bexarotene) on cognition and biomarkers in a patient with mild Alzheimer's disease (AD). Targretin® is a Retinoic X Receptor (RXR) agonist shown to improve synaptic and cognitive functions in animal models of AD by increasing neuronal cholesterol efflux. After 6 months of treatment with Targretin® 300 mg/day, memory improved by about 40% and the tau protein in the cerebrospinal fluid decreased by about 20% . No significant side effects were noticed. This observation in a single patient indicates that Targretin® may improve memory performance and biological markers at an early stage of AD.

The purpose of this study was to investigate associative learning effects in patients with prodromal Alzheimer's disease (prAD) by referring to the Temporal Context Model (TCM; Howard, Jing, Rao, Provyn, & Datey, 2009), in an attempt to enhance the understanding of their associative memory impairment. TCM explains fundamental effects described in classical free-recall tasks and cued-recall tasks involving overlapping word pairs (e.g., A-B, B-C), namely (1) the contiguity effect, which is the tendency to successively recall nearby items in a list, and (2) the observation of backward (i.e., B-A) and transitive associations (i.e., A-C) between items. In TCM, these effects are hypothesized to rely on contextual representation, binding and retrieval processes, which supposedly depend on hippocampal and parahippocampal regions. As these regions are affected in prAD, the current study investigated whether prAD patients would show reduced proportions of backward and transitive associations in free and cued-recall, coupled to a reduced contiguity effect in free-recall. Seventeen older controls and 17 prAD patients performed a cued-recall task involving overlapping word pairs and a final free-recall task. Proportions of backward and transitive intrusions in cued-recall did not significantly differ between groups. However, in free-recall, prAD patients demonstrated a reduced contiguity effect as well as reduced proportions of backward and transitive associations compared to older controls. These findings are discussed within the hypothesis that the contextual representation, binding and/or retrieval processes are affected in prAD patients compared to healthy older individuals.

Background: Olfactory dysfunction is associated with Alzheimer's disease (AD), and already present at pre-dementia stage., Objectives: Based on the assumption that early neurodegeneration in AD is asymmetrical and that olfactory input is primarily processed in the ipsilateral hemisphere, we assessed whether unirhinal psychophysical and electrophysiological assessment of olfactory function can contribute to the diagnostic workup of mild cognitive impairment (MCI)., Methods: Olfactory function of 13 MCI patients with positive amyloid PET, 13 aged-matched controls (AC) with negative amyloid PET and 13 patients with post-infectious olfactory loss (OD) was assessed unirhinally using (1) psychophysical testing of olfactory detection, discrimination and identification performance and (2) the recording of olfactory event-related brain potentials. Time-frequency analysis was used to enhance the signal-to-noise ratio of the electrophysiological responses. Psychophysical and electrophysiological assessment of auditory and trigeminal chemosensory function served as controls., Results: As compared to AC and OD, MCI patients exhibited a significant asymmetry of olfactory performance. This asymmetry efficiently discriminated between MCI and AC (sensitivity: 85% , specificity: 77% ), as well as MCI and OD (sensitivity: 85% , specificity: 70% ). There was also an asymmetry of the electrophysiological responses, but not specific for MCI. In both MCI and OD, olfactory stimulation of the best nostril elicited significantly more activity than stimulation of the worse nostril, between 3-7.5 Hz and 1.2-2.0 s after stimulus onset. Trigeminal and auditory psychophysical testing did not show any difference between groups., Conclusion: MCI patients exhibit a marked asymmetry of behavioral olfactory function, which could be useful for the diagnostic workup of MCI.

Background: New diagnostic criteria for predemential Alzheimer's disease (AD) advocate the use of biomarkers. However, the benefit of using biomarkers has not been clearly demonstrated in clinical practice., Objective: To investigate whether a combination of biomarkers may be helpful in classifying a population of non-demented patients attending a Memory Clinic., Methods: Sixty non-demented patients were compared with 31 healthy elderly subjects. All subjects underwent a neuropsychological examination, brain 3T magnetic resonance imaging, [F18]-fluorodeoxyglucose and [F18]-flutemetamol positron emission tomography. According to their performance on memory, language, executive, and visuo-spatial domains, the patients were classified as mild cognitive impairment (amnestic, non-amnestic, single, or multiple domain) or subjective cognitive impairment. Patients were then classified according to the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, using the normalized mean hippocampal volume (Freesurfer), [F18]-FDG PALZAD, and [F18]-flutemetamol standard uptake value ratio (SUVr) (cut-off at the 10th percentile of controls). The standard of truth was the clinical status at study entry (patient versus control)., Results: The sensitivity/specificity of the clinical classification was 65/84%. The NIA-AA criteria were applicable in 85% of patients and 87% of controls. For biomarkers the best sensitivity (72%) at a fixed specificity of 84% was achieved by a combination of the three biomarkers. The clinical diagnosis was reconsidered in more than one third of the patients (42%) as a result of including the biomarker results., Conclusions: Application of the new NIA-AA AD diagnostic criteria based on biomarkers in an unselected sample of non-demented patients attending a Memory Clinic was useful in allowing for a better classification of the subjects.

Face perception is highly lateralized to the right hemisphere (RH) in humans, as supported originally by observations of face recognition impairment (prosopagnosia) following brain damage. Divided visual field presentations, neuroimaging and event-related potential studies have supported this view. While the latter studies are typically performed in right-handers, the few reported cases of prosopagnosia with unilateral left damage were left-handers, suggesting that handedness may shift or qualify the lateralization of face perception. We tested this hypothesis by recording the whole set of face-sensitive areas in 11 left-handers, using a face-localizer paradigm in functional magnetic resonance imaging (fMRI) (faces, cars, and their phase-scrambled versions). All face-sensitive areas identified (superior temporal sulcus, inferior occipital cortex, anterior infero-temporal cortex, amygdala) were strongly right-lateralized in left-handers, this right lateralization bias being as large as in a population of right-handers (40) tested with the same paradigm (Rossion et al., 2012). The notable exception was the so-called 'Fusiform face area' (FFA), an area that was slightly left lateralized in the population of left-handers. Since the left FFA is localized closely to an area sensitive to word form in the human brain ('Visual Word Form Area' - VWFA), the enhanced left lateralization of the FFA in left-handers may be due to a decreased competition with the representation of words. The implications for the neural basis of face perception, aetiology of brain lateralization in general, and prosopagnosia are also discussed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background and Purpose: Hippocampus volumetry is a useful surrogate marker for the diagnosis of Alzheimer disease, but it seems insufficiently sensitive for the aMCI stage. We postulated that some hippocampus subfields are specifically atrophic in aMCI and that measuring hippocampus subfield volumes will improve sensitivity of MR imaging to detect aMCI., Materials and Methods: We evaluated episodic memory and hippocampus subfield volume in 15 patients with aMCI and 15 matched controls. After segmentation of the whole hippocampus from clinical MR imaging, we applied a new computational method allowing fully automated segmentation of the hippocampus subfields. This method used a Bayesian modeling approach to infer segmentations from the imaging data., Results: In comparison with controls, subiculum and CA2-3 were significantly atrophic in patients with aMCI, whereas total hippocampus volume and other subfields were not. Total hippocampus volume in controls was age-related, whereas episodic memory was the main explanatory variable for both the total hippocampus volume and the subfields that were atrophic in patients with aMCI. Segmenting subfields increases sensitivity to diagnose aMCI from 40% to 73%., Conclusions: Measuring CA2-3 and subiculum volumes allows a better detection of aMCI.

Background: Previous functional MRI studies have shown increased hippocampus activation in response to item encoding in amnestic mild cognitive impairment (aMCI). Recent behavioral studies suggested that associative memory could be more impaired than item memory in aMCI. So far, associative encoding has not been evaluated separately from item encoding in functional MRI studies., Methods: We conducted a volumetric and functional MRI study investigating associative encoding in 16 aMCI and 16 elderly controls while controlling for item encoding., Results: We confirmed the presence of associative memory impairment in aMCI even after controlling for item memory differences between groups. Associative memory but not item memory correlated with hippocampus volume in aMCI. Such a correlation was not observed in elderly controls. The left anterior hippocampus activation in response to successful associative encoding was decreased in aMCI, even after correction for hippocampus atrophy., Conclusion: Associative memory impairment in aMCI appears to be related to hippocampus atrophy and left anterior hippocampus hypoactivation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: TheRI-48 cued recall test was devised to discriminate between healthy elderly and patients with mild cognitive impairment who are at risk of developing Alzheimer's disease (AD). However, no long-term follow-up studies have been conducted using this test., Methods: We analyzed the predictive power of the RI-48 test for determining the patients who will convert to AD dementia within the decade after testing. During 10 years, we followed up 40 non-demented patients who attended our Memory Clinic and underwent complete neuropsychological evaluation including the RI-48., Results: Of the 40 patients, 21 developed dementia (converters, CO) and 19 remained stable patients (SP). Of the tests performed at inclusion, only the RI-48 (p < 0.0001) and semantic fluency (p = 0.030) tests gave significantly different results between CO and SP., Conclusion: The RI-48 had the best overall diagnostic accuracy at 5- and at 10-year follow-ups.