Presymptomatic Alzheimer's Disease Research Articles

Longitudinal Basal Forebrain Degeneration Interacts with TREM2/C3 Biomarkers of Inflammation in Presymptomatic Alzheimer's Disease.

Cholinergic inputs originating from the peripheral nervous system regulate the inflammatory immune responses of macrophages during clearance of blood-based pathogens. Because microglia are involved in clearing amyloid and tau pathology from the central nervous system, we hypothesized that cholinergic input originating from the basal forebrain might similarly regulate inflammatory immune responses to these pathologies in the aging brain. To explore this hypothesis, we leveraged the Alzheimer's Disease Neuroimaging Initiative dataset. Cognitively normal older male and female human adults were differentiated according to the relative concentration of phosphorylated tau and amyloid in their cerebrospinal fluid, yielding neurotypical and preclinical, cognitively healthy, subgroups. We then tracked these two groups longitudinally with structural MRI and biomarkers of inflammation, including soluble sTREM2 levels in the CSF and complement C3 expression in the blood transcriptome. Longitudinal loss of basal forebrain volume was larger in the preclinical compared with the neurotypical subgroup. Across preclinical adults, loss of basal forebrain volume was associated with greater longitudinal accumulation of sTREM2 and higher peripheral blood C3 expression. None of these relationships were attributable to degeneration in the whole-brain gray matter volume. Preclinical APOE e4 carriers exhibited the largest loss of basal forebrain volume and highest C3 expression. Consistent with the known anti-inflammatory influence of the peripheral cholinergic pathways on macrophages, our findings indicate that a loss of central cholinergic input originating from the basal forebrain might remove a key check on microglial inflammation induced by amyloid and tau accumulation.SIGNIFICANCE STATEMENT In the peripheral nervous system, cholinergic modulation holds the reactivity of macrophages to blood-based pathogens in check, promoting clearance while preventing runaway inflammation and immune-triggered cell death. Microglia are the brain's resident macrophages and play an important role in clearing accumulated amyloid and tau from neurons. Here, we demonstrate that a loss of cholinergic integrity in the CNS, indexed by longitudinal decreases of basal forebrain volume, interacts with multiple biomarkers of inflammation in cognitively normal older adults with abnormal amyloid and tau pathology. These interactions were not detected in cognitively normal older adults with "neurotypical" levels of amyloid and tau. An age-related loss of cholinergic neuromodulation may remove key checks on microglial reactivity to amyloid and tau.

Systems modeling of white matter microstructural abnormalities in Alzheimer's disease.

Microstructural abnormalities in white matter (WM) are often reported in Alzheimer's disease (AD). However, it is unclear which brain regions have the strongest WM changes in presymptomatic AD and what biological processes underlie WM abnormality during disease progression. We developed a systems biology framework to integrate matched diffusion tensor imaging (DTI), genetic and transcriptomic data to investigate regional vulnerability to AD and identify genetic risk factors and gene subnetworks underlying WM abnormality in AD. We quantified regional WM abnormality and identified most vulnerable brain regions. A SNP rs2203712 in CELF1 was most significantly associated with several DTI-derived features in the hippocampus, the top ranked brain region. An immune response gene subnetwork in the blood was most correlated with DTI features across all the brain regions. Incorporation of image analysis with gene network analysis enhances our understanding of disease progression and facilitates identification of novel therapeutic strategies for AD.

Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer's disease.

Melanopsin-expressing retinal ganglion cells (mRGCs), intrinsically photosensitive RGCs, mediate the light-based pupil response and the light entrainment of the body's circadian rhythms through their connection to the pretectal nucleus and hypothalamus, respectively. Increased awareness of circadian rhythm dysfunction in neurological conditions including Alzheimer's disease (AD), has led to a wave of research focusing on the role of mRGCs in these diseases. Postmortem retinal analyses in AD patients demonstrated a significant loss of mRGCs, and in vivo measurements of mRGC function with chromatic pupillometry may be a potential biomarker for early diagnosis and progression of AD. We performed a prospective case-control study in 20 cognitively healthy study participants: 10 individuals with pre-symptomatic AD pathology (pre-AD), identified by the presence of abnormal levels of amyloid β42 and total Tau proteins in the cerebrospinal fluid, and 10 age-matched controls with normal CSF amyloid β42 and Tau levels. To evaluate mRGC function, we used a standardized protocol of chromatic pupillometry on a Ganzfeld system using red (640 nm) and blue (450 nm) light stimuli and measured the pupillary light response (PLR). Non-invasive wrist actigraphy and standardized sleep questionnaires were also completed to evaluate rest-activity circadian rhythm. Our results did not demonstrate a significant difference of the PLR between pre-AD and controls but showed a variability of the PLR in the pre-AD group compared with controls on chromatic pupillometry. Wrist actigraphy showed variable sleep-wake patterns and irregular circadian rhythms in the pre-AD group compared with controls. The variability seen in measurements of mRGC function and sleep-wake cycle in the pre-AD group suggests that mRGC dysfunction occurs in the pre-symptomatic AD stages, preceding cognitive decline. Future longitudinal studies following progression of these participants can help in elucidating the relationship between mRGCs and circadian rhythm dysfunction in AD.

C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aβ amyloid and preserves memory in a mouse model of familial Alzheimer's disease.

According to the amyloid hypothesis of Alzheimer's disease (AD) the deposition of prefibrillar and fibrillar Aβ peptide sets off the pathogenic cascades of neuroinflammation and neurodegeneration that lead to synaptic and neuronal loss resulting in cognitive decline. Various approaches to reduce amyloid load by reducing production of the Aβ peptide or enhancing amyloid clearance by primary or secondary immunization have not proven successful in clinical trials. Interfering with the normal function of secretases and suboptimal timing of Aβ peptide removal have been put forward as possible explanations. Complement, an innate component of the immune system, has been found to modulate disease pathology and in particular neuronal loss in the AD mouse model but its mechanism of action is complex. C1Q has been shown to facilitate phagocytosis of Aβ peptide but its Ablation attenuates neuroinflammation. Experiments in AD mouse models show that inhibition of complement component C5a reduces amyloid deposition and alleviates neuroinflammation. Phagocytes including microglia, monocytes and neutrophils carry C5a receptors. Here, a widely used mouse model of AD, 5XFAD, was intermittently treated with the oral C5a receptor agonist EP67 and several neuronal and neuroinflammatory markers as well as memory function were assessed. EP67 treatment enhanced phagocytosis, resulting in a significant reduction of both fibrillar and non-fibrillar Aβ, reduced astrocytosis and preserved synaptic and neuronal markers as well as memory function. Timely and phasic recruitment of the innate immune system offers a new therapeutic avenue of treating pre-symptomatic Alzheimer disease.

Cerebrospinal Fluid Markers of Synaptic Injury and Functional Connectivity in Alzheimer Disease: Protocol for a Cross-Sectional Study.

BackgroundSynaptic loss is the best surrogate for cognitive decline in Alzheimer disease (AD) and is more closely associated with cognitive function than amyloid or tau pathologies. Neurogranin (Ng) and synaptosome–associated protein-25 (SNAP-25) have demonstrated utility as cerebrospinal fluid (CSF) markers of synaptic injury in presymptomatic and symptomatic AD. While these synaptic markers have been shown to correlate with cognitive impairment and whole brain or regional atrophy in previous studies of AD, to our knowledge, the relationship between fluid markers of synaptic injury and functional brain imaging has not been previously investigated.ObjectiveThe main objective of this study is to examine the relationship between CSF markers of synaptic injury (Ng and SNAP-25) and functional connectivity (FC) in the default mode and semantic memory networks in individuals with mild cognitive impairment (MCI) and mild dementia due to AD (Clinical Dementia Rating [CDR] 0.5-1) and cognitively normal controls (CDR 0), adjusting for age, gender, and the apolipoprotein E4 (APOE4) genotype. Secondary objectives include investigating the associations between CSF markers of amyloid and tau pathology (CSF tau, p-tau181, and Aβ42) and FC in the default mode and semantic memory networks in AD (CDR 0.5-1) and controls (CDR 0), adjusting for age, gender, and the APOE4 genotype.MethodsThis is a cross-sectional study of individuals with MCI or mild dementia due to AD (CDR 0.5-1; n=20), and cognitively normal controls (CDR 0; n=20). Participants will undergo detailed clinical and neuropsychological assessments, CSF biomarker assessments (CSF Ng, SNAP-25, tau, p-tau181, and Aβ42 levels) and functional magnetic resonance imaging assessments, using a Siemens 3.0 Tesla Prisma scanner, during resting state and during the performance of a semantic memory task. All study procedures will be completed within 4 months of enrollment. Partial correlation analyses will examine associations of CSF biomarker measures with FC in the default mode and semantic memory networks in AD and controls.ResultsThis study was funded by the Chronic Brain Injury Discovery Themes of the Ohio State University College of Medicine. Study enrollment began in April 2018. Study procedures and data analysis are currently underway. Results are expected by December 2019.ConclusionsFindings from this study will further support the utility of CSF Ng and SNAP-25 as markers of synaptic injury by examining their associations with functional alterations in cortical networks affected by early AD pathology.International Registered Report Identifier (IRRID)DERR1-10.2196/14302

QUANTITATIVE EEG DURING STROOP TESTING UNMASKS PATHOLOGICAL AGING IN COGNITIVELY HEALTHY INDIVIDUALS

Stroop interference has been shown to differentiate higher risk for Alzheimer's disease (AD) in cognitive healthy (CH) aging population, but no studies using detailed brain processing in this population have been described. We aim to explore quantitative electroencephalography (qEEG) during Stroop interference test to investigate the underlying neural oscillatory events of interference in pre-symptomatic AD. We employed qEEG to investigate brain activity during interference processing (Stroop) in a pre-symptomatic AD pilot study. Study participants, age 60–100 years, with normal cognition were recruited from the local community, consisting of two subgroups based on cerebrospinal fluid (CSF) proteins: cognitively healthy with normal amyloid/tau ratio (CH-NAT, n=20) or pathological amyloid/tau ratio (CH-PAT or pre-symptomatic AD, n=30). Behavioral performance and spectral power from 21 recording head sensors were collected during testing. EEG signal regularity (ir) or “noise” levels were measured by spectral entropy (SE). The relationships of alpha power, alpha SE, behavioral measures during Stroop, and spinal fluid amyloid levels were compared for CH-NAT versus CH-PAT. The behavioral performance was similar between the two groups during congruent or incongruent trials. The alpha power from occipital sensors were significantly different (p=0.034) between CH-NAT and CH-PAT groups during the congruent interference trials. The SE from CH-PAT brain occipital alpha signals were higher compared to CH-NATs (p=0.030). There are positive correlations between congruent trial alpha power and resting state heart rate (p<0.05, r>0.35) for frontal, central, left lateral, right lateral, and occipital regions in CH-PAT, but not CH-NAT group. The congruent trial alpha SE was negatively correlated with education (p<0.03, r<-0.60) over frontal and parietal regions in CH-NAT, but not for CH-PATs. Congruent trial alpha SE negatively correlated with fasting glucose (p<0.01, r<-0.45) over central and parietal regions and negatively correlated with CSF amyloid level (p<0.05, r<-0.35) for parietal, left lateral, and occipital regions in CH-PATs, but not in CH-NATs. These results suggest that neuroplasticity occurs during interference processing in the pre-symptomatic AD stage to likely compensate for compromised biochemistry.

Can naproxen slow the progression of Alzheimer disease?

In their study “INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease,” Dr. Meyer and colleagues1 studied how naproxen—a common over-the-counter medicine—could help to prevent the progression of Alzheimer disease (AD). The reason for this is that there have been several observational studies that suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent people from developing AD. Other studies have not shown this effect. In fact, other studies have shown that long-term use of NSAIDs not only is not helpful for AD, but causes side effects.

INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.

ObjectiveTo evaluate the safety and efficacy of low-dose naproxen for prevention of progression in presymptomatic Alzheimer disease (AD) among cognitively intact persons at risk.MethodsInvestigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer's Disease (INTREPAD), a 2-year double-masked pharmaco-prevention trial, enrolled 195 AD family history–positive elderly (mean age 63 years) participants screened carefully to exclude cognitive disorder (NCT-02702817). These were randomized 1:1 to naproxen sodium 220 mg twice daily or placebo. Multimodal imaging, neurosensory, cognitive, and (in ∼50%) CSF biomarker evaluations were performed at baseline, 3, 12, and 24 months. A modified intent-to-treat analysis considered 160 participants who remained on-treatment through their first follow-up examination. The primary outcome was rate of change in a multimodal composite presymptomatic Alzheimer Progression Score (APS).ResultsNaproxen-treated individuals showed a clear excess of adverse events. Among treatment groups combined, the APS increased by 0.102 points/year (SE 0.014; p < 10−12), but rate of change showed little difference by treatment assignment (0.019 points/year). The treatment-related rate ratio of 1.16 (95% confidence interval 0.64–1.96) suggested that naproxen does not reduce the rate of APS progression by more than 36%. Secondary analyses revealed no notable treatment effects on individual CSF, cognitive, or neurosensory biomarker indicators of progressive presymptomatic AD.ConclusionsIn cognitively intact individuals at risk, sustained treatment with naproxen sodium 220 mg twice daily increases frequency of adverse health effects but does not reduce apparent progression of presymptomatic AD.Classification of evidenceThis study provides Class I evidence that, for people who are cognitively intact, low-dose naproxen does not significantly reduce progression of a composite indicator of presymptomatic AD.

Neuron‐Targeted Caveolin‐1 Gene Therapy Preserves Cognitive Function and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease (AD)

Introduction Alzheimer's disease (AD) is a devastating neurodegenerative condition. AD patients develop severe cognitive deficits, which are closely correlated with loss of synapses and decreased plasticity. Caveolin-1 (Cav-1), a scaffolding protein within the microdomains of membrane/lipid rafts (MLRs), organizes signaling complexes that promote functional neuronal and synaptic plasticity. Previously we showed that neuron-targeted overexpression of Cav-1 using a synapsin promoter (SynCav1) promotes neuroplasticity, increases synaptic plasticity, and improves memory in aged mice. The current study investigated the impact of SynCav-1 on markers of synaptic plasticity and cognitive function in an APPSwePS1d9 mouse model of AD. Methods AAV9-SynRFP (red fluorescent protein) or AAV9-SynCav1 was delivered into the hippocampus of wild type (WT) or AD mice at 2.5 months of age. At 9 months, open field and fear conditioning test were used to evaluate learning and memory performance. After behavior tests, animal were sacrificed for immunoblot (IB) and immunofluorence microscopy (IF). Electron microscopy (EM) was used to observe the ultrastructure morphology. Results AD-SynRFP mice exhibited significant decreased fear learning (day 1) compared to WT-SynRFP mice and AD-SynCav1 mice. In contrast, AD-SynCav1 mice showed preserved fear learning (day 1), and improved contextual and cued memory recall (day 2 & 3). Both IB and IF showed decreased Cav-1 expression in 9 month-old AD-SynRFP mice. AD-SynCav1 mice showed preserved Cav-1 levels and increased expression of neuroplasticity markers (TrkB, MAP2) compared to AD-SynRFP mice. IB analysis of MLR (buoyant fractions 4 & 5) demonstrate decreased MLR-localization of TrkB, Cav-1, CT-B, synaptophysin, TrkA, PSD95, LRP in AD-SynRFP mice. In contrast, AD-SynCav1 exhibited preserved MLR-localization of TrkB, Cav-1, CT-B, synaptophysin, TrkA, PSD95 and LRP1. IF showed preserved markers of dendritic integrity (MAP2) in AD-SynCav1 mice. EM analysis of the hippocampus revealed that AD-SynRFP mice had fewer type I excitatory synapses and decreased number of presynaptic vesicles per axonal bouton, and altered spine morphology (reduced spine length and increased spine neck diameter) in CA1 apical dendrites within the stratum radiatum, which were not exhibited by AD-SynCav1 mice. Additional analysis revealed preserved myelinated Schaffer collateral axons in AD-SynCav1 mice compared to AD-SynRFP. Conclusion SynCav1 gene delivery to the hippocampus of pre-symptomatic adult AD mice (2.5 m) preserves fear learning, improves memory, and preserves ultrastructural indicators of synaptic plasticity and myelination in mild symptomatic AD mice (9 months), therefore may serve as a novel gene therapy to restore synaptic and neuroplasticity and improve brain function in individuals afflicted with Alzheimer's disease. Support or Funding Information Veterans Affairs Merit Award from the Department of Veterans Affairs BX003671 (B. P. Head), National Institutes of Health, Bethesda, MD, U.S.A., NS073653 (B. P. Head); GM085179 (P. M. Patel). (A) AD - SynRFP at 2.5 months of age exhibited learning deficits on acquisition Day 1 training compared to both WT -SynRFP and AD -SynCav1 at 9 months of age. There was no significant difference between WT - SynRFP versus AD-SynCav1. SynCav1 delivery to AD mice significantly improved hippocampal-dependent contextual memory recall on Day 2 (B) and hippocampal-independent cued memory recall on Day 3 (C). Data are presented as mean ± SEM. Significance was assumed when p < 0.05. IF microscopy revealed that, in 9 month-old age, AD-SynRFP exhibited decreased in hippocampal Cav-1 expression compared to WT-SynRFP, while SynCav1 gene delivery preserved Cav-1 expression. Scale bar = 50 mm. IB analysis of MLR fractions (buoyant fractions 4 & 5) demonstrates decreased MLR-localization of full length TrkB, Cav-1, CT-B, synaptophysin, TrkA, LRP1 in AD-SynRFP mice; while SynCav1 treatment preserve MLR-localized synaptic proteins. CA1 distal apical dendrites in the stratum radiatum were examined for ultrastructure changes of type I asymmetric synapses and presynaptic vesicles (PSVs)/axonal bouton. SynCav1 preserves total number of synapses and PSVs in the hippocampus of 9 month old AD mice. CA1 distal apical dendrites in the stratum radiatum were examined for alterations in dendritic spine morphology, i.e., spine length (mm), spine neck diameter (mm), and spine area (mm2). SynCav1 preserves dendritic spine morphology in the hippocampus of 9 month old APPSwePS1d9 mice. G ratio analysis (axon lumen diameter (Di)/fiber (axon lumen + myelin) diameter (Do)) was used to measure changes in axonal myelin fiber content of CA3 Schaffer collaterals innervating the CA1 apical dendritic arbor. SynCav1 preserves axonal myelin fiber content of hippocampal CA3 Schaffer collaterals in 9 month old APPSwePS1d9 mice. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The relative efficiency of time-to-progression and continuous measures of cognition in presymptomatic Alzheimer's disease

IntroductionClinical trials on preclinical Alzheimer’s disease are challenging because of the slow rate of disease progression. We use a simulation study to demonstrate that models of repeated cognitive assessments detect treatment effects more efficiently than models of time to progression. MethodsMultivariate continuous data are simulated from a Bayesian joint mixed-effects model fit to data from the Alzheimer’s Disease Neuroimaging Initiative. Simulated progression events are algorithmically derived from the continuous assessments using a random forest model fit to the same data. ResultsWe find that power is approximately doubled with models of repeated continuous outcomes compared with the time-to-progression analysis. The simulations also demonstrate that a plausible informative missing data pattern can induce a bias that inflates treatment effects, yet 5% type I error is maintained. DiscussionGiven the relative inefficiency of time to progression, it should be avoided as a primary analysis approach in clinical trials of preclinical Alzheimer’s disease.

Predicting Alzheimer Disease From Mild Cognitive Impairment With a Deep Belief Network Based on 18F-FDG-PET Images.

Objective:Accurate diagnosis of early Alzheimer disease (AD) plays a critical role in preventing the progression of memory impairment. We aimed to develop a new deep belief network (DBN) framework using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) metabolic imaging to identify patients at the mild cognitive impairment (MCI) stage with presymptomatic AD and to discriminate them from other patients with MCI.Methods:18F-fluorodeoxyglucose-PET images of 109 patients recruited in the ongoing longitudinal Alzheimer’s Disease Neuroimaging Initiative study were included in this analysis. Patients were grouped into 2 classes: (1) stable mild cognitive impairment (n = 62) or (2) progressive mild cognitive impairment (n = 47). Our framework is composed of 4 steps: (1) image preprocessing: normalization and smoothing; (2) identification of regions of interest (ROIs); (3) feature learning using deep neural networks; and (4) classification by support vector machine with 3 kernels. All classification experiments were performed with a 5-fold cross-validation. Accuracy, sensitivity, and specificity were used to validate the results.Result:A total of 1103 ROIs were obtained. One hundred features were learned from ROIs using the DBN. The classification accuracy using linear, polynomial, and RBF kernels was 83.9%, 79.2%, and 86.6%, respectively. This method may be a powerful tool for personalized precision medicine in the population with prediction of early AD progression.

Activity-Induced Amyloid-β Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice

BackgroundA consistent proportion of individuals at risk for Alzheimer’s disease show intact cognition regardless of the extensive accumulation of amyloid-β (Aβ) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for Aβ can compensate for the underactivation of Aβ-positive ones to preserve cognition, but the underlying synaptic changes are still unexplored. MethodsUsing Golgi staining, we investigate how dendritic spines rearrange following contextual fear conditioning (CFC) in the hippocampus and amygdala of presymptomatic Tg2576 mice, a genetic model for Aβ accumulation. A molecular biology approach combined with intrahippocampal injection of a γ-secretase inhibitor evaluates the impact of Aβ fluctuations on spine rearrangements. ResultsEncoding of CFC increases Aβ oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of Aβ oligomers predicts vulnerability to network dysfunctions, as low c-Fos activation and spine maturation are detected in the hippocampus of Tg2576 mice upon recall of CFC memory. Rather, enhanced c-Fos activation and new spines are evident in the amygdala of Tg2576 mice compared with wild-type control mice. Preventing Aβ increase in the hippocampus of Tg2576 mice restores CFC-associated spine changes to wild-type levels in both the hippocampus and amygdala. ConclusionsOur study provides the first evidence of neural compensation consisting of enhanced synaptic activity in brain regions spared by Aβ load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors Aβ oligomerization in the hippocampus and prevents synaptic rearrangements in this region.

A review of biomarkers of Alzheimer's disease in noninvasive samples.

The discovery of biomarkers that confer high confidence of presymptomatic Alzheimer's disease (AD) diagnosis would be a valuable tool to study the etiology of the disease, to find risk factors, to discover more treatments and medicines. The present work reviews the potential biomarkers of AD based on the concentration changes of small molecules and chemical elements in noninvasive samples (urine, saliva, hair and others). An updated table with 74 target compounds is produced and ranked. Until the present date, there are a few biomarkers, present in urine, with the most promising potential: isoprostane 8,12-iso-iPF2a-VI, total free amino acids, 8-hydroxy-2'-deoxyguanosine, glycine and enzymatic activity of NaCl-stimulated PON1. All show increased levels in AD carriers, with the exception of NaCl-stimulated PON1.

Quantitative EEG during memory testing indicates pre‐symptomatic Alzheimer's disease and correlation with MRI

Background and ObjectivesIncreasing attention for Alzheimer's disease (AD) have been focused on pre‐symptomatic stage for potential effective treatment. We aim to explore the quantitative electroencephalography (qEEG) during memory testing and evaluate qEEG correlations with MRI volumetric data to investigate the underlying events of pre‐symptomatic AD.MethodsWe employed qEEG test to investigate brain activity during working memory processing (N‐back) in a pre‐symptomatic AD study. Study participants, age 60–100 years, with normal cognition were recruited from the local community, consisting of two subdivisions from cerebrospinal fluid proteins: cognitively healthy with normal amyloid/tau ratio (CH‐NAT, n=10) or pathological amyloid/tau ratio (CH‐PAT, n=14). Behavioral performance and spectral power from 21 recording head sensors were collected during testing. EEG signal (ir)regularity or “noise” levels were measured by spectral entropy (SE). To assess brain anatomical structures, MRI was collected from the same individuals. We analyzed the EEG data for all channels, and explored the spectral power correlations with MRI total gray matter and hippocampal volumes.Results &amp; DiscussionThe behavioral performance was similar between the two groups during lower memory load, and CH‐PATs had significantly less accuracy of performance than CH‐NATs during higher memory load. The qEEG from several sensors were significantly different (p&lt;0.01) between CH‐NAT and CH‐PAT groups during the lower load memory testing when behavioral performances did not differ. The CH‐PAT brain signals were “noisier” compared to CH‐NATs. We interpret the altered brain activity in the CH‐PAT group to indicate a compensation mechanism for the CH‐PATs. qEEG measures from specific sensors correlated with total gray matter volume (p&lt;0.001) and hippocampal volumes (p&lt;0.001); these unexpected results suggest neuroplasticity occurs in the pre‐symptomatic AD stage to compensate for reduction in brain regional volumes. We propose that intervention at the pre‐symptomatic phase of AD using strategies that improve cognitive efficiency may attenuate neurodegeneration.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Multiscale deep neural network based analysis of FDG-PET images for the early diagnosis of Alzheimer’s disease

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases with a commonly seen prodromal mild cognitive impairment (MCI) phase where memory loss is the main complaint progressively worsening with behavior issues and poor self-care. However, not all individuals clinically diagnosed with MCI progress to AD. A fraction of subjects with MCI either progress to non-AD dementia or remain stable at the MCI stage without progressing to dementia. Although a curative treatment of AD is currently unavailable, it is extremely important to correctly identify the individuals in the MCI phase that will go on to develop AD so that they may benefit from a curative treatment when one becomes available in the near future. At the same time, it would be highly desirable to also correctly identify those in the MCI phase that do not have AD pathology so they may be spared from unnecessary pharmocologic interventions that, at best, may provide them no benefit, and at worse, could further harm them with adverse side-effects. Additionally, it may be easier and simpler to identify the cause of the cognitive impairment in these non-AD cases, and hence proper identification of prodromal AD will be of benefit to these individuals as well. Fluorodeoxy glucose positron emission tomography (FDG-PET) captures the metabolic activity of the brain, and this imaging modality has been reported to identify changes related to AD prior to the onset of structural changes. Prior work on designing classifier using FDG-PET imaging has been promising. Since deep-learning has recently emerged as a powerful tool to mine features and use them for accurate labeling of the group membership of given images, we propose a novel deep-learning framework using FDG-PET metabolism imaging to identify subjects at the MCI stage with presymptomatic AD and discriminate them from other subjects with MCI (non-AD / non-progressive). Our multiscale deep neural network obtained 82.51% accuracy of classification just using measures from a single modality (FDG-PET metabolism data) outperforming other comparable FDG-PET classifiers published in the recent literature.

Editors' note: Odor identification as a biomarker of preclinical AD in older adults at risk

In their study “Odor identification as a biomarker of preclinical AD in older adults at risk,” Lafaille-Magnan et al. found that decrease in odor identification (OI) was associated with increasing CSF biomarker evidence of Alzheimer disease (AD) pathology and that the association between OI deficits and cognition in older adults at increased risk of AD was driven by the presence of AD-related CSF biomarkers rather than the effects of age or other confounders. Commenting on the study, Drs. Bohnen and Muller suggest that OI deficits may herald the presence of not only AD but also Lewy body pathologies. Lafaille-Magnan et al. agree but argue that the association of odor identification with presymptomatic AD may be particularly useful owing to the paucity of other inexpensive and noninvasive robust biomarker measures in AD. In their study “Odor identification as a biomarker of preclinical AD in older adults at risk,” Lafaille-Magnan et al. found that decrease in odor identification (OI) was associated with increasing CSF biomarker evidence of Alzheimer disease (AD) pathology and that the association between OI deficits and cognition in older adults at increased risk of AD was driven by the presence of AD-related CSF biomarkers rather than the effects of age or other confounders. Commenting on the study, Drs. Bohnen and Muller suggest that OI deficits may herald the presence of not only AD but also Lewy body pathologies. Lafaille-Magnan et al. agree but argue that the association of odor identification with presymptomatic AD may be particularly useful owing to the paucity of other inexpensive and noninvasive robust biomarker measures in AD.

Author response: Odor identification as a biomarker of preclinical AD in older adults at risk.

Drs. Bohnen and Muller describe associations in other tauopathies, including the Lewy body–Parkinson spectrum, similar to the association we identified between odor identification deficit and Alzheimer disease biomarkers driven mostly by tau pathology.1 We agree; however, the association of odor identification with presymptomatic Alzheimer disease may be particularly useful owing to the paucity of other inexpensive and noninvasive robust biomarker measures in this prevalent neurodegenerative illness.

Accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer's disease: a cross-sectional study

SummaryBackgroundTests sensitive to presymptomatic changes in Alzheimer's disease could be valuable for clinical trials. Accelerated long-term forgetting—during which memory impairment becomes apparent over longer periods than usually assessed, despite normal performance on standard cognitive testing—has been identified in other temporal lobe disorders. We assessed whether accelerated long-term forgetting is a feature of presymptomatic autosomal dominant (familial) Alzheimer's disease, and whether there is an association between accelerated long-term forgetting and early subjective memory changes.MethodsThis was a cross-sectional study at the Dementia Research Centre, University College London (London, UK). Participants were recruited from a cohort of autosomal dominant Alzheimer's disease families already involved in research at University College London, and had to have a parent known to be affected by an autosomal dominant Alzheimer's disease mutation, and not report any current symptoms of cognitive decline. Accelerated long-term forgetting of three tasks (list, story, and figure recall) was assessed by comparing 7-day recall with initial learning and 30-min recall. 7-day recognition was also assessed. Subjective memory was assessed using the Everyday Memory Questionnaire. The primary outcome measure for each task was the proportion of material retained at 30 min that was recalled 7 days later (ie, 7-day recall divided by 30-min recall). We used linear regression to compare accelerated long-term forgetting scores between mutation carriers and non-carriers (adjusting for age, IQ, and test set) and, for mutation carriers, to assess whether there was an association between accelerated long-term forgetting and estimated years to symptom onset (EYO). Spearman's correlation was used to examine the association between accelerated long-term forgetting and subjective memory scores.FindingsBetween Feb 17, 2015 and March 30, 2016, we recruited 35 people. 21 participants were mutation carriers (mean EYO 7·2 years, SD 4·5). Across the three tasks, we detected no differences between carriers and non-carriers for initial learning or 30-min recall. The proportion of material recalled at 7 days was lower in carriers than non-carriers for list (estimated difference in mean for list recall −30·94 percentage points, 95% CI −45·16 to −16·73; p=0·0002), story (–20·10, −33·28 to −6·91; p=0·0048), and figure (–15·41, −26·88 to −3·93; p=0·012) recall. Accelerated long-term forgetting was greater in carriers nearer to their estimated age at onset (p≤0·01 for all three tests). Mutation carriers' 7-day recognition memory was also lower across all tasks (list [mean difference −5·80, 95% CI −9·96 to −2·47; p<0·01], story [–6·84, −10·94 to −3·37; p<0·01], and figure [–17·61, −27·68 to −7·72; p<0·01] recognition). Subjective memory scores were poorer in asymptomatic carriers compared with non-carriers (adjusted difference in means 7·88, 95% CI 1·36 to 14·41; p=0·016), and we found a correlation between accelerated long-term forgetting and subjective memory in mutation carriers.InterpretationAccelerated long-term forgetting is an early presymptomatic feature of autosomal dominant Alzheimer's disease, which appears to pre-date other amnestic deficits and might underpin subjective memory complaints in Alzheimer's disease. Accelerated long-term forgetting testing might be useful in presymptomatic Alzheimer's disease trials.FundingMRC, NIHR, Alzheimer's Research UK, Dementias Platform UK, Dunhill Medical Trust, ERUK, Great Western Research, Health Foundation, Patrick Berthoud Trust.

Deep Learning based Classification of FDG-PET Data for Alzheimers Disease Categories.

Fluorodeoxyglucose (FDG) positron emission tomography (PET) measures the decline in the regional cerebral metabolic rate for glucose, offering a reliable metabolic biomarker even on presymptomatic Alzheimer's disease (AD) patients. PET scans provide functional information that is unique and unavailable using other types of imaging. However, the computational efficacy of FDG-PET data alone, for the classification of various Alzheimers Diagnostic categories, has not been well studied. This motivates us to correctly discriminate various AD Diagnostic categories using FDG-PET data. Deep learning has improved state-of-the-art classification accuracies in the areas of speech, signal, image, video, text mining and recognition. We propose novel methods that involve probabilistic principal component analysis on max-pooled data and mean-pooled data for dimensionality reduction, and multilayer feed forward neural network which performs binary classification. Our experimental dataset consists of baseline data of subjects including 186 cognitively unimpaired (CU) subects, 336 mild cognitive impairment (MCI) subjects with 158 Late MCI and 178 Early MCI, and 146 AD patients from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. We measured F1-measure, precision, recall, negative and positive predictive values with a 10-fold cross validation scheme. Our results indicate that our designed classifiers achieve competitive results while max pooling achieves better classification performance compared to mean-pooled features. Our deep model based research may advance FDG-PET analysis by demonstrating their potential as an effective imaging biomarker of AD.

Spotlight on the July 25 issue

#### Notable in Neurology This issue features an article that assesses odor identification as an indicator of presymptomatic Alzheimer disease pathogenesis and another that addresses whether a sex bias exists in care after intracerebral hemorrhage. A featured article examines the possible genotype–phenotype correlations of mutations in DNM1 -related epileptic encephalopathy and the functional consequences based on structural modeling. ### A new potential biomarker for dementia with Lewy bodies: Skin nerve α-synuclein deposits![Graphic][1] In this article, the authors describe a sensitive biomarker for dementia with Lewy bodies (DLB). Abnormal synuclein deposits in skin nerves were found … [1]: /embed/inline-graphic-1.gif