Amyloid-β Deposition Research Articles

Adamantinomatous craniopharyngioma cyst fluid can trigger inflammatory activation of microglia to damage the hypothalamic neurons by inducing the production of β-amyloid

IntroductionThe mechanism by which adamantinomatous craniopharyngioma (ACP) damages the hypothalamus is still unclear. Cyst fluid rich in lipids and inflammatory factors is a characteristic pathological manifestation of ACP and may play a very important role in hypothalamic injury caused by tumors.ObjectiveThe objective of this study was to construct a reliable animal model of ACP cyst fluid-induced hypothalamic injury and explore the specific mechanism of hypothalamic injury caused by cyst fluid.MethodsAn animal model was established by injecting human ACP cyst fluid into the bilateral hypothalamus of mice. ScRNA-seq was performed on the mice hypothalamus and on an ACP sample to obtain a complete gene expression profile for analysis. Data verification was performed through pathological means.ResultsACP cystic fluid caused growth retardation and an increased obesity index in mice, affected the expression of the Npy, Fgfr2, Rnpc3, Sst, and Pcsk1n genes that regulate growth and energy metabolism in hypothalamic neurons, and enhanced the cellular interaction of Agrp–Mc3r. ACP cystic fluid significantly caused inflammatory activation of hypothalamic microglia. The cellular interaction of CD74–APP is significantly strengthened between inflammatory activated microglia and hypothalamic neurons. Beta-amyloid, a marker of neurodegenerative diseases, was deposited in the ACP tumor tissues and in the hypothalamus of mice injected with ACP cyst fluid.ConclusionIn this study, a novel animal model of ACP cystic fluid-hypothalamic injury was established. For the first time, it was found that ACP cystic fluid can trigger inflammatory activation of microglia to damage the hypothalamus, which may be related to the upregulation of the CD74–APP interaction and deposition of β-amyloid, implying that there may be a similar mechanism between ACP cystic fluid damage to the hypothalamus and neurodegenerative diseases.

Astrocytic function is associated with both amyloid-β and tau pathology in non-demented APOE ϵ4 carriers.

A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimer’s disease. Given that APOE is primarily expressed in astrocytes, these cells might be an important link between the APOE ε4 allele and the development of Alzheimer’s disease pathology. Here, we investigate this hypothesis in vivo by measuring myo-inositol, a metabolite involved in astrocytic functions, with magnetic resonance spectroscopy. Currently, there is conflicting evidence regarding the relationship between APOE ε4 and myo-inositol concentration. Furthermore, data supporting a relationship between APOE ε4, myo-inositol and Alzheimer’s disease pathology (amyloid-beta and tau proteins) in the preclinical stage of Alzheimer’s disease are limited. A previous study revealed differences in myo-inositol levels between APOE ε4 carriers and non-carriers already in preclinical Alzheimer’s disease participants. However, other reports showed no impact of APOE genotype on the association between myo-inositol and the rate of amyloid-beta accumulation. In the present study, we determined the effect of APOE genotype on the association between myo-inositol and both amyloid-β and tau deposition quantified by PET in 428 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. APOE genotype impacted the associations between myo-inositol and amyloid-β pathology as revealed by an interaction effect between APOE genotype and levels of myo-inositol (P < 0.001) such that higher myo-inositol concentration was related to more amyloid-beta pathology in APOE ε4 carriers only. A similar interaction effect was also found when investigating the effect of APOE on the association between myo-inositol and tau pathology (P < 0.01). Focusing on the APOE ε4 subsample, myo-inositol partially (17%) mediated the association between amyloid-beta and tau pathology (P < 0.05). Furthermore, in a subgroup of participants with available plasma levels of glial fibrillary acidic protein, a marker of astroglial activation and astrocytosis, we found that glial fibrillary acidic protein correlated with myo-inositol only in APOE e4 carriers (APOE ε4 carriers: P < 0.01; APOE ε4 non-carriers: P > 0.8), suggesting that myo-inositol might reflect an aspect of the astrocytic involvement in Alzheimer’s pathology which is specific to the impact of APOE ε4. Therefore, we suggest that myo-inositol is a candidate in vivo marker to study the impact of APOE ε4 on the interplay between astrocytes and the pathophysiology of Alzheimer’s disease.

Brain Imaging Features Associated with 20-Year Cognitive Decline in a Community-Based Multiethnic Cohort without Dementia

Introduction: This study aimed to characterize the association of cognitive decline starting in midlife with brain pathology in late life in the absence of dementia. Methods: Nondemented Atherosclerosis Risk in Communities participants with brain imaging, all cognitive factor scores (CFSs), and nonmissing covariates were included. CFSs were collected at three visits across 21 years (1990–2013) (short-term cognitive change [1990–1996], long-term cognitive change [1990–2013]), and brain magnetic resonance imaging and florbetapir positron emission tomography (PET) imaging were collected in 2011–13 (PET subset n = 327). Outcomes of interest were total and regional brain volumes (cm³), log₂ (white matter hyperintensity volume), white matter integrity (fractional anisotropy, mean diffusivity), ≥1 lacunar infarct (3–20 mm), and elevated brain β-amyloid (SUVR >1.2). Multivariable linear/logistic regression related outcomes to CFS slopes after adjusting for demographics and total intracranial volume. Results: At baseline, the 1,734 participants had a mean (SD) age of 55 (5.2) years, and were 60% female and 26% Black. After adjustment, a 1-SD larger long-term decline in CFS was associated with a smaller relative total brain volume by 1.2% (95% CI: 1.0, 1.5), a smaller relative temporal lobe meta region volume by 1.9% (1.5, 2.3), a 13% (9, 17) larger volume of white matter hyperintensities, a 1.3-fold (1.2, 1.4) higher odds of having ≥1 lacune, and 1.7-fold (1.3, 2.2) higher odds of elevated brain β-amyloid deposition and worse white matter integrity. Some long-term associations were also found for midlife short-term declines in CFS. Conclusions: This study provides evidence that starting in midlife, short-term and long-term declines in cognition are associated with multiple deleterious late-life differences in nondemented brains.

NeuroProtect, a Candidate Formula From Traditional Chinese Medicine, Attenuates Amyloid-β and Restores Synaptic Structures in APP/PS1 Transgenic Mice.

Background: Alzheimer’s disease (AD) is the most common cause of dementia. The emerging data suggest that cognitive decline occurred in the setting of Aβ accumulation with synaptic dysfunction, which started to happen at preclinical stages. Then, presymptomatic intervention is more critical to postponing AD processing. Traditional Chinese medicine has a long history of treating and preventing dementia. Findings have shown that the decoction of Panax notoginseng and Gardenia jasminoides Ellis enhances memory functions in patients with stroke, and their main components, Panax notoginseng saponins (PNS) and geniposide (GP), improved memory abilities in experimental AD models. Since herbal medicine has advantages in protection with few side effects, we wish to extend observations of the NeuroProtect (NP) formulation for reducing amyloid-β and restoring synaptic structures in APP/PS1 transgenic mice. Methods: APP/PS1 transgenic mice and their wild-type littermates were fed with control, NP, and their components from 4 to 7 months of age. We assessed the synaptic structure by Golgi staining, analyzed the amyloid deposits by Thioflavin-S staining, and measured related protein levels by Western blot or ELISA. We used the Morris water maze and shuttle box test to evaluate cognitive functions. Results: Compared to WT mice, APP/PS1 mice are characterized by the accumulation of amyloid plaques, reducing synaptic structure richness and memory deficits. NP prevents these changes and ameliorates cognitive deficits. These effects may have been due to the contribution of its components by inhibition of insoluble amyloid-β deposition and restoration of synaptic structures. Conclusion: These findings reveal a beneficial effect of NP on AD progression under an early intervention strategy and provide a food supplement for AD prevention.

Enhanced Brain Retention of Aβ4‐x Proteoforms and its Contribution to Amyloid Deposits in Alzheimer’s Disease

The deposition of amyloid‐β (Aβ) in brain parenchyma and cerebral vasculature together with intraneuronal neurofibrillary tangles and the gradual loss of synapsis are central neuropathological hallmarks of Alzheimer’s disease (AD). Although it remains unclear what primarily triggers and drives the progression of AD, different lines of investigation point out to a central role of oligomeric Aβ conformations for the disease pathogenesis. Recent studies revealed that the molecular heterogeneity of Aβ deposits is significantly more complex than originally anticipated, extending well beyond the classic Aβ1‐40/Aβ1‐42 dichotomy and being substantially expanded by the presence of multiple post‐translational modifications that increase the proteome diversity. Although N‐terminal truncations at glutamates 3 and 11 and their subsequent cyclation to pyroglutamate are perhaps the most extensively studied modifications, many others have been reported, with species beginning at phenylalanine 4 and bearing an intact C‐terminus being especially relevant. Indeed, Aβ4‐42 peptides were reported as major components of amyloid plaque cores and the limited studies available seem to indicate their relative abundance in patients with AD, Down’s syndrome, and vascular dementia. In this work we assessed the topographic distribution of these species with in‐house‐generated anti‐Aβ4‐x monoclonal 18H6 – specific for Aβ species starting at position 4 and blind for the full‐length Aβ40 and Aβ42 – and used in conjunction with thioflavin S and antibodies specific for the C‐terminus 40 and 42 in confirmed AD cases. All types of Aβ deposits – parenchymal plaques, pre‐amyloid lesions and CAA – contained the Aβ epitopes tested, albeit expressed in different proportions. These co‐localizations were further stressed by combining double immunohistochemical analysis with Thioflavin S staining, showing the preferential location of Aβ4‐x species in CAA and cored plaques with fibrillar amyloid conformation, strongly suggesting poor clearance characteristics. To investigate the brain clearance of Aβ4‐x species in comparison with full‐length Aβ40 and Aβ42 homologues, peptides were synthesized, biochemically and biophysically characterized, radiolabeled with [125I]Na and utilized for in vivo brain clearance experiments in 5–6‐week‐old C57Bl/6 mice. Brain efflux of all monomeric Aβ species tested was fast, with &gt;80% cleared within the 60 min duration of the experiment whereas retention of oligomeric preparations was consistently higher than that of monomeric forms. Notably, clearance of Aβ4‐40 and Aβ4‐42 was significantly lower (&lt;45%) than the full‐length counterparts (61% ‐ 68%), further supporting a pathogenic role for Aβ oligomerization in AD and specifically highlighting the importance of oligomeric Aβ4‐x species exhibiting higher brain retention compared to their full‐length counterparts. Since the process of multimerization is concentration dependent, failing to remove these oligomeric forms of Aβ from the brain will further contribute to exacerbate the amyloidogenic loop and the persistence of amyloid deposits.

TARBP2-stablized SNHG7 regulates blood-brain barrier permeability by acting as a competing endogenous RNA to miR-17-5p/NFATC3 in Aβ-microenvironment

Breakdown of blood-brain barrier (BBB) is recognized as serious pathological marker of Alzheimer’s disease development. Studies confirmed that β-amyloid (Aβ) deposition induced high BBB permeability by disrupting tight junction (TJ) proteins formed from endothelial cells (ECs). Here, we found TARBP2, SNHG7 and NFATC3 in expressions were increased and miR-17-5p expression was decreased in Aβ(1-42)-incubated ECs. Overexpression of TARBP2, SNHG7 and NFATC3 elevated BBB permeability and knockdown of them had converse results. Agomir-17-5p decreased BBB permeability and antagomir-17-5p increased BBB permeability. TARBP2 as a RNA-binding protein (RBP) bound to SNHG7 and resulted in longer half-life of SNHG7. The decreased expression of miR-17-5p had a negative post-transcriptional regulation to NFATC3, leading to the increased expression of NFATC3. In addition, SNHG7 regulated NFATC3 expression by acting as a molecule sponge targeting to miR-17-5p. NFATC3 inhibited TJ proteins expression by functioning as a transcription factor. TARBP2/SNHG7/miR-17-5p/NFATC3 pathway implied a potential mechanism in studies of BBB changes in AD pathological progression.

Physiological Roles of Monomeric Amyloid-β and Implications for Alzheimer's Disease Therapeutics.

Alzheimer’s disease (AD) progressively inflicts impairment of synaptic functions with notable deposition of amyloid-β (Aβ) as senile plaques within the extracellular space of the brain. Accordingly, therapeutic directions for AD have focused on clearing Aβ plaques or preventing amyloidogenesis based on the amyloid cascade hypothesis. However, the emerging evidence suggests that Aβ serves biological roles, which include suppressing microbial infections, regulating synaptic plasticity, promoting recovery after brain injury, sealing leaks in the blood-brain barrier, and possibly inhibiting the proliferation of cancer cells. More importantly, these functions were found in in vitro and in vivo investigations in a hormetic manner, that is to be neuroprotective at low concentrations and pathological at high concentrations. We herein summarize the physiological roles of monomeric Aβ and current Aβ-directed therapies in clinical trials. Based on the evidence, we propose that novel therapeutics targeting Aβ should selectively target Aβ in neurotoxic forms such as oligomers while retaining monomeric Aβ in order to preserve the physiological functions of Aβ monomers.

Vascular Health Is Associated With Functional Connectivity Decline in Higher-Order Networks of Older Adults.

BackgroundPoor vascular health may impede brain functioning in older adults, thus possibly increasing the risk of cognitive decline and Alzheimer’s disease (AD). The emerging link between vascular risk factors (VRF) and longitudinal decline in resting-state functional connectivity (RSFC) within functional brain networks needs replication and further research in independent cohorts.MethodWe examined 95 non-demented older adults using the IMAP+ cohort (Caen, France). VRF were assessed at baseline through systolic and diastolic blood pressure, body-mass-index, and glycated hemoglobin (HbA1c) levels. Brain pathological burden was measured using white matter hyperintensity (WMH) volumes, derived from FLAIR images, and cortical β-Amyloid (Aβ) deposition, derived from florbetapir-PET imaging. RSFC was estimated from functional MRI scans within canonical brain networks at baseline and up to 3 years of follow-up. Linear mixed-effects models evaluated the independent predictive value of VRF on longitudinal changes in network-specific and global RSFC as well as a potential association between these RSFC changes and cognitive decline.ResultsWe replicate that RSFC increased over time in global RSFC and in the default-mode, salience/ventral-attention and fronto-parietal networks. In contrast, higher diastolic blood pressure levels were independently associated with a decrease of RSFC over time in the default-mode, salience/ventral-attention, and fronto-parietal networks. Moreover, higher HbA1c levels were independently associated with a reduction of the observed RSFC increase over time in the salience/ventral-attention network. Both of these associations were independent of brain pathology related to Aβ load and WMH volumes. The VRF-related changes in RSFC over time were not significantly associated with longitudinal changes in cognitive performance.ConclusionOur longitudinal findings corroborate that VRF promote RSFC alterations over time within higher-order brain networks, irrespective of pathological brain burden. Altered RSFC in large-scale cognitive networks may eventually increase the vulnerability to aging and AD.

Induction of Brain Insulin Resistance and Alzheimer's Molecular Changes by Western Diet.

The term Western diet (WD) describes the consumption of large amounts of highly processed foods, rich in simple sugars and saturated fats. Long-term WD feeding leads to insulin resistance, postulated as a risk factor for Alzheimer’s disease (AD). AD is the main cause of progressive dementia characterized by the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles consisting of the hyperphosphorylated tau (p-Tau) protein in the brain, starting from the entorhinal cortex and the hippocampus. In this study, we report that WD-derived impairment in insulin signaling induces tau and Aβ brain pathology in wild-type C57BL/6 mice, and that the entorhinal cortex is more sensitive than the hippocampus to the impairment of brain insulin signaling. In the brain areas developing WD-induced insulin resistance, we observed changes in p-Tau(Thr231) localization in neuronal subcellular compartments, indicating progressive tauopathy, and a decrease in amyloid precursor protein levels correlating with the appearance of Aβ peptides. These results suggest that WD promotes the development of AD and may be considered not only a risk factor, but also a modifiable trigger of AD.

The Interaction Between Vascular Risk Factors, Cerebral Small Vessel Disease, and Amyloid Burden in Older Adults.

Cerebral small vessel disease (SVD) and Alzheimer's disease pathology, namely amyloid-β (Aβ) deposition, commonly co-occur. Exactly how they interact remains uncertain. Using participants from the Alzheimer's Disease Neuroimaging Initiative (n = 216; mean age 73.29±7.08 years, 91 (42.1%) females), we examined whether the presence of vascular risk factors and/or baseline cerebral SVD was related to a greater burden of Aβ cross-sectionally, and at 24 months follow-up. Amyloid burden, assessed using 18F-florbetapir PET, was quantified as the global standardized uptake value ratio (SUVR). Multimodal imaging was used to strengthen the quantification of baseline SVD as a composite variable, which included white matter hyperintensity volume using MRI, and peak width of skeletonized mean diffusivity using diffusion tensor imaging. Structural equation modeling was used to analyze the associations between demographic factors, Apolipoprotein E ɛ4 carrier status, vascular risk factors, SVD burden and cerebral amyloid. SVD burden had a direct association with Aβ burden cross-sectionally (coeff. = 0.229, p = 0.004), and an indirect effect over time (indirect coeff. = 0.235, p = 0.004). Of the vascular risk factors, a history of hypertension (coeff. = 0.094, p = 0.032) and a lower fasting glucose at baseline (coeff. = -0.027, p = 0.014) had a direct effect on Aβ burden at 24 months, but only the direct effect of glucose persisted after regularization. While Aβ and SVD burden have an association cross-sectionally, SVD does not appear to directly influence the accumulation of Aβ longitudinally. Glucose regulation may be an important modifiable risk factor for Aβ accrual over time.

Predicting Brain Amyloid-β PET Grades with Graph Convolutional Networks Based on Functional MRI and Multi-Level Functional Connectivity.

The detection of amyloid-β (Aβ) deposition in the brain provides crucial evidence in the clinical diagnosis of Alzheimer's disease (AD). However, the current positron emission tomography (PET)-based brain Aβ examination suffers from the problems of coarse visual inspection (in many cases, with 2-class stratification) and high scanning cost. 1) To characterize the non-binary Aβ deposition levels in the AD continuum based on clustering of PET data, and 2) to explore the feasibility of predicting individual Aβ deposition grades with non-invasive functional magnetic resonance imaging (fMRI). 1) Individual whole-brain Aβ-PET images from the OASIS-3 dataset (N = 258) were grouped into three clusters (grades) with t-SNE and k-means. The demographical data as well as global and regional standard uptake value ratios (SUVRs) were compared among the three clusters with Chi-square tests or ANOVA tests. 2) From resting-state fMRI, both conventional functional connectivity (FC) and high-order FC networks were constructed and the topological architectures of the two networks were jointly learned with graph convolutional networks (GCNs) to predict the Aβ-PET grades for each individual. We found three clearly separated clusters, indicating three Aβ-PET grades. There were significant differences in gender, age, cognitive ability, APOE type, as well as global and regional SUVRs among the three grades we found. The prediction of Aβ-PET grades with GCNs on FC for the 258 samples in the AD continuum reached a satisfactory averaged accuracy (78.8%) in the two-class classification tasks. The results demonstrated the feasibility of using deep learning on a non-invasive brain functional imaging technique to approximate PET-based Aβ deposition grading.

Impaired Experience-Dependent Refinement of Place Cells in a Rat Model of Alzheimer's Disease.

Hippocampal place cells play an integral role in generating spatial maps. Impaired spatial memory is a characteristic pathology of Alzheimer's disease (AD), yet it remains unclear how AD influences the properties of hippocampal place cells. To record electrophysiological activity in hippocampal CA1 neurons in freely-moving 18-month-old male TgF344-AD and age-matched wild-type (WT) littermates to examine place cell properties. We implanted 32-channel electrode arrays into the CA1 subfield of 18-month-old male WT and TgF344-AD (n = 6/group) rats. Ten days after implantation, single unit activity in an open field arena was recorded across days. The spatial information content, in-field firing rate, and stability of each place cell was compared across groups. Pathology was assessed by immunohistochemical staining, and a deep neural network approach was used to count cell profiles. Aged TgF344-AD rats exhibited hippocampal amyloid-β deposition, and a significant increase in Iba1 immunoreactivity and microglia cell counts. Place cells from WT and TgF344-AD rat showed equivalent spatial information, in-field firing rates, and place field stability when initially exposed to the arena. However, by day 3, the place cells in aged WT rats showed characteristic spatial tuning as evidenced by higher spatial information content, stability, and in-field firing rates, an effect not seen in TgF344-AD rats. These findings support the notion that altered electrophysiological properties of place cells may contribute to the learning and memory deficits observed in AD.

SIRT1 Is Involved in the Neuroprotection of Pterostilbene Against Amyloid β 25-35-Induced Cognitive Deficits in Mice.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposits and neurofibrillary tangles. Pterostilbene (PTE), a bioactive component mainly in blueberries, is found to have neuroprotective properties. However, the specific underlying mechanisms of PTE in protecting AD remain unclear. Herein, we explored its effects on Aβ25–35-induced neuronal damage in vivo and in vitro and further compared the roles with its structural analog resveratrol (RES) in improving learning–memory deficits. We found that intragastric administration of PTE (40 mg/kg) displayed more effective neuroprotection on Aβ25–35-induced cognitive dysfunction assessed using the novel object test, Y-maze test, and Morris water maze test. Then, we found that PTE improved neuronal plasticity and alleviated neuronal loss both in vivo and in vitro. Additionally, PTE upregulated the expression of sirtuin-1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2) and the level of superoxide dismutase (SOD), and inhibited mitochondria-dependent apoptosis in the Aβ25–35-treated group. However, SIRT1 inhibitor EX527 reversed the neuroprotection and induced a drop in mitochondrial membrane potential in PTE-treated primary cortical neurons. Our data suggest that PTE’s enhancing learning–memory ability and improving neuroplasticity might be related to inhibiting mitochondria-dependent apoptosis via the antioxidant effect regulated by SIRT1/Nrf2 in AD.

Glucose Metabolism, Neural Cell Senescence and Alzheimer’s Disease

Alzheimer’s disease (AD), an elderly neurodegenerative disorder with a high incidence and progressive memory decline, is one of the most expensive, lethal, and burdening diseases. To date, the pathogenesis of AD has not been fully illustrated. Emerging studies have revealed that cellular senescence and abnormal glucose metabolism in the brain are the early hallmarks of AD. Moreover, cellular senescence and glucose metabolism disturbance in the brain of AD patients may precede amyloid-β deposition or Tau protein phosphorylation. Thus, metabolic reprogramming targeting senescent microglia and astrocytes may be a novel strategy for AD intervention and treatment. Here, we recapitulate the relationships between neural cell senescence and abnormal glucose metabolism (e.g., insulin signaling, glucose and lactate metabolism) in AD. We then discuss the potential perspective of metabolic reprogramming towards an AD intervention, providing a theoretical basis for the further exploration of the pathogenesis of and therapeutic approach toward AD.

Hippocampal-subfield microstructures and their relation to plasma biomarkers in Alzheimer's disease.

Hippocampal subfields exhibit differential vulnerabilities to Alzheimer's disease-associated pathology including abnormal accumulation of amyloid-β deposition and neurofibrillary tangles. These pathological processes extensively impact on the structural and functional interconnectivities of the subfields and may explain the association between hippocampal dysfunction and cognitive deficits. In this study, we investigated the degree of alterations in the microstructure of hippocampal subfields across the clinical continuum of Alzheimer's disease. We applied a grey matter-specific multi-compartment diffusion model (Cortical-Neurite orientation dispersion and density imaging) to understand the differential effects of Alzheimer's disease pathology on the hippocampal subfield microstructure. A total of 119 participants were included in this cross-sectional study. Participants were stratified into three categories, cognitively normal (n = 47), mild cognitive impairment (n = 52), and Alzheimer's disease (n = 19). Diffusion MRI, plasma biomarkers and neuropsychological test scores were used to determine the association between the microstructural integrity and Alzheimer's disease-associated molecular indicators and cognition. For Alzheimer's disease-related plasma biomarkers, we studied amyloid-β, total tau and neurofilament light; for Alzheimer's disease-related neuropsychological tests, we included the Trail Making Test, Rey Auditory Verbal Learning Test, Digit Span and Montreal Cognitive Assessment. Comparisons between cognitively normal subjects and those with mild cognitive impairment showed significant microstructural alterations in the hippocampal cornu ammonis (CA) 4 and dentate gyrus region, whereas CA 1-3 was the most sensitive region for the later stages in the Alzheimer's disease clinical continuum. Among imaging metrics for microstructures, the volume fraction of isotropic diffusion for interstitial free water demonstrated the largest effect size in between-group comparisons. Regarding the plasma biomarkers, neurofilament light appeared to be the most sensitive biomarker for associations with microstructural imaging findings in CA4-dentate gyrus. CA 1-3 was the subfield which had stronger correlations between cognitive performance and microstructural metrics. Particularly, poor performance on the Rey Auditory Verbal Learning Test and Montreal Cognitive Assessment was associated with decreased intracellular volume fraction. Overall, our findings support the value of tissue-specific microstructural imaging for providing pathologically relevant information manifesting in the plasma biomarkers and neuropsychological outcomes across various stages of Alzheimer's disease.

Editors' Note: Progressive Auditory Verbal Agnosia Secondary to Alzheimer Disease

In this issue of Neurology ®, Dr. Buciuc et al. describe the case of a patient with suspected Alzheimer disease and progressive auditory verbal agnosia. The clinical diagnosis is supported by nicely rendered [18F]-fluorodeoxyglucose PET imaging demonstrating hypometabolism in Heschl gyrus (primary auditory cortex), which corresponds with the patient's auditory verbal agnosia. The diagnosis of Alzheimer disease was reached on the basis of radiographic evidence of cortical atrophy with increased flortaucipir uptake in the bilateral temporal lobes (reflecting tau accumulation) and β-amyloid deposition on PET imaging, in the absence of other cognitive impairment. In response, Dr. Dasheiff commends the imaging findings and biologic explanation of this patient's condition; however, Dr. Dasheiff questions the diagnosis of Alzheimer disease given the lack of clinical pathology. The DSM-5 currently requires longitudinal follow-up and confirmation of progressive impairment in one or more cognitive domains to make the diagnosis of Alzheimer disease. The authors emphasize that their findings are consistent with Alzheimer pathology; however, they cannot confirm that an alternative tauopathy (or other clinical pathology) may account for this patient's neuroimaging and clinical manifestations. In this issue of Neurology ®, Dr. Buciuc et al. describe the case of a patient with suspected Alzheimer disease and progressive auditory verbal agnosia. The clinical diagnosis is supported by nicely rendered [18F]-fluorodeoxyglucose PET imaging demonstrating hypometabolism in Heschl gyrus (primary auditory cortex), which corresponds with the patient's auditory verbal agnosia. The diagnosis of Alzheimer disease was reached on the basis of radiographic evidence of cortical atrophy with increased flortaucipir uptake in the bilateral temporal lobes (reflecting tau accumulation) and β-amyloid deposition on PET imaging, in the absence of other cognitive impairment. In response, Dr. Dasheiff commends the imaging findings and biologic explanation of this patient's condition; however, Dr. Dasheiff questions the diagnosis of Alzheimer disease given the lack of clinical pathology. The DSM-5 currently requires longitudinal follow-up and confirmation of progressive impairment in one or more cognitive domains to make the diagnosis of Alzheimer disease. The authors emphasize that their findings are consistent with Alzheimer pathology; however, they cannot confirm that an alternative tauopathy (or other clinical pathology) may account for this patient's neuroimaging and clinical manifestations.

Identifying Mild Alzheimer's Disease With First 30-Min 11C-PiB PET Scan.

Introduction11C-labeled Pittsburgh compound B (11C-PiB) PET imaging can provide information for the diagnosis of Alzheimer's disease (AD) by quantifying the binding of PiB to β-amyloid deposition in the brain. Quantification index, such as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR), has been exploited to effectively distinguish between healthy and subjects with AD. However, these measures require a long wait/scan time, as well as the selection of an optimal reference region. In this study, we propose an alternate measure named amyloid quantification index (AQI), which can be obtained with the first 30-min scan without the selection of the reference region.Methods11C-labeled Pittsburgh compound B PET scan data were obtained from the public dataset “OASIS-3”. A total of 60 mild subjects with AD and 60 healthy controls were included, with 50 used for training and 10 used for testing in each group. The proposed measure AQI combines information of clearance rate and mid-phase PIB retention in featured brain regions from the first 30-min scan. For each subject in the training set, AQI, SUVR, and DVR were calculated and used for classification by the logistic regression classifier. The receiver operating characteristic (ROC) analysis was performed to evaluate the performance of these measures. Accuracy, sensitivity, and specificity were reported. The Kruskal–Wallis test and effect size were also performed and evaluated for all measures. Then, the performance of three measures was further validated on the testing set using the same method. The correlations between these measures and clinical MMSE and CDR-SOB scores were analyzed.ResultsThe Kruskal–Wallis test suggested that AQI, SUVR, and DVR can all differentiate between the healthy and subjects with mild AD (p < 0.001). For the training set, ROC analysis showed that AQI achieved the best classification performance with an accuracy rate of 0.93, higher than 0.88 for SUVR and 0.89 for DVR. The effect size of AQI, SUVR, and DVR were 2.35, 2.12, and 2.06, respectively, indicating that AQI was the most effective among these measures. For the testing set, all three measures achieved less superior performance, while AQI still performed the best with the highest accuracy of 0.85. Some false-negative cases with below-threshold SUVR and DVR values were correctly identified using AQI. All three measures showed significant and comparable correlations with clinical scores (p < 0.01).ConclusionAmyloid quantification index combines early-phase kinetic information and a certain degree of β-amyloid deposition, and can provide a better differentiating performance using the data from the first 30-min dynamic scan. Moreover, it was shown that clinically indistinguishable AD cases regarding PiB retention potentially can be correctly identified.

Lights and Shadows of Cerebrospinal Fluid Biomarkers in the Current Alzheimer's Disease Framework.

Background: The most significant biomarkers that are included in the Alzheimer’s disease (AD) research framework are amyloid-β plaques deposition, p-tau, t-tau, and neurodegeneration.Although cerebrospinal fluid (CSF) biomarkers are included in the most recent AD research criteria, their use is increasing in the routine clinical practice and is applied also to the preclinical phases of AD, including mild cognitive impairment. The role of these biomarkers is still unclear concerning the preclinical stage of AD diagnosis, the CSF methodology, and the costs-benefits of the biomarkers’ tests. The controversies regarding the use of biomarkers in the clinical practice are related to the concepts of analytical validity, clinical validity, and clinical utility and to the question of whether they are able to diagnose AD without the support of AD clinical phenotypes.Objective: The objective of the present work is to expose the strengths and weaknesses of the use of CSF biomarkers in the diagnosis of AD in a clinical context.Methods: We used PubMed as main source for articles published and the final reference list was generated on the basis of relevance to the topics covered in this work.Results: The use of CSF biomarkers for AD diagnosis is certainly important but its indication in routine clinical practice, especially for prodromal conditions, needs to be regulated and also contextualized considering the variety of possible clinical AD phenotypes.Conclusion: We suggest that the diagnosis of AD should be understood both as clinical and pathological.

Isolated Amyloid-β Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer's Disease Patients.

Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer's disease (AD) patients. In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer's Association (NIA-AA) classification and APOE genotype. 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of amyloid-β (Aβ) deposition (A) and fibrillar tau (T), in four groups: A+/T-E4 (n = 9), A+/T-E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation protocol over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination (MMSE) scores respect to the baseline. A+/T-E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T-E3 and to A+/T+ patients independently from genotype (p < 0.001). In addition, A+/T-E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (delta MMSE -0.5±2.12 versus -6.05±4.95; post-hocp = 0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p = 0.028). No differences were found for SAI protocol (p > 0.05). Our results suggest that APOE4 in patients with isolated Aβ pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

Characterizing Amyloid-Positive Individuals With Normal Tau PET Levels After 5 Years: An ADNI Study.

Individuals with biomarker evidence of β-amyloid (Aβ) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether Aβ-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aβ PET positivity was defined based on ADNI cutpoints. We identified all Aβ-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aβ PET (amyloid with low tau [ALT] group) and all Aβ-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE ε4 carriership, Aβ Centiloid, and hippocampal volume. We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE ε4 carriers, lower Aβ Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE ε4, higher Aβ Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. Aβ-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aβ cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.