Early Stages Of AD Research Articles

Neuroinflammation, amyloid, NFT markers and initial cognitive status predict cognitive decline in MCI patients

AbstractBackgroundNeuroinflammation has been established as a key component of Alzheimer’s pathology. Numerous cross‐sectional studies have found associations between neuroinflammatory markers and neuronal damage in AD, suggesting neuroinflammation as a potential drive force of disease progression. However, there have been debate on whether neuroinflammation has a causal effect on disease progression. Here we questioned whether neuroinflammation is predictive of future cognitive decline in early stage of the disease.Method21 MCI patients were recruited and had baseline T1‐MRI and 11C‐PBR28 scans. Patients were followed up for at least one year (mean follow‐up period 3.1±1.3 years) and had mini‐mental state examinations (MMSE) at each visit. 19 of them had baseline 18F‐Flutemetamol PET, 11 had 18F‐AV1451 scans. 18F‐AV1451 and 11C‐PBR28 SUVR in the medial temporal lobe were measured, while PCA analyses were performed to evaluate uptakes in the neocortex for all 3 tracers. Principle components of temporal lobe volumetric measurements were computed as the neurodegeneration marker. A linear growth model was fitted for each subjects using all available time points, giving the intercept and slope of individual cognition trajectory. Age, intercept, 11C‐PBR28, and T1 MRI markers were then put into linear models to predict slope, and a backward model selection procedure was conducted. To further validate that neuroinflammation is not just a mediator of amyloid and tau pathologies, we further included amyloid and tau markers in the sub‐cohorts and inspected the final model.ResultThe average baseline MMSE was 28±1.9 in the study cohort and the average annual change of MMSE was ‐0.46. We found 11C‐PBR28 SUVR in neocortex and MMSE intercept, but not temporal cortical thickness, were predictive of the slope of MMSE decline. In subgroups where 18F‐Flutemetamol and 18F‐AV1451 SUVRs were included respectively, we found neocortical amyloid and tau load were also predictive of MMSE slope, while 11C‐PBR28 SUVR remained its significance in the models.ConclusionOur findings suggest that neuroinflammation is an independent factor that drives disease progression and cognitive decline in early stage of AD. Molecular imaging biomarkers may better predict patients’ outcome as they detect underlying biological processes.

Unfolding the medial temporal lobe to characterize neurodegeneration due to Alzheimer's disease pathology

AbstractBackgroundMeasurements of medial temporal lobe (MTL) neurodegeneration derived using MRI have been shown to be sensitive to changes during the early stages of AD. The specificity of these measurements to tau neurofibrillary tangle (NFT) pathology is limited by other frequently comorbid non‐AD factors which also cause structural changes in the MTL. Here, we directly link changes in MTL structure to underlying NFT pathology by combining ex vivo MRI with ratings of NFT severity derived from serial histology using a dataset of 18 human MTL specimens. We hypothesize that such an analysis can be used to define MTL “hotspots” where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers.MethodEx vivo specimens from 18 donors were scanned at 0.2x0.2x0.2mm3 on 9.4T MRI. Following MRI scanning, the specimens underwent histological processing with staining for cytoarchitecture and in 15 specimens, immunohistochemistry (IHC) with the anti‐tau AT8 antibody. Using a topological unfolding method (DeKraker et al. 2018), we created 2D representations of the extra‐hippocampal cortex which implicitly align cortical folding patterns across specimens (Fig. 1). An average MTL subregion segmentation was generated in unfolded space using manual segmentations completed in 11 specimens on the basis of cytoarchitecture. Additionally, heat maps quantifying NFT burden in each of the specimens with anti‐tau IHC sections were generated using a deep learning algorithm (Yushkevich et al. 2021). Using the heatmaps and the average subregion segmentation, we investigated the relationship between NFT severity and cortical thickness.ResultCorrelation analysis between NFT measures and thickness (correcting for age) reveals strong associations in the entorhinal cortex and the border of Brodmann Area 35, consistent with the early Braak regions, and parts of Brodmann Area 36 (Fig. 2).ConclusionWe present an unfolding framework applied to the MTL cortex, which allows us to visualize, for the first time, the distribution of MTL subregions and NFT pathology in an unfolded space. This framework provides a promising tool for detailed investigation of structural changes due to NFT pathology while explicitly accounting for the complex topology of the MTL, thereby enhancing our understanding of early AD.

Early-stage hippocampal hyperexcitability and impaired synaptic plasticity in the TgF344-AD rat model of Alzheimer's disease.

The transgenic TgF344-AD (TG) rat is emerging as a useful model for investigating age-dependent AD features that include behavioural, electrophysiological and pathological phenotypes of relevance to disease. In this study we investigated changes related to early stages of AD in 9 month old animals. Male and female TG rats and wild-type (WT) littermates undertook longitudinal behavioural testing at 3, 6 & 9 months (n=6-13/sex-genotype combination) and were tested for: (i) hippocampus-dependent rapid place learning in a delayed-matching-to place watermaze (DMP) test, (ii) novel object recognition (NOR) memory, (iii) expression of startle/pre-pulse inhibition; and (iv) open-field locomotor activity. In another cohort of rats at 9 months (n=8 males per genotype), spontaneous and evoked activities were record and measured in hippocampal CA3->CA1 circuit to study synaptic plasticity using in vivo electrophysiology under urethane anaesthesia. Following behavioural or electrophysiology testing brains were collected for post-mortem analyses (n=10 males per genotype). GABAergic and synaptic markers including parvalbumin, GAD67 , GABAA α5, SNAP-25 and PSD95 were measured by Simple Western analysis in the frontal cortex, prefrontal cortex, dorsal and ventral hippocampus. Behaviour: WT rats showed poor DMP performance with no clear genotype effect. Object exploration was low with no significant NOR. We found startle and locomotor sex differences, replicating previous reports. Interestingly, at 9 months, TG rats showed locomotor hypoactivity at the beginning and hyperactivity at the end of the 30-min open-field test, indicating impaired habituation, which may reflect impaired hippocampal contextual memory. Electrophysiology: 9-month-old TG rats showed reduced long-term potentiation with an increased baseline connectivity. A general decrease in power across frequency bands was found in the TG, especially for theta band. Western analysis: TG rats showed reduced levels of parvalbumin with a clear effect of genotype at 9-months. There was no detectable changes in synaptic markers. Impaired locomotor habituation of TG rats suggests abnormal hippocampal function emerges around 9 months, reflected by impaired hippocampal CA1 plasticity. A reduction of parvalbumin was also seen in the TG animals at this age. However, poor memory performance may limit the suitability of the TG model for testing clinically relevant memory deficits.

Cortical microstructural changes in autosomal dominant Alzheimer’s disease

AbstractBackgroundAutosomal dominant Alzheimer's Disease (ADAD) is an important area of study to understand the pathogenesis of AD. Previous studies suggested that mutations in the genes coding for amyloid precursor protein cause early deposition of amyloid‐β peptide (Aβ), resulting in an amyloid‐induced inflammatory response and cortical microstructural changes during the cognitively asymptomatic phase, several years before clinical onset. The aim of this work was to investigate the cortical microstructural changes in an ADAD population, using novel diffusion tensor imaging (DTI) metrics that are correlated with specific neuropathology and disruption of cortical minicolumns.MethodA total of 270 individuals from families with known mutations in the PSEN1, PSEN2, and APP genes (168 mutation carriers and 102 non‐carriers) from the Dominantly Inherited Alzheimer’s Network (DIAN) were included in the study. 3DT1 and DTI scans at baseline were used to calculate the cortical grey matter fraction, cortical thickness, mean diffusivity (MD), and three novel cortical diffusivity measures, namely: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD), and the principal diffusion component parallel with the minicolumns (ParlPD). A multivariate General Linear model (GLM) was used to investigate cross‐sectional differences. Mutation carrier status was added as a fixed factor, and “sex” and “age” as covariates. Differences across the clinical spectrum are evaluated with box‐plots of metrics grouped by clinical dementia rating (CDR) Figure 1.ResultDifferences in cortical diffusivity measures were found between mutation carriers and non‐carriers. The GLM results revealed a significant main effect of mutation carrier status (p<0.05) as well as age (p<0.001) and sex (p<0.001). Between‐subjects effects revealed that PerpPD (p<0.0001), ParlPD (p<0.0001), and MD (p<0.0001) were significantly higher in the mutation carrier group. As expected, the cortical grey matter fraction (p<0.005) and cortical thickness (p<0.01) were significantly lower in the mutation carrier group.ConclusionIn autosomal dominant (inherited) Alzheimer’s disease, differences emerge in several novel cortical diffusivity measures, years before the expected diagnosis based on parental age of onset. These findings support using cortical diffusivity measures as a surrogate of cortical microstructure quality for identification of the early stages of AD.

Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors

BackgroundAldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons remain unknown.MethodsWe generated a mutant mouse line in which cyclization recombination enzyme (CRE) was expressed under the control of the Aldh1a1 promotor (Aldh1a1-CRE mice). Using this mutant strain of mice together with the heterozygous male Alzheimer’s disease (AD) related model mice (APPswe/PSEN1dE9, or AD mice) and a genetically modified retrograde and anterograde synaptic tracing strategy, we have studied a specific synaptic circuit of Aldh1a1 neurons with system-level function and disease progression in AD mice.ResultsWe demonstrate that Aldh1a1 neurons encode delay of gratification that measures self-control skills in decision making by projecting inhibitory synapses directly onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS) and receiving synaptic inputs from layer 5b pyramidal neurons in the medial prefrontal cortex (L5PN). L5PN → Aldh1a1 synaptic transmission undergoes long-term potentiation (LTP). Pathway specific inhibition by either genetic silencing presynaptic terminals or antagonizing postsynaptic receptors impairs delay of gratification, resulting in the impulsive behaviors. Further studies show that reconstitution of Aldh1a1-deficient neurons with the expression of exogenous Aldh1a1 (eAldh1a1) restores Aldh1a1 → EGNIS synaptic transmission and rescues the impulsive behaviors in AD mice.ConclusionsThese results not only identify a specific function and circuit of Aldh1a1 neurons but also provide a cellular point of entry to an important but understudied synaptic mechanism for the induction of impulsive behaviors at an early stage of AD.

Pragmatic Language Disorders Resulting from Semantic Degradation in Patients with Alzheimer’s Disease

Objective: The aim of this study is to create an inventory of pragmatic language disorders specific to Alzheimer’s disease, to illustrate them by case examples, to determine the severity of disorders according to the stages of Alzheimer’s, and to specify the impact of patients’ demographic characteristics on the pragmatic disorders experienced by them. Method: The study adopted a descriptive research design. The sample was selected using the stratified sampling method. Interviews were conducted with the patients using the free association technique. The feedbacks from the participants were collected as audio recordings and transcribed using the SALT program. The findings were analysed and compared with the control group data, and the conclusion was drawn from the results obtained. Results: In the course of study 19 types of pragmatic language disorders of AD patients were identified. The differences between the pragmatic disorders detected at various stages of the disease were illustrated in detail using case examples, and the effect of the demographic variables on the disorders was determined. Conclusion: As a result of the research, pragmatic language disorders resulting from semantic degradation experienced by AD patients were identified. It was found out that the early stage of AD is characterised by mild pragmatic disorders, which tend to get more distinct at the middle stage and even more severe at the late stage. In addition, it was determined that the demographic characteristics of patients have an impact on the severity of pragmatic language disorders.

Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer\u2019s disease, but not in cerebral amyloid angiopathy

BackgroundNeuroleukin (NLK) is a protein with neurotrophic properties and is present in a proportion of senile plaques and amyloid laden vessels. It has been suggested that NLK is part of a neuroprotective response to amyloid β-induced cell death. The aim of our study was to investigate the value of cerebrospinal fluid (CSF) NLK levels as a biomarker of vascular amyloid deposition in patients with cerebral amyloid angiopathy (CAA) and in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD).MethodsCSF NLK levels were quantified by ELISA in CAA patients (n = 25) and controls (n = 27) and in two independent samples of aMCI patients, AD patients, and controls: (1) From the Radboud University Medical Center (Nijmegen), we included n = 19 aMCI patients, n = 40 AD patients, and n = 32 controls. (2) From the Hospital of Sant Pau (Barcelona), we included n = 33 aMCI patients, n = 17 AD patients, and n = 50 controls.ResultsCSF NLK levels were similar in CAA patients and controls (p = 0.95). However, we found an elevated CSF concentration of NLK in aMCI (p < 0.0001) and AD patients (p < 0.0001) compared to controls in both samples sets. In addition, we found a correlation of CSF NLK with CSF YKL-40 (age-adjusted-spearman-rank-coefficient = 0.82, p < 0.0001) in aMCI/AD patients, a well-known glial marker of neuro-inflammation.ConclusionsWe found that CSF NLK levels are elevated in aMCI and AD patients compared to controls, but are not increased in CAA patients. CSF NLK levels may be related to an increased neuroinflammatory state in early stages of AD, given its association with YKL-40.

Mild Cognitive Impairment and Donepezil Impact Mitochondrial Respiratory Capacity in Skeletal Muscle.

Alzheimer's Disease (ad) associates with insulin resistance and low aerobic capacity, suggestive of impaired skeletal muscle mitochondrial function. However, this has not been directly measured in AD. This study ( n = 50) compared muscle mitochondrial respiratory function and gene expression profiling in cognitively healthy older adults (CH; n = 24) to 26 individuals in the earliest phase of ad-related cognitive decline, mild cognitive impairment (MCI; n = 11) or MCI taking the ad medication donepezil (MCI + med; n = 15). Mitochondrial respiratory kinetics were measured in permeabilized muscle fibers from muscle biopsies of the vastus lateralis. Untreated MCI exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH ( P = .043) and MCI + med (P = .007) groups. MCI also exhibited poorer mitochondrial coupling control compared to CH (P = .014). RNA sequencing of skeletal muscle revealed unique differences in mitochondrial function and metabolism genes based on both MCI status (CH vs MCI) and medication treatment (MCI vs MCI + med). MCI + med modified over 600 skeletal muscle genes compared to MCI suggesting donepezil powerfully impacts the transcriptional profile of muscle. Overall, skeletal muscle mitochondrial respiration is altered in untreated MCI but normalized in donepezil-treated MCI participants while leak control is impaired regardless of medication status. These results provide evidence that mitochondrial changes occur in the early stages of AD, but are influenced by a common ad medicine. Further study of mitochondrial bioenergetics and the influence of transcriptional regulation in early ad is warranted.

Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer\u2019s disease

BackgroundDiscovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology.ResultsThis AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice.ConclusionsThe current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD.Graphical abstract

Anaerobic co-digestion of a lignocellulosic residue with different organic wastes: Relationship between biomethane yield, soluble organic matter and process stability

The aim of this paper was to deepen the knowledge of anaerobic co-digestion of lignocellulosic residues and evaluate the role of soluble organic matter during co-digestion. Buckwheat milling residue (buckwheat hull) was co-digested with different organic wastes to evaluate the effect of co-digestion on biomethane yield, process stability, and their relationship with soluble organic matter.Results showed that co-digestion increased the biomethane yields of buckwheat hull and the best result was achieved from the co-digestion with slaughterhouse wastes (+254% of cumulative biomethane production). Kinetic analysis showed that fruit wastes and brewery trub affected positively anaerobic digestion of lignocellulosic residues, enhancing biomethane potential (+84% and +166%, respectively) and reducing lag phase duration. A positive correlation was found between the soluble organic matter and the biomethane yields during co-digestion experiments. Nevertheless, co-digestion with fruit wastes was affected by an excessive acidification in the early stage of AD (pH 5.7) caused by the rapid conversion of sugars into volatile fatty acids (7 g L-1 at day 15). Although all the digestates showed high concentrations of plant nutrients (the average content of total N was 7.8% dry weight), they were also characterized by residual phytotoxicity (germination index was always 0.0%). results.Increasing the amount of easy biodegradable organic matter during lignocellulosic residues treatment should be the main goal when selecting co-digestion substrates. Chemical composition of co-digestion substrates should be carefully considered, with particular regard to soluble organic matter, to ensure the optimal development of anaerobic digestion with lignocellulosic residues.

The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

Background: Apolipoprotein E (APOE) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of APOE ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of APOE ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). Methods: Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, APOE ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of APOE ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). Results: The prevalence of APOE ε4 is higher in EMCI and LMCI than in CN (p < 0.001 for both), and in LMCI than in EMCI (p = 0.001). APOE ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (p < 0.001). Subjects who had a lower CSF Aβ42 level and were APOE ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. Conclusions: An APOE ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that APOE ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

Bioinformatics analysis of differentially expressed genes and identification of an miRNA\u2013mRNA network associated with entorhinal cortex and hippocampus in Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) is a fatal neurodegenerative disorder, and the lesions originate in the entorhinal cortex (EC) and hippocampus (HIP) at the early stage of AD progression. Gaining insight into the molecular mechanisms underlying AD is critical for the diagnosis and treatment of this disorder. Recent discoveries have uncovered the essential roles of microRNAs (miRNAs) in aging and have identified the potential of miRNAs serving as biomarkers in AD diagnosis.MethodsWe sought to apply bioinformatics tools to investigate microarray profiles and characterize differentially expressed genes (DEGs) in both EC and HIP and identify specific candidate genes and pathways that might be implicated in AD for further analysis. Furthermore, we considered that DEGs might be dysregulated by miRNAs. Therefore, we investigated patients with AD and healthy controls by studying the gene profiling of their brain and blood samples to identify AD-related DEGs, differentially expressed miRNAs (DEmiRNAs), along with gene ontology (GO) analysis, KEGG pathway analysis, and construction of an AD-specific miRNA–mRNA interaction network.ResultsOur analysis identified 10 key hub genes in the EC and HIP of patients with AD, and these hub genes were focused on energy metabolism, suggesting that metabolic dyshomeostasis contributed to the progression of the early AD pathology. Moreover, after the construction of an miRNA–mRNA network, we identified 9 blood-related DEmiRNAs, which regulated 10 target genes in the KEGG pathway.ConclusionsOur findings indicated these DEmiRNAs having the potential to act as diagnostic biomarkers at an early stage of AD.

Early Detection of Parkinson’s and Alzheimer’s Diseases using the VOT_Mean Feature

Alzheimer’s (AD) and Parkinson’s diseases (PD) are tw of the most common neurological diseases in the world. Several studies have been conducted on the identification of these diseases using speech and laryngeal disorders. Those symptoms can appear even at the early stages of AD and PD, but not in very specific and prominent ways. Voice Onset Time (VOT) is an acoustic specification of the stopping consonant that is commonly discussed in studies of phonetic perception. In this study, the VOT_Mean feature was explored to identify AD and PD early using /pa/, /ka/, and /ta/ syllables for the diadochokinetic task (DDK). VOT_Mean was calculated as the average of the first and the second VOT values (VOT_1 and VOT_2), corresponding to the second and the penultimate VOT measurement cycles. Experimental tests were performed on Tunisian Arabic and Spanish databases for the early detection of AD and PD respectively. The results showed a very high significance of VOT_Mean on the early detection of AD and PD. Moreover, the best results were achieved using the XGBoost (XGBT) algorithm as a classifier on the VOT_Mean feature.

Pharmacological inhibition of asparaginyl endopeptidase by \u03b4-secretase inhibitor 11 mitigates Alzheimer\u2019s disease-related pathologies in a senescence-accelerated mouse model

BackgroundCurrently, there is no cure for Alzheimer’s disease (AD). Therapeutics that can modify the early stage of AD are urgently needed. Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase (AEP). Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD. However, more than 90% of AD cases are age-related sporadic AD rather than hereditary AD. The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown.MethodsThe senescence-accelerated mouse prone 8 (SAMP8) was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,: δ-secretase inhibitor 11. Activation of AEP was determined by enzymatic activity assay. Concentration of soluble amyloid β (Aβ) in the brain was determined by ELISA. Morris water maze test was performed to assess the learning and memory-related cognitive ability. Pathological changes in the brain were explored by morphological and western blot analyses.ResultsThe enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the age-matched SAMR1 mice. The half maximal inhibitory concentration (IC50) for δ-secretase inhibitor 11 to inhibit AEP in vitro is was around 150 nM. Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity, reduced the generation of Aβ1–40/42 and ameliorated memory loss. The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation, but also attenuated neuroinflammation in the form of microglial activation. Moreover, treatment with δ-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain.ConclusionsPharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD. The up-regulated AEP in the brain could be a promising target for early treatment of AD. The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.

Citrulline supplementation improves spatial memory in a murine model for Alzheimer's disease

ObjectivesAlzheimer's disease (AD) correlates with the dysfunction of metabolic pathways that translates into neurological symptoms. An arginine deficiency, a precursor of nitric oxide (NO), has been reported for patients with AD. We aimed to evaluate the effect of citrulline oral supplementation on cognitive decline in an AD murine model. MethodsThree-month citrulline or water supplementation was blindly given to male and female wild-type and 3 × Tg mice with AD trained and tested in the Morris water maze. Cerebrospinal fluid and brain tissue were collected. Ultra-performance liquid chromatography was used for arginine determinations and the Griess method for NO. ResultsEight-month-old male 3 × Tg mice with AD supplemented with citrulline performed significantly better in the Morris water maze task. Arginine levels increased in the cerebrospinal fluid although no changes were seen in brain tissue and only a tendency of increase of NO was observed. ConclusionsCitrulline oral administration is a viable treatment for memory improvement in the early stages of AD, pointing to NO as a viable, efficient target for memory dysfunction in AD.

Early loss of cerebellar Purkinje cells in human and a transgenic mouse model of Alzheimer’s disease

ABSTRACT Background: The cerebellum’s involvement in AD has been under-appreciated by historically labeling as a normal control in AD research. Methods: We determined the involvement of the cerebellum in AD progression. Postmortem human and APPswe/PSEN1dE9 mice cerebellums were used to assess the cerebellar Purkinje cells (PC) by immunohistochemistry. The locomotor and spatial cognitive functions were assessed in 4- to 5-month-old APPswe/PSEN1dE9 mice. Aβ plaque and APP processing were determined in APPswe/PSEN1dE9 mice at different age groups by immunohistochemistry and Western blot. Results: We observed loss of cerebellar PC in mild cognitive impairment and AD patients compared with cognitively normal controls. A strong trend towards PC loss was found in AD mice as early as 5 months. Impairment of balance beam and rotorod performance, but no spatial learning and memory dysfunction was observed in AD mice at 4–5 months. Aβ plaque in the cerebral cortex was evidenced in AD mice at 2 months and dramatically increased at 6 months. Less and smaller Aβ plaques were observed in the cerebellum than in the cerebrum of AD mice. Similar intracellular APP staining was observed in the cerebellum and cerebrum of AD mice at 2 to 10 months. Similar expression of full-length APP and C-terminal fragments were indicated in the cerebrum and cerebellum of AD mice during aging. Discussion: Our study in post-mortem human brains and transgenic AD mice provided neuropathological and functional evidence that cerebellar dysfunction may occur at the early stage of AD and likely independent of Aβ plaque.

Alzheimer's Disease Projection From Normal to Mild Dementia Reflected in Functional Network Connectivity: A Longitudinal Study.

BackgroundAlzheimer’s disease (AD) is the most common age-related problem and progresses in different stages, including mild cognitive impairment (early stage), mild dementia (middle-stage), and severe dementia (late-stage). Recent studies showed changes in functional network connectivity obtained from resting-state functional magnetic resonance imaging (rs-fMRI) during the transition from healthy aging to AD. By assuming that the brain interaction is static during the scanning time, most prior studies are focused on static functional or functional network connectivity (sFNC). Dynamic functional network connectivity (dFNC) explores temporal patterns of functional connectivity and provides additional information to its static counterpart.MethodWe used longitudinal rs-fMRI from 1385 scans (from 910 subjects) at different stages of AD (from normal to very mild AD or vmAD). We used group-independent component analysis (group-ICA) and extracted 53 maximally independent components (ICs) for the whole brain. Next, we used a sliding-window approach to estimate dFNC from the extracted 53 ICs, then group them into 3 different brain states using a clustering method. Then, we estimated a hidden Markov model (HMM) and the occupancy rate (OCR) for each subject. Finally, we investigated the link between the clinical rate of each subject with state-specific FNC, OCR, and HMM.ResultsAll states showed significant disruption during progression normal brain to vmAD one. Specifically, we found that subcortical network, auditory network, visual network, sensorimotor network, and cerebellar network connectivity decrease in vmAD compared with those of a healthy brain. We also found reorganized patterns (i.e., both increases and decreases) in the cognitive control network and default mode network connectivity by progression from normal to mild dementia. Similarly, we found a reorganized pattern of between-network connectivity when the brain transits from normal to mild dementia. However, the connectivity between visual and sensorimotor network connectivity decreases in vmAD compared with that of a healthy brain. Finally, we found a normal brain spends more time in a state with higher connectivity between visual and sensorimotor networks.ConclusionOur results showed the temporal and spatial pattern of whole-brain FNC differentiates AD form healthy control and suggested substantial disruptions across multiple dynamic states. In more detail, our results suggested that the sensory network is affected more than other brain network, and default mode network is one of the last brain networks get affected by AD In addition, abnormal patterns of whole-brain dFNC were identified in the early stage of AD, and some abnormalities were correlated with the clinical score.

A novel paradigm for assessing olfactory working memory capacity in mice

A decline in working memory (WM) capacity is suggested to be one of the earliest symptoms observed in Alzheimer’s disease (AD). Although WM capacity is widely studied in healthy subjects and neuropsychiatric patients, few tasks are developed to measure this variation in rodents. The present study describes a novel olfactory working memory capacity (OWMC) task, which assesses the ability of mice to remember multiple odours. The task was divided into five phases: context adaptation, digging training, rule-learning for non-matching to a single-sample odour (NMSS), rule-learning for non-matching to multiple sample odours (NMMS) and capacity testing. During the capacity-testing phase, the WM capacity (number of odours that the mice could remember) remained stable (average capacity ranged from 6.11 to 7.00) across different testing sessions in C57 mice. As the memory load increased, the average errors of each capacity level increased and the percent correct gradually declined to chance level, which suggested a limited OWMC in C57 mice. Then, we assessed the OWMC of 5 × FAD transgenic mice, an animal model of AD. We found that the performance displayed no significant differences between young adult (3-month-old) 5 × FAD mice and wild-type (WT) mice during the NMSS phase and NMMS phase; however, during the capacity test with increasing load, we found that the OWMC of young adult 5 × FAD mice was significantly decreased compared with WT mice, and the average error was significantly increased while the percent correct was significantly reduced, which indicated an impairment of WM capacity at the early stage of AD in the 5 × FAD mice model. Finally, we found that FOS protein levels in the medial prefrontal cortex and entorhinal cortex after the capacity test were significantly lower in 5 × FAD than WT mice. In conclusion, we developed a novel paradigm to assess the capacity of olfactory WM in mice, and we found that OWMC was impaired in the early stage of AD.

Cortical microstructural changes and amyloid beta burden in cognitively normal subjective memory complainers

AbstractBackgroundThe aim of the present study was to investigate the association between brain amyloid β (Aβ) accumulation and cortical microstructural changes in cognitively normal individuals with subjective memory complaints.MethodA total of 258 individuals (100 males,158 females) from the Investigation of Alzheimer’s Predictors in Subjective Memory Complainers (INSIGHT‐preAD) study [Dubois et al., 2018], were included. The 18F‐florbetapir PET images were used to compute whole brain and regional standard uptake value ratios (SUVr), while T1 structural and diffusion tensor imaging (DTI) scans were analysed to calculate 3 novel cortical grey matter diffusion measures (AngleR, PerpPD and ParlPD) and the mean diffusivity (MD) [McKavanagh et al., 2019]. A linear regression model was used to study the association between the global SUVr value and whole brain cortical diffusion measures, by including the diffusion measure as the dependent variable, and age, sex, APOE genotype and global amyloid SUVr as independent predictors. Partial correlation analysis, controlling for sex, was used to investigate regional associations between SUVr and diffusion values in 6 regions of interest (bilateral anterior cingulate, posterior cingulate, frontal superior orbital, inferior parietal, precuneus, middle temporal cortex). Results were considered statistically significant after false discovery rate correction (FDR &lt;0.05).ResultLinear regression revealed that whole brain amyloid SUVr values were positively associated with whole brain AngleR (the angle between the principal diffusion direction and the radial minicolumn direction within the cortical grey matter) (β = 0.23, p&lt;0.001). Regional partial correlations indicated significant associations between SUVr and AngleR regional values in left anterior cingulate cortex (r=0.168;p=0.010) and bilateral precuneus (left r=0.173;p=0.005; right r=0.178;p=0.004).ConclusionThese results showed a significant relationship between Aβ accumulation and cortical architectural change in subjective memory complainers. The regional associations revealed the presence of microstructural changes in key regions commonly affected in the early stage of AD [Palmqvist et al., 2017]. Our novel cortical DTI measures could offer additional information about cortical changes, playing a potential role as index of “neurodegeneration” in the ATN framework [Jack et al., 2018] of Alzheimer’s biomarkers.

Surface‐based amyloid and tau correlates of digital clock drawing performance

AbstractBackgroundUsing a digital pen to record performance on neuropsychological tasks allows for the capture of much more subtle and nuanced aspects of cognitive performance. Previous research showed that lower DCTClock summary score was associated with greater entorhinal tau in clinically‐normal older adults (CN) (Rentz, AAIC 2019). Additionally, spatial reasoning was related to elevated entorhinal tau, inferior temporal tau, and neocortical amyloid. Given the observed cognitive heterogeneity in early stages of AD, we explored the relationship between different aspects of digital clock performance and amyloid and tau pathology across the cortical surface.MethodCN from the Harvard Aging Brain Study completed both a spontaneous (COM) and copy (COP) clock drawing test using a digital pen. We used a summary score (DCTScore) and four main composite scores (drawing efficiency, simple motor, information processing and spatial reasoning) calculated by Digital Cognition Technologies. Participants also underwent [11C]PiB‐PET (n = 112) and [18F]T807‐PET (n = 116) acquisition within one year of cognitive testing. We utilized a vertex‐wise analysis with a cluster‐wise multiple comparison correction (minimum cluster extent=100mm2) and a threshold of ‐log(p)&gt;2 to analyze relationships with clock scores across the vertices, adjusting for age, sex, and education.ResultLower DCTScore strongly correlated with greater amyloid signal in the frontal lobe, with some significant clusters also observed within the lateral temporal and inferior parietal cortices (Figure 1). Lower DCTScore also related to elevated tau signal in the right lateral temporal and inferior parietal lobes. Tau was most strongly associated with COM spatial reasoning score in the right lateral temporal lobe (Figure 2), reflecting known functional associations with this region; this was not reflected with COP spatial reasoning scores.ConclusionIn clinically‐normal older adults, lower scores on clock drawing were associated with greater cortical amyloid and tau. Lower spatial reasoning scores were related to tauopathy, but only in spontaneous clock drawing, supporting the notion that more complex cognitive tasks are compromised earlier in the clinical continuum. More fine‐grained measurements of cognition using digital tasks in relation to neuroimaging markers has the potential to improve our understanding of the pathogenesis of early AD.