Nasal Extracts from Patients with Alzheimer’s Disease Induce Tau Aggregates in a Cellular Model of Tau Propagation

Background: Emerging evidence indicates that the misfolded tau protein can propagate aggregates between cells in a prion-like manner. This prion activity has been typically studied in brain extracts of patients with Alzheimer’s disease (AD), but not in the olfactory region that can be a potential biomarker in AD. Objective: To investigate the prion seeding activity of tau in nasal mucosa tissues using a cell culture model of tau propagation. Methods: Brain and nasal mucosa homogenates were added to HEK293T cells expressing three repeat or four-repeat domains of tau with the L266V, V337M (3RD *VM-EGFP) and P301L and V377M mutations (4RD *LM) fused to the enhanced green fluorescence protein (EGFP) respectively. We also measured the level of phosphorylated tau (p-tau), total tau (t-tau), and p-tau/t-tau ratio and performed correlation analysis between tau prion activity and the level of tau. Results: We found that brain and nasal tissue homogenates from patients with AD significantly induced tau aggregation in HEK293T cells either expressing tau 3RD *VM-EGFP or 4RD *LM-EGFP compared with control brain and nasal tissue homogenates. The levels of p-tau and p-tau/t-tau ratio were significantly increased in the brain of patients with AD; however, no significant difference was found in nasal tissue compared with their respective control tissue homogenates. Conclusion: These results suggest that the nasal tissues contain tau seeds, similar to the brain, albeit without changes in the levels of p-tau and t-tau. Therefore, a cellular bioassay using nasal tissues would have great potential as an AD biomarker because of the usefulness of nasal tissue biopsy.

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Elevated CSF LRG and Decreased Alzheimer’s Disease Biomarkers in Idiopathic Normal Pressure Hydrocephalus

Journal of Clinical Medicine ◽

10.3390/jcm10051105 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1105

Author(s):

Aleksi Vanninen ◽

Madoka Nakajima ◽

Masakazu Miyajima ◽

Tuomas Rauramaa ◽

Merja Kokki ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Normal Pressure Hydrocephalus ◽

Brain Biopsy ◽

Normal Pressure ◽

Idiopathic Normal Pressure Hydrocephalus ◽

Potential Biomarker ◽

Shunt Response ◽

T Tau ◽

The Brain

Leucine-rich-alpha-2-glykoprotein (LRG) is suggested as a potential biomarker for idiopathic normal pressure hydrocephalus (iNPH). Our goal was to compare the cerebrospinal fluid (CSF) LRG levels between 119 iNPH patients and 33 age-matched controls and with the shunt responses and the brain biopsy Alzheimer’s disease (AD) pathology among the iNPH patients. CSF LRG, Aβ1-42, P-tau181, and T-tau were measured by using commercial ELISAs. The LRG levels in the CSF were significantly increased in the iNPH patients (p < 0.001) as compared to the controls, regardless of the AD pathology. However, CSF LRG did not correlate with the shunt response in contrast to the previous findings. The CSF AD biomarkers, i.e., Aβ1-42, T-tau, and P-tau correlated with the brain biopsy AD pathology as expected but were systematically lower in the iNPH patients when compared to the controls (<0.001). Our findings support that the LRG levels in the CSF are potentially useful for the diagnostics of iNPH, independent of the brain AD pathology, but contrary to previous findings, not for predicting the shunt response. Our findings also suggest a need for specific reference values of the CSF AD biomarkers for the diagnostics of comorbid AD pathology in the iNPH patients.

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Non-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in Alzheimer’s disease

Nature Communications ◽

10.1038/s41467-019-12242-1 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 39

Author(s):

Xavier Hadoux ◽

Flora Hui ◽

Jeremiah K. H. Lim ◽

Colin L. Masters ◽

Alice Pébay ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hyperspectral Imaging ◽

Spectral Difference ◽

Non Invasive ◽

Potential Biomarker ◽

Negative Controls ◽

The Brain ◽

Independent Cohort

Abstract Studies of rodent models of Alzheimer’s disease (AD) and of human tissues suggest that the retinal changes that occur in AD, including the accumulation of amyloid beta (Aβ), may serve as surrogate markers of brain Aβ levels. As Aβ has a wavelength-dependent effect on light scatter, we investigate the potential for in vivo retinal hyperspectral imaging to serve as a biomarker of brain Aβ. Significant differences in the retinal reflectance spectra are found between individuals with high Aβ burden on brain PET imaging and mild cognitive impairment (n = 15), and age-matched PET-negative controls (n = 20). Retinal imaging scores are correlated with brain Aβ loads. The findings are validated in an independent cohort, using a second hyperspectral camera. A similar spectral difference is found between control and 5xFAD transgenic mice that accumulate Aβ in the brain and retina. These findings indicate that retinal hyperspectral imaging may predict brain Aβ load.

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Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319266 ◽

2019 ◽

Vol 90 (7) ◽

pp. 740-746 ◽

Cited By ~ 7

Author(s):

Martha S Foiani ◽

Claudia Cicognola ◽

Natalia Ermann ◽

Ione O C Woollacott ◽

Carolin Heller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Frontotemporal Dementia ◽

Neurodegenerative Disorder ◽

The Novel ◽

Tau Pathology ◽

Total Tau ◽

Significant Difference ◽

T Tau

BackgroundFrontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer’s disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.Methods86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aβ42 level into those likely to have underlying Alzheimer’s disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.ResultsSignificantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.ConclusionsDespite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

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

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00988-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Shan-Shan Wang ◽

Zi-Kai Liu ◽

Jing-Jing Liu ◽

Qing Cheng ◽

Yan-Xia Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Senile Plaques ◽

Disease Stage ◽

Assay Method ◽

Imaging Probe ◽

Asparaginyl Endopeptidase ◽

Potential Biomarker ◽

The Brain

Abstract Background Discovery 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. Results This 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. Conclusions The 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

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Olfactory response as a marker for Alzheimer’s disease: Evidence from perceptual and frontal lobe oscillation coherence deficit

PLoS ONE ◽

10.1371/journal.pone.0243535 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243535

Author(s):

Mohammad Javad Sedghizadeh ◽

Hadi Hojjati ◽

Kiana Ezzatdoost ◽

Hamid Aghajan ◽

Zahra Vahabi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontal Cortex ◽

High Frequency ◽

Medial Temporal Lobe ◽

Spatial Coherence ◽

Olfactory Stimulation ◽

Olfactory Perception ◽

Potential Biomarker ◽

The Brain

High-frequency oscillations of the frontal cortex are involved in functions of the brain that fuse processed data from different sensory modules or bind them with elements stored in the memory. These oscillations also provide inhibitory connections to neural circuits that perform lower-level processes. Deficit in the performance of these oscillations has been examined as a marker for Alzheimer’s disease (AD). Additionally, the neurodegenerative processes associated with AD, such as the deposition of amyloid-beta plaques, do not occur in a spatially homogeneous fashion and progress more prominently in the medial temporal lobe in the early stages of the disease. This region of the brain contains neural circuitry involved in olfactory perception. Several studies have suggested that olfactory deficit can be used as a marker for early diagnosis of AD. A quantitative assessment of the performance of the olfactory system can hence serve as a potential biomarker for Alzheimer’s disease, offering a relatively convenient and inexpensive diagnosis method. This study examines the decline in the perception of olfactory stimuli and the deficit in the performance of high-frequency frontal oscillations in response to olfactory stimulation as markers for AD. Two measurement modalities are employed for assessing the olfactory performance: 1) An interactive smell identification test is used to sample the response to a sizable variety of odorants, and 2) Electroencephalography data are collected in an olfactory perception task with a pair of selected odorants in order to assess the connectivity of frontal cortex regions. Statistical analysis methods are used to assess the significance of selected features extracted from the recorded modalities as Alzheimer’s biomarkers. Olfactory decline regressed to age in both healthy and mild AD groups are evaluated, and single- and multi-modal classifiers are also developed. The novel aspects of this study include: 1) Combining EEG response to olfactory stimulation with behavioral assessment of olfactory perception as a marker of AD, 2) Identification of odorants most significantly affected in mild AD patients, 3) Identification of odorants which are still adequately perceived by mild AD patients, 4) Analysis of the decline in the spatial coherence of different oscillatory bands in response to olfactory stimulation, and 5) Being the first study to quantitatively assess the performance of olfactory decline due to aging and AD in the Iranian population.

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Predicting Alzheimer's Disease Based on Network Topological Latent Representations

Journal of Medical Imaging and Health Informatics ◽

10.1166/jmihi.2020.2915667 ◽

2020 ◽

Vol 10 (3) ◽

pp. 667-671

Author(s):

Jing Sun ◽

Yanhui Ding ◽

Kun Zhao ◽

Haiyan Xu ◽

Yongxin Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Parietal Lobe ◽

Structural Features ◽

Brain Network ◽

Feature Representation ◽

Support Vector ◽

Functional Connection ◽

Potential Biomarker ◽

The Brain

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Right now there is no cure for AD. As we know, the brain structure is constantly changing as it progresses to AD. If we can detect these changes, it may be helpful to discover new biomarkers and early diagnosis of AD. We use the deep learning method DeepWalk to extract the structural features of each subject based on brain function connection. The method takes a brain topology network based on functional connection transformations as input and outputs a potential feature representation for each brain region in the brain network structure. In the current research, a new potential biomarker is found, which is based on a structural feature that can represent changes in brain connectivity. In our experiment, 79 Resting-state fMRI were used from ADNI dataset, including 49 normal controls (NCs) and 30 AD patients. By analyzing the structural features between AD patients and NCs, obvious differences are detected in the temporal lobe, parietal lobe, and frontal lobe. We use a support vector machine (SVM) model to evaluate the performance of these structural features, and its classification performance achieves 80.36% accuracy (specificity = 73.67%, sensitivity = 87.17%). In general, these findings indicate that structural features may be a new potential biomarker between NCs and AD patients.

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Olfactory Response as a Marker for Alzheimer's Disease: Evidence from Perceptual and Frontal Oscillation Coherence Deficit

10.1101/840934 ◽

2019 ◽

Author(s):

Mohammad Javad Sedghizadeh ◽

Hadi Hojjati ◽

Kiana Ezzatdoost ◽

Hamid Aghajan ◽

Zahra Vahabi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontal Cortex ◽

High Frequency ◽

Medial Temporal Lobe ◽

Spatial Coherence ◽

Olfactory Stimulation ◽

Olfactory Perception ◽

Potential Biomarker ◽

The Brain

High-frequency oscillations of the frontal cortex are involved in functions of the brain that fuse processed data from different sensory modules or bind them with elements stored in the memory. These oscillations also provide inhibitory connections to neural circuits that perform lower-level processes. Deficit in the performance of these oscillations has been examined as a marker for Alzheimer's disease (AD). Additionally, the neurodegenerative processes associated with AD, such as the deposition of amyloid-beta plaques, do not occur in a spatially homogeneous fashion and progress more prominently in the medial temporal lobe in the early stages of the disease. This region of the brain contains neural circuitry involved in olfactory perception. Several studies have suggested that olfactory deficit can be used as a marker for early diagnosis of AD. A quantitative assessment of the performance of the olfactory system can hence serve as a potential biomarker for Alzheimer's disease, offering a relatively convenient and inexpensive diagnosis method. This study examines the decline in the perception of olfactory stimuli and the deficit in the performance of high-frequency frontal oscillations in response to olfactory stimulation as markers for AD. Two measurement modalities are employed for assessing the olfactory performance: 1) An interactive smell identification test is used to sample the response to a sizable variety of odorants, and 2) Electrophysiological data are collected in an olfactory perception task with a pair of selected odorants in order to assess the connectivity of frontal cortex regions. Statistical analysis methods are used to assess the significance of selected features extracted from the recorded modalities as Alzheimer's biomarkers. Olfactory decline regressed to age in both healthy and Mild AD groups are evaluated, and single- and multi-modal classifiers are also developed. The novel aspects of this study include: 1) Combining EEG response to olfactory stimulation with behavioral assessment of olfactory perception as a marker of AD, 2) Identification of odorants most significantly affected in Mild AD patients, 3) Identification of odorants which are still adequately perceived by Mild AD patients, 4) Analysis of the decline in the spatial coherence of different oscillatory bands in response to olfactory stimulation, and 5) Being the first study to quantitatively assess the performance of olfactory decline due to aging and AD in the Iranian population.

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Predicting Alzheimer's Disease Based on Network Topological Latent Representations

Journal of Medical Imaging and Health Informatics ◽

10.1166/jmihi.2020.2915 ◽

2020 ◽

Vol 10 (3) ◽

pp. 667-671

Author(s):

Jing Sun ◽

Yanhui Ding ◽

Kun Zhao ◽

Haiyan Xu ◽

Yongxin Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Parietal Lobe ◽

Structural Features ◽

Brain Network ◽

Feature Representation ◽

Support Vector ◽

Functional Connection ◽

Potential Biomarker ◽

The Brain

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Mapping Exchangeable Protons to Monitor Protein Alterations in the Brain of an Alzheimer’s Disease Mouse Model by Using MRI

Current Alzheimer Research ◽

10.2174/1567205015666180911143518 ◽

2018 ◽

Vol 15 (14) ◽

pp. 1343-1353 ◽

Cited By ~ 2

Author(s):

Geon-Ho Jahng ◽

Wonmin Choi ◽

Julius J. Chung ◽

Sang T. Kim ◽

Hak Y. Rhee

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Water Saturation ◽

Chemical Exchange ◽

Magnetization Transfer Ratio ◽

Saturation Power ◽

Significant Difference ◽

Left Thalamus ◽

The Brain

Objective: The study aimed to investigate exchangeable proton signals of Aβ proteins of the brains of Alzheimer’s disease (AD) model mice by using a chemical exchange-sensitive spin-lock (CESL) MR imaging technique. Method: Eight non-transgenic (Tg) mice (5 young and 3 old) and twelve Tg-APPswe/PSdE9 mice (5 young and 7 old) were used in this study. CESL Z-spectra were obtained by using two saturation powers, which were ω1 = 25 Hz with TSL = 3.0 s and ω1 = 500 Hz with TSL = 150 ms, at 71 offsets with uneven intervals between the offset frequencies at Ω = ±7.0 ppm at a 9.4-T animal MRI system. For Zspectrum analyses, regions of interest (ROIs) were drawn in the cortex, hippocampus, and thalamus of both hemispheres. Magnetization transfer ratio asymmetry (MTRasym) curves were obtained from the Zspectra. The Mann-Whitney test was used to compare the MTRasym values between the Tg and non-Tg mice for each offset frequency and for each ROI. Results: The water saturation width of the full Z-spectrum was narrow with the 25-Hz saturation power, but relatively broad with the 500-Hz saturation power. With the 25-Hz CESL saturation power, most of the MTRasym values were negative for 3.5-, 3.0-, 2.0-, and 0.9-ppm offset frequencies and the MTRasym values were significantly different between the control and Tg groups only in the left thalamus region at 3.5 ppm offset (p=0.0487). The MTRasym values were -6% to -7% for both 3.5 and 3.0 ppm, but less than -2% for both 2.0 and 0.9 ppm. With 500-Hz CESL saturation power, all the MTRasym values were positive for the 3.5-, 3.0-, 2.0-, and 0.9-ppm offset frequencies and the MTRasym values were not significantly different between the control and Tg groups at all ROIs and at all offset frequencies. However, a trend towards a significant difference was observed between the control and Tg groups in the right cortex at 3.5 ppm (p=0.0578). The MTRasym values were 6% to 9% for 3.5, 3.0, and 2.0 ppm, but less than 2% for 0.9 ppm. Conclusion: In an in-vivo AD model experiment, MTRasym values increased with the high saturation power than with the low saturation power. The MTRasym values were not significantly different, except in the left thalamus region at 3.5 ppm offset. The CESL technique should be further developed to enable its application in the brain of patients with neurodegenerative diseases.

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Total alpha-synuclein assay in the Cerebro-Spinal-Fluid is of interest in the differential diagnosis between Alzheimer's disease and dementia with Lewy bodies from the prodromal stage

10.21203/rs.3.rs-18905/v1 ◽

2020 ◽

Author(s):

Olivier BOUSIGES ◽

Nathalie Philippi ◽

Thomas Lavaux ◽

Armand Perret-Liaudet ◽

Ingolf Lachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Differential Diagnosis ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Enzyme Linked Immunosorbent Assay ◽

Prodromal Stage ◽

Significant Difference ◽

T Tau

Abstract Background: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage. Methods: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD) and 32 AD patients at the demented stage (AD-d). CSF levels of total alpha-synuclein were assessed using commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer's biomarkers (t-Tau, P-Tau, Aβ42 and Aβ40) were also measured.Results: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels are significantly higher in AD patients than in DLB patients. Interestingly is that the levels seem to be altered from the prodromal stage in both AD and DLB. Furthermore, by dividing the patients according to the profiles of Alzheimer's biomarkers typically found or not for each of the two pathologies and then classifying the patients according to the level of alpha-synuclein, we find that alpha-synuclein levels are elevated not only for AD patients with typical “Alzheimer” profile (i.e. 2 or 3 pathological biomarkers) but also for AD patients with a non-typical “Alzheimer” profile (i.e. none or one pathological biomarker).Conclusions: The modification of total alpha-synuclein levels in the CSF of patients occurs early from the prodromal stage. Moreover, alpha-synuclein assay appears to be of particular interest in the differential diagnosis of AD in cases where the Alzheimer biomarkers do not have a typical profile of the disease, i.e. when there is only one or no pathological biomarker.Trial registration: ClinicalTrials.gov, (AlphaLewyMa, Identifier: NCT01876459)

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