scholarly journals Olfactory impairment is related to tau pathology and neuroinflammation in Alzheimer's disease

2020 ◽  
Author(s):  
Julia Klein ◽  
Xinyu Yan ◽  
Aubrey Johnson ◽  
Zeljko Tomljanovic ◽  
James Zou ◽  
...  
Keyword(s):  
Brain Mri ◽  
Temporal Cortex ◽  
Posterior Cingulate Cortex ◽  
Cognitive Status ◽  
Odor Identification ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Olfactory Impairment ◽  
T Tau

Background: Olfactory impairment is evident in Alzheimers disease (AD), however, its precise relationships with in vivo measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET and fifty-three underwent 11C-PBR28 PET to measure tau pathology and neuroinflammation, respectively. Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau) and beta;-amyloid (AB42). Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01). Conclusions: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. That amyloid-positivity and cognitive impairment are independently associated with odor identification suggests that low UPSIT performance may signify risk of AD pathophysiology in cognitively normal individuals and that impaired odor identification is associated with AD and non-AD-related neurodegeneration.

scholarly journals Olfactory Impairment is Related to Tau Pathology and Neuroinflammation in Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Julia Klein ◽  
Xinyu Yan ◽  
Aubrey Johnson ◽  
Zeljko Tomljanovic ◽  
James Zou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Mri ◽  
Amyloid Β ◽  
Cognitive Status ◽  
Odor Identification ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Olfactory Impairment ◽  
T Tau

Background: Olfactory impairment is evident in Alzheimer’s disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ 42). Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p <  0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p <  0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p <  0.01). Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration. NCT Registration Numbers: NCT03373604; NCT02831283

scholarly journals Regional binding of tau and amyloid PET tracers in Down syndrome autopsy brain tissue

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
L. Lemoine ◽  
A. Ledreux ◽  
E. J. Mufson ◽  
S. E. Perez ◽  
G. Simic ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Binding Properties ◽  
Pet Tracers ◽  
Binding Characteristics ◽  
Age Related ◽  
Autopsy Brain Tissue ◽  
Tau Pet

Abstract Introduction Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. Methods Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. Results The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PIB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites. Conclusions This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.

scholarly journals Frontotemporal dementia with the V337M MAPT mutation

Neurology ◽  
2017 ◽  
Vol 88 (8) ◽  
pp. 758-766 ◽  
Author(s):  
Salvatore Spina ◽  
Daniel R. Schonhaut ◽  
Bradley F. Boeve ◽  
William W. Seeley ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Mutation Carrier ◽  
Brain Atrophy ◽  
Brain Mri ◽  
Strong Association ◽  
Paired Helical Filaments ◽  
Structural Mri ◽  
Tau Pathology ◽  
Pet Tracer

Objective:To assess the efficacy of [18F]AV1451 PET in visualizing tau pathology in vivo in a patient with frontotemporal dementia (FTD) associated with the V337M microtubule-associated protein tau (MAPT) mutation.Methods:MAPT mutations are associated with the deposition of hyperphosphorylated tau protein in neurons and glia. The PET tracer [18F]AV1451 binds with high affinity to paired helical filaments tau that comprises neurofibrillary tangles in Alzheimer disease (AD), while postmortem studies suggest lower or absent binding to the tau filaments of the majority of non-AD tauopathies. We describe clinical, structural MRI, and [18F]AV1451 PET findings in a V337M MAPT mutation carrier affected by FTD and pathologic findings in his affected mother and in an unrelated V337M MAPT carrier also affected with FTD. The biochemical similarity between paired helical filament tau in AD and MAPT V337M predicts that the tau pathology associated with this mutation constitutes a compelling target for [18F]AV1451 imaging.Results:We found a strong association between topography and degree of [18F]AV1451 tracer retention in the proband and distribution of tau pathology in the brain of the proband's mother and the unrelated V337M mutation carrier. We also found a significant correlation between the degree of regional MRI brain atrophy and the extent of [18F]AV1451 binding in the proband and a strong association between the proband's clinical presentation and the extent of regional brain atrophy and tau accumulation as assessed by structural brain MRI and [18F]AV1451PET.Conclusion:Our study supports the usefulness of [18F]AV1451 to characterize tau pathology in at least a subset of pathogenic MAPT mutations.

scholarly journals Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012513
Author(s):  
Michel J. Grothe ◽  
Alexis Moscoso ◽  
Nicholas J. Ashton ◽  
Thomas K. Karikari ◽  
Juan Lantero-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Braak Stage ◽  
Neuritic Plaques ◽  
Neurofilament Light ◽  
T Tau

Objective:To study cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method.Methods:We studied ante-mortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized post-mortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC).Results:All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC=0.89[0.79-0.99] and 0.88[0.77-0.99], respectively). Optimal Elecsys biomarker cut-offs were derived at 1097/229/19 pg/ml for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC=0.91[0.86-0.96]) and NfL (AUC=0.93[0.87-0.99]) accurately distinguished pathology-confirmed AD (N=14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (N=4; AUC=0.96[0.88-1.00]), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52-0.98]) and Braak stage (AUC=0.71[0.44-0.98]) as CSF p-tau181.Conclusions:Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in-vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.Classification of Evidence:This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.

Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer’s Disease

2021 ◽  
pp. 1-14
Author(s):  
Ana Baena ◽  
Yamile Bocanegra ◽  
Valeria Torres ◽  
Clara Vila-Castelar ◽  
Edmarie Guzmán-Vélez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Personality Traits ◽  
Autosomal Dominant ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Mutation Carriers ◽  
Imaging Results ◽  
Increased Risk

Background: Greater neuroticism has been associated with higher risk for Alzheimer’s disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology. Objective: To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers. Methods: A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27–46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging. Results: Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels. Conclusion: The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.

scholarly journals Regional binding of tau and amyloid PET tracers in Down Syndrome autopsy brain tissue

2020 ◽  
Author(s):  
Laetitia Lemoine ◽  
Aurelie Ledreux ◽  
Elliott J Mufson ◽  
Sylvia E Perez ◽  
Goran Simic ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Binding Properties ◽  
Pet Tracers ◽  
Binding Characteristics ◽  
Age Related ◽  
Autopsy Brain Tissue ◽  
Tau Pet

Abstract INTRODUCTION: Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PiB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. METHODS: Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. RESULTS: The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PiB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites. CONCLUSIONS: This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.

PET Amyloid and Tau Status Are Differently Affected by Patient Features

2020 ◽  
Vol 78 (3) ◽  
pp. 1129-1136
Author(s):  
Meng-Shan Tan ◽  
Yu-Xiang Yang ◽  
Hui-Fu Wang ◽  
Wei Xu ◽  
Chen-Chen Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Pet ◽  
Tau Pathology ◽  
Clinical Genetic ◽  
Multivariable Logistic Regression Model ◽  
Tau Pet ◽  
Pet Amyloid

Background: Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer’s disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms. Objective: Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status. Methods: We included 372 nondemented elderly from the Alzheimer’s Disease Neuroimaging Initiative cohort. All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels. Results: Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42, APOE ɛ4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels. Conclusion: Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis.

scholarly journals Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Gloria Biechele ◽  
Nicolai Franzmeier ◽  
Tanja Blume ◽  
Michael Ewers ◽  
Jose Medina Luque ◽  
...  
Keyword(s):  
Mouse Models ◽  
Microglial Activation ◽  
Translocator Protein ◽  
Amyloid Pet ◽  
Wild Type ◽  
Tau Pathology ◽  
Female Mice ◽  
Β Amyloid ◽  
The Impact

Abstract Background In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls. Methods TSPO-PET (18F-GE-180) data of C57Bl/6 (wild-type), AppNL-G-F (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The AppNL-G-F group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; 18F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry. Results Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction (T = − 4.171, p < 0.001). The Aβ model AppNL-G-F mice also showed a significant sex × age interaction (T = − 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female AppNL-G-F mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same AppNL-G-F mice indicated no significant sex × age interaction (T = 0.425, p = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction (T = − 0.671, p = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry. Conclusion Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies.

scholarly journals Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum

Neurology ◽  
2018 ◽  
Vol 90 (14) ◽  
pp. e1231-e1239 ◽  
Author(s):  
Lieke H.H. Meeter ◽  
Everard G. Vijverberg ◽  
Marta Del Campo ◽  
Annemieke J.M. Rozemuller ◽  
Laura Donker Kaat ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Corticobasal Syndrome ◽  
Class Iii ◽  
Tau Pathology ◽  
Clinical Value ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Semantic Variant ◽  
T Tau

ObjectiveTo examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort.MethodsCSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS).ResultsNfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t-tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau).ConclusionNfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo.Classification of evidenceThis study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders.

Challenges in Alzheimer’s Disease Diagnostic Work-Up: Amyloid Biomarker Incongruences

2020 ◽  
Vol 77 (1) ◽  
pp. 203-217
Author(s):  
Gemma Lombardi ◽  
Alberto Pupi ◽  
Valentina Bessi ◽  
Cristina Polito ◽  
Sonia Padiglioni ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fdg Pet ◽  
Cognitively Impaired ◽  
Amyloid Pet ◽  
Csf Analysis ◽  
Diagnostic Work ◽  
T Tau ◽  
Work Up

Background: Discordance among amyloid biomarkers is a challenge to overcome in order to increase diagnostic accuracy in dementia. Objectives: 1) To verify that cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio (AβR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aβ42; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AβR and Amy-PET results; 3) to define the suspected underlying pathology of discordant cases using in vivo biomarkers. Method: We retrospectively enrolled 39 cognitively impaired participants in which neuropsychological tests, apolipoprotein E genotype determination, TC/MRI, FDG-PET, Amy-PET, and CSF analysis had been performed. In all cases, CSF analysis was repeated using the automated Lumipulse method. In discordant cases, FDG-PET scans were evaluated visually and using automated classifiers. Results: CSF AβR better agreed with Amy-PET compared to CSF Aβ42 (Cohen’s K 0.431 versus 0.05). Comparisons among groups did not show any difference in clinical characteristics except for age at symptoms onset that was higher in the 6 discordant cases with abnormal CSF AβR values and negative Amy-PET (CSF AβR+/AmyPET–). FDG-PET and all CSF markers (Aβ42, AβR, p-Tau, t-Tau) were suggestive of Alzheimer’s disease (AD) in 5 of these 6 cases. Conclusion: 1) CSF AβR is the CSF amyloid marker that shows the better level of agreement with Amy-PET results; 2) The use of FDG-PET and CSF-Tau markers in CSFAβR+/Amy-PET–discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AβR and negative Amy-PET in symptomatic aged AD patients could be due to the variability in plaques conformation and a negative Amy-PET scan cannot be always sufficient to rule out AD.

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