scholarly journals Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

Neurology ◽  
2020 ◽  
Vol 96 (1) ◽  
pp. e81-e92
Author(s):  
Joseph Therriault ◽  
Tharick A. Pascoal ◽  
Melissa Savard ◽  
Andrea L. Benedet ◽  
Mira Chamoun ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Clinical Symptoms ◽  
Characteristic Curve ◽  
Tertiary Care ◽  
Amyloid Β ◽  
Executive Dysfunction ◽  
Anterior Cingulate ◽  
Amyloid Pet ◽  
Clinical Criteria ◽  
Tau Pet

ObjectiveTo determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity– and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI, and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.

scholarly journals Frequency of biologically-defined AD in relation to age, sex, APOEε4 and cognitive impairment

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011416
Author(s):  
Joseph Therriault ◽  
Tharick A. Pascoal ◽  
Andrea L. Benedet ◽  
Cecile Tissot ◽  
Melissa Savard ◽  
...  
Keyword(s):  
Positive Predictive Value ◽  
Clinical Diagnosis ◽  
Predictive Value ◽  
Tertiary Care ◽  
Amyloid Β ◽  
Elderly Subjects ◽  
Complete Agreement ◽  
Amyloid Pet ◽  
Memory Clinics ◽  
Tau Pet

Objective:To assess the frequency of biologically-defined Alzheimer’s disease (AD) in relation to age, sex, APOEε4, and clinical diagnosis in a prospective cohort study evaluated with amyloid-PET and tau-PET.Methods:We assessed cognitively unimpaired (CU) elderly (n=166), amnestic MCI (n=77) and probable AD dementia (n=62) subjects who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [18F]AZD4694 and tau-PET with [18F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically-defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles were assessed using logistic regressions with odds ratios and 95% CIs.Results:The clinical diagnosis of probable AD dementia demonstrated good agreement with biologically-defined AD (positive predictive value: 85.2%). 7.88% of CU elderly subjects were positive for both amyloid-PET and tau-PET. Frequency of biologically-defined AD increased with age (OR: 1.14; p<0.0001) and frequency of APOEε4 allele carriers (Single ε4: OR: 3.82; p<0.0001; Double ε4: OR: 17.55, p<0.0001).Discussion:While we observed strong, but not complete, agreement between clinically-defined “probable AD” dementia and biomarker positivity for both amyloid-β and tau, we also observed that biologically-defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically-defined AD and related entities.Classification of evidence:This study provides Class I evidence that biologically-defined AD (abnormal amyloid PET and tau PET) was observed in 85.2% of people with clinically defined AD and 7.88% of cognitively unimpaired elderly.

scholarly journals Current and Future Treatments in Alzheimer Disease: An Update

2020 ◽  
Vol 12 ◽  
pp. 117957352090739 ◽  
Author(s):  
Konstantina G Yiannopoulou ◽  
Sokratis G Papageorgiou
Keyword(s):  
Alzheimer Disease ◽  
Clinical Symptoms ◽  
Neurofibrillary Tangle ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Amyloid Β ◽  
Cell Therapies ◽  
Novel Biomarkers ◽  
Disease Modifying ◽  
Underlying Mechanisms

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

scholarly journals Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease

Neurology ◽  
2018 ◽  
Vol 91 (9) ◽  
pp. e859-e866 ◽  
Author(s):  
Andrew J. Aschenbrenner ◽  
Brian A. Gordon ◽  
Tammie L.S. Benzinger ◽  
John C. Morris ◽  
Jason J. Hassenstab
Keyword(s):  
Alzheimer Disease ◽  
Executive Functioning ◽  
Episodic Memory ◽  
Cognitive Decline ◽  
Hippocampal Volume ◽  
Cognitive Change ◽  
Pet Scan ◽  
Cognitive Domain ◽  
Amyloid Pet ◽  
Tau Pet

ObjectiveTo examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline.MethodsA total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (18F-AV-1451) tau PET scan, a florbetapir (18F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed.ResultsResults from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning.ConclusionsTogether, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression.

Elevated Tau PET Signal Depends on Abnormal Amyloid Levels and Correlates with Cognitive Impairment in Elderly Persons without Dementia

2020 ◽  
Vol 78 (1) ◽  
pp. 395-404 ◽  
Author(s):  
Rui-Qi Zhang ◽  
Shi-Dong Chen ◽  
Xue-Ning Shen ◽  
Yu-Xiang Yang ◽  
Jia-Ying Lu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Executive Function ◽  
Amyloid Β ◽  
Amyloid Pet ◽  
Elderly Persons ◽  
Cross Sectional ◽  
Memory Decline ◽  
Tau Pet

Background: The recent developed PET ligands for amyloid-β (Aβ) and tau allow these two neuropathological hallmarks of Alzheimer’s disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. Objective: To assess the associations among Aβ, tau, and cognition in non-demented subjects. Methods: Three hundred eighty-nine elderly participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aβ and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory and executive function were measured. Results: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aβ+ but not Aβ– subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. Conclusion: These findings suggested PET-detectable Aβ plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented subjects.

scholarly journals Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012410
Author(s):  
Alexandra L Young ◽  
Martina Bocchetta ◽  
Lucy L. Russell ◽  
Rhian S. Convery ◽  
Georgia Peakman ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Temporal Lobe ◽  
Clinical Symptoms ◽  
Neuropsychological Test ◽  
Temporal Cortex ◽  
Executive Dysfunction ◽  
Underlying Disease ◽  
Anterior Cingulate ◽  
Mutation Carriers ◽  
One To One

Background and Objective:Mutations in the MAPT gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of MAPT mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. However, the variability in atrophy patterns between each particular MAPT mutation is less well characterised. We aimed to investigate whether there were distinct groups of MAPT mutation carriers based on their neuroanatomical signature.Methods:We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterise patterns of regional atrophy in MAPT-associated FTD within the Genetic FTD Initiative (GENFI) cohort study.Results:82 MAPT mutation carriers were analysed, the majority of whom had P301L, IVS10+16 or R406W mutations, along with 48 healthy non-carriers. SuStaIn identified two groups of MAPT mutation carriers with distinct atrophy patterns: a ‘temporal’ subtype in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex and insula, and a ‘frontotemporal’ subtype in which atrophy was more localised to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was a one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype, and a near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction.Discussion:Our results demonstrate that different MAPT mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology, and potential utility for patient stratification in therapeutic trials.

scholarly journals Association of Tau Pathology With Clinical Symptoms in the Subfields of Hippocampal Formation

2021 ◽  
Vol 13 ◽  
Author(s):  
Xinting Ge ◽  
Dan Zhang ◽  
Yuchuan Qiao ◽  
Jiong Zhang ◽  
Junhai Xu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Executive Function ◽  
Clinical Symptoms ◽  
Acquisition Time ◽  
Amyloid Pet ◽  
Hippocampal Subfields ◽  
Assessment Scores ◽  
Tau Pet ◽  
The Relationship

Objective: To delineate the relationship between clinical symptoms and tauopathy of the hippocampal subfields under different amyloid statuses.Methods: One hundred and forty-three subjects were obtained from the ADNI project, including 87 individuals with normal cognition, 46 with mild cognitive impairment, and 10 with Alzheimer’s disease (AD). All subjects underwent the tau PET, amyloid PET, T1W, and high-resolution T2W scans. Clinical symptoms were assessed by the Neuropsychiatric Inventory (NPI) total score and Alzheimer’s Disease Assessment Scale cognition 13 (ADAS-cog-13) total score, comprising memory and executive function scores. The hippocampal subfields including Cornu Ammonis (CA1–3), subiculum (Sub), and dentate gyrus (DG), as well as the adjacent para-hippocampus (PHC) and entorhinal cortex (ERC), were segmented automatically using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. The relationship between tauopathy/volume of the hippocampal subfields and assessment scores was calculated using partial correlation analysis under different amyloid status, by controlling age, gender, education, apolipoprotein E (APOE) allele ɛ4 carrier status, and, time interval between the acquisition time of tau PET and amyloid PET scans.Results: Compared with amyloid negative (A−) group, individuals from amyloid positive (A+) group are more impaired based on the Mini-mental State Examination (MMSE; p = 3.82e-05), memory (p = 6.30e-04), executive function (p = 0.0016), and ADAS-cog-13 scores (p = 5.11e-04). Significant decrease of volume (CA1, DG, and Sub) and increase of tau deposition (CA1, Sub, ERC, and PHC) of the hippocampal subfields of both hemispheres were observed for the A+ group compared to the A- group. Tauopathy of ERC is significantly associated with memory score for the A- group, and the associated regions spread into Sub and PHC for the A+ group. The relationship between the impairment of behavior or executive function and tauopathy of the hippocampal subfield was discovered within the A+ group. Leftward asymmetry was observed with the association between assessment scores and tauopathy of the hippocampal subfield, which is more prominent for the NPI score for the A+ group.Conclusion: The associations of tauopathy/volume of the hippocampal subfields with clinical symptoms provide additional insight into the understanding of local changes of the human HF during the AD continuum and can be used as a reference for future studies.

scholarly journals Tau PET: the next frontier in molecular imaging of dementia

2016 ◽  
Vol 28 (9) ◽  
pp. 1403-1406 ◽  
Author(s):  
Chenjie Xia ◽  
Bradford C. Dickerson
Keyword(s):  
Molecular Imaging ◽  
Amyloid Β ◽  
Amyloid Pet ◽  
Paired Helical Filament ◽  
Prodromal Ad ◽  
Dementia Research ◽  
Tau Pet ◽  
Potential Impact ◽  
First Time ◽  
Amyloid Pet Imaging

We have arrived at an exciting juncture in dementia research: the second major pathological hallmark of Alzheimer's disease (AD)–tau–can now be seen for the first time in the living human brain. The major proteinopathies in AD include amyloid-β plaques and neurofibrillary tangles (NFTs) made of hyperphosphorylated paired helical filament (PHF) tau. Since its advent more than a decade ago, amyloid PET imaging has revolutionized the field of dementia research, enabling more confident diagnosis of the likely pathology in patients with a variety of clinical dementia syndromes, paving the way for the identification of people with preclinical or prodromal AD pathology, and serving as a minimally invasive molecular readout in clinical trials of putative disease-modifying interventions. Now that we are on the brink of a second revolution in molecular imaging in dementia, it is worth considering the likely potential impact of this development on the field.

scholarly journals The implications of different approaches to define AT(N) in Alzheimer disease

Neurology ◽  
2020 ◽  
Vol 94 (21) ◽  
pp. e2233-e2244 ◽  
Author(s):  
Niklas Mattsson-Carlgren ◽  
Antoine Leuzy ◽  
Shorena Janelidze ◽  
Sebastian Palmqvist ◽  
Erik Stomrud ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Cognitive Decline ◽  
Clinical Stage ◽  
Hippocampal Volume ◽  
Cognitively Impaired ◽  
Amyloid Pet ◽  
Prognostic Information ◽  
Neurofilament Light ◽  
Amyloid Aβ ◽  
Tau Pet

ObjectiveTo compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies.MethodsA total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aβ42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation.ResultsAmong CU participants, A−T−(N)− or A+T−(N)− variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.ConclusionsOur findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.

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 Clinical aspects for differential diagnosis of Kawasaki disease shock syndrome: a case control study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Woo Young Park ◽  
Sang Yun Lee ◽  
Gi Beom Kim ◽  
Mi Kyoung Song ◽  
Hye Won Kwon ◽  
...  
Keyword(s):  
Septic Shock ◽  
Differential Diagnosis ◽  
Clinical Symptoms ◽  
Characteristic Curve ◽  
Laboratory Finding ◽  
Laboratory Data ◽  
Treatment Guideline ◽  
Coronary Aneurysm ◽  
Clinical Aspects ◽  
Clinical Criteria

Abstract Background Because of the absence of a specific diagnostic test and pathognomonic clinical features, physicians must rely on the presence of specific clinical criteria and laboratory data that support the diagnosis of KD. To help clinicians distinguish KD, KDSS, septic shock, and TSS earlier, we suggest differential diagnosis and treatment guideline. Methods Medical records of immunocompetent patients who were admitted to the pediatric department with a diagnosis of KDSS, septic shock or TSS (SS group) were retrospectively reviewed. In addition, KD patients were selected by seasonal matching to each case of KDSS patient by date of admission (± 2 weeks). Results There were 13 patients with KDSS, 35 patients with SS group, and 91 patients with KD. In comparison between KDSS and septic shock group, KDSS group had significantly higher rate of coronary aneurysm incidence, and higher left ventricle dysfunction rate. In comparison between KDSS and TSS, patients with KDSS had a significantly higher erythrocyte sedimentation rate (ESR) and significantly lower creatinine. Receiver operation characteristic curve revealed that the optimal ESR cut off value for determining the KDSS was 56.0 (sensitivity 75.0%, specificity of 100.0%) and the optimal creatinine cut off value for determining the TSS was 0.695 (sensitivity 76.9%, specificity 84.6%). Conclusions Clinical symptoms, laboratory finding, echocardiography, and culture studies can be used to differentiate KD, KDSS, septic shock and TSS.

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