Utility of FDG-PET in diagnosis of Alzheimer-related TDP-43 proteinopathy

ObjectiveTo evaluate FDG-PET as an antemortem diagnostic tool for Alzheimer-related TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy.MethodsWe conducted a cross-sectional neuroimaging–histologic analysis of patients with antemortem FDG-PET and postmortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center and Study of Aging with Alzheimer spectrum pathology. TDP-43-positive status was assigned when TDP-43-immunoreactive inclusions were identified in the amygdala. Statistical parametric mapping (SPM) analyses compared TDP-43-positive (TDP-43[+]) with TDP-43-negative cases (TDP-43[−]), correcting for field strength, sex, Braak neurofibrillary tangle, and neuritic plaque stages. Cross-validated logistic regression analyses were used to determine whether regional FDG-PET values predict TDP-43 status. We also assessed the ratio of inferior temporal to medial temporal (IMT) metabolism as this was proposed as a biomarker of hippocampal sclerosis.ResultsOf 73 cases, 27 (37%) were TDP-43(+), of which 6 (8%) had hippocampal sclerosis. SPM analysis showed TDP-43(+) cases having greater hypometabolism of medial temporal, frontal superior medial, and frontal supraorbital (FSO) regions (punc < 0.001). Logistic regression analysis showed only FSO and IMT to be associated with TDP-43(+) status, identifying up to 81% of TDP-43(+) cases (p < 0.001). An IMT/FSO ratio was superior to the IMT in discriminating TDP-43(+) cases: 78% vs 48%, respectively.ConclusionsAlzheimer-related TDP-43 proteinopathy is associated with hypometabolism in the medial temporal and frontal regions. Combining FDG-PET measures from these regions may be useful for antemortem prediction of Alzheimer-related TDP-43 proteinopathy.Classification of evidenceThis study provides Class II evidence that hypometabolism in the medial temporal and frontal regions on FDG-PET is associated with Alzheimer-related TDP-43 proteinopathy.

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Brain α-tocopherol concentration is inversely associated with neurofibrillary tangle counts in brain regions affected in earlier Braak stages: A cross-sectional finding in the oldest old

Journal of Aging Research and Lifestyle ◽

10.14283/jarlife.2021.2 ◽

2021 ◽

pp. 1-9

Author(s):

J. Tanprasertsuk ◽

T.M. Scott ◽

M.A. Johnson ◽

L.W. Poon ◽

P.T. Nelson ◽

...

Keyword(s):

Vitamin E ◽

Oldest Old ◽

Neurofibrillary Tangle ◽

Brain Structures ◽

Brain Regions ◽

Phase Iii ◽

Neuritic Plaque ◽

Tocopherol Concentration ◽

Cross Sectional ◽

Braak Staging

Objectives: Higher vitamin E status has been associated with lower risk of Alzheimer’s disease (AD). However, evidence of the association of vitamin E concentration in neural tissue with AD pathologies is limited. Design: The cross-sectional relationship between the human brain concentrations of α- and γ-tocopherol and the severity of AD pathologies – neurofibrillary tangle (NFT) and neuritic plaque (NP) – was investigated. Setting & Participants: Brains from 43 centenarians (≥ 98 years at death) enrolled in the Phase III of the Georgia Centenarian Study were collected at autopsy. Measurements: Brain α- and γ-tocopherol concentrations (previously reported) were averaged from frontal, temporal, and occipital cortices. NP and NFT counts (previously reported) were assessed in frontal, temporal, parietal, entorhinal cortices, amygdala, hippocampus, and subiculum. NFT topological progression was assessed using Braak staging. Multiple linear regression was performed to assess the relationship between tocopherol concentrations and NP or NFT counts, with and without adjustment for covariates. Results: Brain α-tocopherol concentrations were inversely associated with NFT but not NP counts in amygdala (β = -2.67, 95% CI [-4.57, -0.79]), entorhinal cortex (β = -2.01, 95% CI [-3.72, -0.30]), hippocampus (β = -2.23, 95% CI [-3.82, -0.64]), and subiculum (β = -2.52, 95% CI [-4.42, -0.62]) where NFT present earlier in its topological progression, but not in neocortices. Subjects with Braak III-IV had lower α-tocopherol (median = 69,622 pmol/g, IQR = 54,389-72,155 pmol/g) than those with Braak I-II (median = 72,108 pmol/g, IQR = 64,056-82,430 pmol/g), but the difference was of borderline significance (p = 0.063). γ-Tocopherol concentrations were not associated with either NFT or NP counts in any brain regions assessed. Conclusions: Higher brain α-tocopherol level is specifically associated with lower NFT counts in brain structures affected in earlier Braak stages. Our findings emphasize the possible importance of α-tocopherol intervention timing in tauopathy progression and warrant future clinical trials.

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18F-FDG-PET patterns of surgical success and failure in mesial temporal lobe epilepsy

Neurology ◽

10.1212/wnl.0000000000003714 ◽

2017 ◽

Vol 88 (11) ◽

pp. 1045-1053 ◽

Cited By ~ 28

Author(s):

Francine Chassoux ◽

Eric Artiges ◽

Franck Semah ◽

Agathe Laurent ◽

Elisabeth Landré ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Fdg Pet ◽

Hippocampal Sclerosis ◽

Statistical Parametric Mapping ◽

Mesial Temporal Lobe Epilepsy ◽

Epileptogenic Zone ◽

Metabolic Pattern ◽

Suboptimal Outcome ◽

Mesial Temporal Lobe

Objective:To search for [18F]-fluorodeoxyglucose (FDG)-PET patterns predictive of long-term prognosis in surgery for drug-resistant mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis (HS).Methods:We analyzed metabolic data with [18F]-FDG-PET in 97 patients with MTLE (53 female participants; age range 15–56 years) with unilateral HS (50 left) and compared the metabolic patterns, electroclinical features, and structural atrophy on MRI in patients with the best outcome after anteromesial temporal resection (Engel class IA, completely seizure-free) to those with a non-IA outcome, including suboptimal outcome and failure. Imaging processing was performed with statistical parametric mapping (SPM5).Results:With a mean follow-up of >6 years (range 2–14 years), 85% of patients achieved a class I outcome, including 45% in class IA. Class IA outcome was associated with a focal anteromesial temporal hypometabolism, whereas non-IA outcome correlated with extratemporal metabolic changes that differed according to the lateralization: ipsilateral mesial frontal and perisylvian hypometabolism in right HS and contralateral fronto-insular hypometabolism and posterior white matter hypermetabolism in left HS. Suboptimal outcome presented a metabolic pattern similar to the best outcome but with a larger involvement of extratemporal areas, including the contralateral side in left HS. Failure was characterized by a mild temporal involvement sparing the hippocampus and relatively high extratemporal hypometabolism on both sides. These findings were concordant with electroclinical features reflecting the organization of the epileptogenic zone but were independent of the structural abnormalities detected on MRI.Conclusions:[18F]-FDG-PET patterns help refine the prognostic factors in MTLE and should be implemented in predictive models for epilepsy surgery.

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Microglia Activation in the Brain as Inflammatory Biomarker of Alzheimer’s Disease Neuropathology and Clinical Dementia

Disease Markers ◽

10.1155/2006/276239 ◽

2006 ◽

Vol 22 (1-2) ◽

pp. 95-102 ◽

Cited By ~ 65

Author(s):

Zhongmin Xiang ◽

Vahram Haroutunian ◽

Lap Ho ◽

Dushant Purohit ◽

Giulio Maria Pasinetti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Layer ◽

Neurofibrillary Tangle ◽

Microglia Activation ◽

Postmortem Brain ◽

Neuritic Plaque ◽

Clinical Dementia Rating ◽

Inflammatory Biomarker ◽

Hla Dr

The role of microglia-mediated inflammation in the progression of Alzheimer’s disease (AD) neuropathology remains unclear. In this study, postmortem brain sections from AD and control cases were subjected to Human Leukocyte Antigen (HLA)-DR immunohistochemistry to examine microglia activation in the progression of AD assessed by pre-mortem clinical dementia rating (CDR) and postmortem pathological manifestations of neuritic plaque (NP) and neurofibrillary tangle (NT) according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). In both gray and white matter of the entorhinal cortex (EC) and HLA-DR immunostaining increased with the progression of CDR or CERAD NP, and to a lesser degree with CERAD NT. Between CDR stages HLA-DR significance was found in moderate (CDR 2) to severe dementia (CDR 5) where as between CERAD NP stages staining increased significantly from NP 0 (no plaque) to NP 1 (sparse plaques), suggesting increased microglia activation begins with amyloid NP deposition. In the hippocampus, a significant increase in microglia immunostaining was found in the pyramidal cell layer of CA1 as early as CDR 1, and in the upper molecular layer of the dentate gyrus in CDR 0.5. This increase continues with the progression of CDR and reaches maximum in CDR 5. When assessed by CERAD NP stages however, a significant increase in microglia immunostaining was found only in mid-to-late stages (NP 3) and reduced staining was seen in NP 5. These results suggest that microglia activation increases with the progression of AD, with the increase varying depending on the involved brain region.

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Dietary carotenoids related to risk of incident Alzheimer dementia (AD) and brain AD neuropathology: a community-based cohort of older adults

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqaa303 ◽

2020 ◽

Vol 113 (1) ◽

pp. 200-208

Author(s):

Changzheng Yuan ◽

Hui Chen ◽

Yamin Wang ◽

Julie A Schneider ◽

Walter C Willett ◽

...

Keyword(s):

Sex Education ◽

Neurofibrillary Tangle ◽

Cox Proportional Hazards ◽

Activity Level ◽

Postmortem Brain ◽

Neuritic Plaque ◽

Inverse Association ◽

Total Carotenoids ◽

Diagnostic Score ◽

Alzheimer Dementia

ABSTRACT Background Studies have reported a protective relation to cognitive decline with long-term intake of total and individual dietary carotenoids. However, the underlying mechanisms have not yet been clearly established in humans. Objectives To evaluate the prospective association between intakes of total and individual carotenoids and risk of incident Alzheimer dementia (AD) and explore the underlying neuropathological basis. Methods Among 927 participants from the Rush Memory and Aging Project who were free from AD at baseline and were followed up for a mean of 7 y, we estimated HRs for AD using Cox proportional hazards models by intakes of energy-adjusted carotenoids. Brain AD neuropathology was assessed in postmortem brain autopsies among 508 deceased participants. We used linear regression to assess the association of carotenoid intake with AD-related neuropathology. Results Higher intake of total carotenoids was associated with substantially lower hazard of AD after controlling for age, sex, education, ApoE-ε4, participation in cognitively stimulating activities, and physical activity level. Comparing the top and bottom quintiles (median intake: 24.8 compared with 6.7 mg/d) of total carotenoids, the multivariate HR (95% CI) was 0.52 (0.33, 0.81), P-trend < 0.01. A similar association was observed for lutein-zeaxanthin, a weaker linear inverse association was observed for β-carotene, and a marginally significant linear inverse association was found for β-cryptoxanthin. Among the deceased participants, consumers of higher total carotenoids (top compared with bottom tertile, 18.2 compared with 8.2 mg/d) had less global AD pathology (b: −0.10; SE = 0.04; P-trend = 0.01). For individual carotenoids, lutein-zeaxanthin and lycopene were inversely associated with brain global pathology, whereas lutein-zeaxanthin showed additional inverse associations with AD diagnostic score, neuritic plaque severity, and neurofibrillary tangle density and severity. Conclusions Our findings support a beneficial role of total carotenoid consumption, in particular lutein/zeaxanthin, on AD incidence that may be related to the inhibition of brain β-amyloid deposition and fibril formation.

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BDNF-trkB signaling in late life cognitive decline and Alzheimer’s disease

Translational Neuroscience ◽

10.2478/s13380-011-0015-4 ◽

2011 ◽

Vol 2 (2) ◽

Cited By ~ 7

Author(s):

Hoau-Yan Wang ◽

Andres Stucky ◽

Chang-Gyu Hahn ◽

Robert Wilson ◽

David Bennett ◽

...

Keyword(s):

Cognitive Decline ◽

Signaling Pathway ◽

Neurofibrillary Tangle ◽

Anterior Cingulate ◽

Postmortem Brain ◽

Downstream Signaling ◽

Postmortem Brain Tissue ◽

Neurotrophin Signaling ◽

Neurodegenerative Dementias ◽

Stimulation Paradigm

AbstractExpression levels of BDNF and trkB, primary components of an important neurotrophin signaling pathway, have been reported to be abnormal in neurodegenerative dementias. Here, we used a novel postmortem brain tissue stimulation paradigm to examine BDNF-induced trkB signaling in participants of the Religious Orders Study, a large longitudinal clinicopathological study of aging and cognition. Thawed slices of anterior cingulate cortex were incubated in BDNF and changes in phosphorylated trkB and downstream signaling molecules ERK2 and Akt were measured, as well as the association of NMDA receptors with trkB. We found that stimulation with BDNF induced much greater activity of the BDNF-trkB signaling pathway in brain tissues of people with cognitive decline and AD, as evidenced by significantly more phosphorylation of trkB (pY-trkB), ERK2 (pY/pT-ERK2), Akt (pS-Akt), and greater BDNF-induced coupling of trKB with NMDAR2A/B. These findings were independent of PHFtau neurofibrillary tangle and amyloid-b plaque densities and other potentially confounding variables. Regression analyses with clinical features further characterized significant relationships between measures of BDNF-trkB activation and domains of cognition and emotional functioning. Increased BDNF-trkB signaling with cognitive decline could reflect a primary derangement of pathway functioning or a compensatory neuroplastic response to counteract neural injury associated with neurodegenerative processes.

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Tau protein aggregation induces cellular senescence in the brain

10.1101/369074 ◽

2018 ◽

Cited By ~ 1

Author(s):

Nicolas Musi ◽

Joseph M. Valentine ◽

Kathryn R. Sickora ◽

Eric Baeuerle ◽

Cody S. Thompson ◽

...

Keyword(s):

Cellular Senescence ◽

Tau Protein ◽

Expression Patterns ◽

Neurofibrillary Tangle ◽

Postmortem Brain ◽

Brain Diseases ◽

Surrounding Tissue ◽

Protein Accumulation ◽

Postmortem Brain Tissue ◽

The Brain

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others1. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss, yet the mechanisms mediating tau toxicity are poorly understood. NFT-containing neurons do not die, which suggests secondary mechanisms are driving toxicity2. We evaluated gene expression patterns of NFT-containing neurons microdissected from AD patient brains3 and found they develop an expression profile consistent with cellular senescence described in dividing cells. This complex stress response induces a near permanent cell cycle arrest, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction4. Moreover, senescent cells induce chronic degeneration of surrounding tissue through the secretion of pro-inflammatory, pro-apoptotic molecules termed the senescence-associated secretory phenotype (SASP)5. Using transgenic mouse models of tau-associated pathogenesis we found that NFTs induced a senescence-like phenotype including DNA damage, karyomegaly, mitochondrial dysfunction and SASP. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT load. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, senolytic treatment reduced total NFT burden, neuron loss and ventricular enlargement; and normalized cerebral blood flow to that of non-transgenic control mice. Collectively, these findings indicate that NFTs induce cellular senescence in the brain, which contributes to neurodegeneration and brain dysfunction. Moreover, given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

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Classification of Alzheimer’s and MCI Patients from Semantically Parcelled PET Images: A Comparison between AV45 and FDG-PET

International Journal of Biomedical Imaging ◽

10.1155/2018/1247430 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Seyed Hossein Nozadi ◽

Samuel Kadoury ◽

Keyword(s):

Fdg Pet ◽

Classification Accuracy ◽

Patient Specific ◽

Cross Sectional ◽

Registration Method ◽

Slowing Down ◽

Positron Emission ◽

Late Stages

Early identification of dementia in the early or late stages of mild cognitive impairment (MCI) is crucial for a timely diagnosis and slowing down the progression of Alzheimer’s disease (AD). Positron emission tomography (PET) is considered a highly powerful diagnostic biomarker, but few approaches investigated the efficacy of focusing on localized PET-active areas for classification purposes. In this work, we propose a pipeline using learned features from semantically labelled PET images to perform group classification. A deformable multimodal PET-MRI registration method is employed to fuse an annotated MNI template to each patient-specific PET scan, generating a fully labelled volume from which 10 common regions of interest used for AD diagnosis are extracted. The method was evaluated on 660 subjects from the ADNI database, yielding a classification accuracy of 91.2% for AD versus NC when using random forests combining features from cross-sectional and follow-up exams. A considerable improvement in the early versus late MCI classification accuracy was achieved using FDG-PET compared to the AV-45 compound, yielding a 72.5% rate. The pipeline demonstrates the potential of exploiting longitudinal multiregion PET features to improve cognitive assessment.

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Correlation of Amyloid PET Ligand Florbetapir F 18 Binding With Aβ Aggregation and Neuritic Plaque Deposition in Postmortem Brain Tissue

Alzheimer Disease & Associated Disorders ◽

10.1097/wad.0b013e31821300bc ◽

2012 ◽

Vol 26 (1) ◽

pp. 8-16 ◽

Cited By ~ 80

Author(s):

Seok Rye Choi ◽

Julie A. Schneider ◽

David A. Bennett ◽

Thomas G. Beach ◽

Barry J. Bedell ◽

...

Keyword(s):

Brain Tissue ◽

Postmortem Brain ◽

Neuritic Plaque ◽

Amyloid Pet ◽

Plaque Deposition ◽

Postmortem Brain Tissue ◽

Aβ Aggregation

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Golgin A4 in CSF and granulovacuolar degenerations of patients with Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000006457 ◽

2018 ◽

Vol 91 (19) ◽

pp. e1799-e1808 ◽

Cited By ~ 4

Author(s):

Felix Kork ◽

Joachim Jankowski ◽

Anand Goswami ◽

Joachim Weis ◽

Gary Brook ◽

...

Keyword(s):

Alzheimer Disease ◽

Diagnostic Marker ◽

Characteristic Curve ◽

Treatment Strategies ◽

Postmortem Brain ◽

Class Iii ◽

Granulovacuolar Degeneration ◽

Direct Role ◽

Postmortem Brain Tissue

ObjectiveTo isolate and identify a new, as yet unknown molecule in CSF that could serve as marker for Alzheimer disease.MethodsWe immunized mice with human CSF and fused hybridomas for monoclonal antibodies and screened these antibodies for their capacity to discriminate CSF of patients with Alzheimer disease from CSF of controls. We then chromatographically isolated the antigen to the best discriminating antibody and identified the antigen using mass spectrometric methods. Thereafter, we quantified the CSF concentration of the antigen in a new cohort of patients with Alzheimer disease and controls and performed immunohistochemistry of postmortem brain tissue derived from patients with Alzheimer disease and controls.ResultsWe generated >200 hybridomas and selected 1 antibody that discriminated CSF from patients with Alzheimer disease from that of controls. We identified golgin A4 as the antigen detected by this antibody. Golgin A4 concentration was significantly higher in CSF from patients with Alzheimer disease than in CSF of controls (145 [interquartile range 125–155] vs 115 [ 99–128] pg/mL, p < 0.001) and demonstrated a substantial discriminative power (area under the receiver operating characteristic curve 0.80, 95% confidence interval 0.67–0.94). Immunohistochemistry of postmortem brain sections from patients with Alzheimer disease revealed a significant accumulation of golgin A4 in granulovacuolar degeneration bodies (GVBs).ConclusionsThese results support the notion that golgin A4 could serve as a diagnostic marker in Alzheimer disease. For validation of this notion, prospective multicenter diagnostic studies will evaluate golgin A4 as diagnostic marker for Alzheimer disease. Furthermore, it has to be determined whether the association of golgin A4 with GVBs is an epiphenomenon or whether golgin A4 plays a more direct role in Alzheimer disease, allowing it to serve as a target in therapeutic treatment strategies.Classification of evidenceThis study provides Class III evidence that elevated CSF golgin A4 levels identify patients with Alzheimer disease.

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