Diminished Glucose Transport in Alzheimer's Disease: Dynamic PET Studies

Dynamic positron emission tomography with [18F]fluorodeoxyglucose was used in six patients with Alzheimer's disease (AD) and seven healthy age-matched control subjects to estimate the kinetic parameters K1*, k2*, and k3* that describe glucose transport and phosphorylation. A high-resolution tomograph was used to acquire brain uptake data in one tomographic plane, and a radial artery catheter connected to a plastic scintillator was used to acquire arterial input data. A nonlinear iterative least-squares fitting procedure that included terms for the vascular fraction and time delay to the peripheral sampling site was used to fit a three-compartment model to the brain data. Regions studied included frontal, temporal, occipital, and the entire cortex and subcortical white matter. The values obtained for the individual rate constants and regional CMRglc (rCMRglc; calculated using regional values of the rate constants) were higher than those reported previously. A significant (p < 0.05) decrease was found in K1* in frontal and temporal cortex in the AD patients compared with the controls, with values of 0.157 and 0.161 ml/g/min in frontal and temporal cortex, respectively, of controls and 0.127 and 0.126 ml/ g/min in frontal and temporal cortex of the AD patients. rCMRglc was also significantly (p < 0.02) lower in the AD patients than controls in all cortical brain regions. Lower values of k3* were found in all brain regions in the AD patients, although these were not statistically significant. These findings provide evidence of an in vivo abnormality of forward glucose transport in AD. This transport defect, however, is probably not the cause of the diminution in glucose metabolism that has been widely found in AD patients, since a diminution of this magnitude should not lower intracerebral glucose content enough to alter rCMRglc.

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Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01189-4 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Jonathan D. Cherry ◽

Camille D. Esnault ◽

Zachary H. Baucom ◽

Yorghos Tripodis ◽

Bertrand R. Huber ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Chronic Traumatic Encephalopathy ◽

Temporal Cortex ◽

Head Impacts ◽

Hippocampal Subfields ◽

Mild Disease ◽

Tau Isoforms ◽

Ghost Tangles

AbstractChronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

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In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-010-1612-0 ◽

2010 ◽

Vol 38 (2) ◽

pp. 343-351 ◽

Cited By ~ 97

Author(s):

Masamichi Yokokura ◽

Norio Mori ◽

Shunsuke Yagi ◽

Etsuji Yoshikawa ◽

Mitsuru Kikuchi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation ◽

Brain Regions ◽

Amyloid Deposits

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P3-250: The APOE-E4 allele is associated with greater atrophy of the temporal cortex in Alzheimer's disease: An in vivo MRI study

Alzheimer s & Dementia ◽

10.1016/j.jalz.2008.05.1817 ◽

2008 ◽

Vol 4 ◽

pp. T594-T595 ◽

Cited By ~ 1

Author(s):

Michela Pievani ◽

Cristina Testa ◽

Francesca Sabattoli ◽

Matteo Bonetti ◽

Kiralee M. Hayashi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Cortex ◽

E4 Allele ◽

Mri Study

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Investigating Markers of the NLRP3 Inflammasome Pathway in Alzheimer’s Disease: A Human Post-Mortem Study

Genes ◽

10.3390/genes12111753 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1753

Author(s):

Hao Tang ◽

Michael Harte

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Expression ◽

Glial Cell ◽

Nlrp3 Inflammasome ◽

Cell Activation ◽

Temporal Cortex ◽

Activation Markers

Neuroinflammatory mechanisms with glial cell activation have been implicated in the pathogenic process of Alzheimer’s disease (AD). Activation of the NLRP3 inflammasome is an essential component of the neuroinflammatory response. A role for NLRP3 activation in AD is supported by both in vitro and in vivo preclinical studies with little direct investigation of AD brain tissue. RNA expression of genes of three glial cell markers, HLA-DRA, AIF-1 and GFAP; the components of the NLRP3 inflammasome NLRP3, ASC, and caspase-1; and downstream pre-inflammatory cytokines IL-1 β and IL-18, were investigated in the temporal cortex of AD patients and age- and sex-matched controls. Protein expression of GFAP was also assessed. Increases in both mRNA and protein expression were observed for GFAP in AD. There were no significant changes in other NLRP3 activation markers between groups. Our results indicate the involvement of astrocyte activation in AD, particularly in more severe patients. We found no evidence for the specific involvement of the NLRP3 inflammasome.

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Association Between Visual Memory and In Vivo Amyloid and Tau Pathology in Preclinical Autosomal Dominant Alzheimer’s Disease

Journal of the International Neuropsychological Society ◽

10.1017/s1355617720000673 ◽

2020 ◽

pp. 1-9

Author(s):

Yamile Bocanegra ◽

Joshua T. Fox-Fuller ◽

Ana Baena ◽

Edmarie Guzmán-Vélez ◽

Clara Vila-Castelar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Verbal Memory ◽

Visual Memory ◽

Autosomal Dominant ◽

Clinical Symptoms ◽

Temporal Cortex ◽

Inferior Temporal Cortex ◽

Amyloid Burden

Abstract Objective: Visual memory (ViM) declines early in Alzheimer’s disease (AD). However, it is unclear whether ViM impairment is evident in the preclinical stage and relates to markers of AD pathology. We examined the relationship between ViM performance and in vivo markers of brain pathology in individuals with autosomal dominant AD (ADAD). Methods: Forty-five cognitively unimpaired individuals from a Colombian kindred with the Presenilin 1 (PSEN1) E280A ADAD mutation (19 carriers and 26 noncarriers) completed the Rey–Osterrieth Complex Figure immediate recall test, a measure of ViM. Cortical amyloid burden and regional tau deposition in the entorhinal cortex (EC) and inferior temporal cortex (IT) were measured using 11C-Pittsburgh compound B positron emission tomography (PET) and 11F-flortaucipir PET, respectively. Results: Cognitively unimpaired carriers and noncarriers did not differ on ViM performance. Compared to noncarriers, carriers had higher levels of cortical amyloid and regional tau in both the EC and IT. In cognitively unimpaired carriers, greater cortical amyloid burden, higher levels of regional tau, and greater age were associated with worse ViM performance. Only a moderate correlation between regional tau and ViM performance remained after adjusting for verbal memory scores. None of these correlations were observed in noncarriers. Conclusions: Results suggest that AD pathology and greater age are associated with worse ViM performance in ADAD before the onset of clinical symptoms. Further investigation with larger samples and longitudinal follow-up is needed to examine the utility of ViM measures for identifying individuals at high risk of developing dementia later in life.

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Astrocytic TSPO Upregulation Appears Before Microglial TSPO in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-200136 ◽

2020 ◽

Vol 77 (3) ◽

pp. 1043-1056 ◽

Cited By ~ 3

Author(s):

Benjamin B. Tournier ◽

Stergios Tsartsalis ◽

Kelly Ceyzériat ◽

Ben H. Fraser ◽

Marie-Claude Grégoire ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glial Cells ◽

Binding Sites ◽

Temporal Cortex ◽

Population Expansion ◽

Cell Types ◽

Translocator Protein ◽

Cellular Origin

Background: In vivo PET/SPECT imaging of neuroinflammation is primarily based on the estimation of the 18 kDa-translocator-protein (TSPO). However, TSPO is expressed by different cell types which complicates the interpretation. Objective: The present study evaluates the cellular origin of TSPO alterations in Alzheimer’s disease (AD). Methods: The TSPO cell origin was evaluated by combining radioactive imaging approaches using the TSPO radiotracer [125I]CLINDE and fluorescence-activated cell sorting, in a rat model of AD (TgF344-AD) and in AD subjects. Results: In the hippocampus of TgF344-AD rats, TSPO overexpression not only concerns glial cells but the increase is visible at 12 and 24 months in astrocytes and only at 24 months in microglia. In the temporal cortex of AD subjects, TSPO upregulation involved only glial cells. However, the mechanism of this upregulation appears different with an increase in the number of TSPO binding sites per cell without cell proliferation in the rat, and a microglial cell population expansion with a constant number of binding sites per cell in human AD. Conclusion: These data indicate an earlier astrocyte intervention than microglia and that TSPO in AD probably is an exclusive marker of glial activity without interference from other TSPO-expressing cells. This observation indicates that the interpretation of TSPO imaging depends on the stage of the pathology, and highlights the particular role of astrocytes.

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A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0823-2 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 6

Author(s):

Ebru Ercan-Herbst ◽

Jens Ehrig ◽

David C. Schöndorf ◽

Annika Behrendt ◽

Bernd Klaus ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Temporal Cortex ◽

Brain Regions ◽

Phosphorylation Sites ◽

Post Translational Modification ◽

Post Translational Modifications ◽

Small Set ◽

Human Brains

AbstractTau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer’s disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0–I, II or III–IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III–IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

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Comparison of [11C]UCB-J and [18F]FDG PET in Alzheimer’s disease: A tracer kinetic modeling study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211004312 ◽

2021 ◽

pp. 0271678X2110043

Author(s):

Ming-Kai Chen ◽

Adam P Mecca ◽

Mika Naganawa ◽

Jean-Dominique Gallezot ◽

Takuya Toyonaga ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medial Temporal Lobe ◽

Brain Regions ◽

Volume Of Distribution ◽

Synaptic Density ◽

Cognitively Normal ◽

Tracer Kinetic ◽

Suitable Marker

[11C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer’s disease (AD). We compared [11C]UCB-J binding for synaptic density and [18F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K1 or R1 for [11C]UCB-J perfusion, VT (volume of distribution) or DVR to cerebellum for [11C]UCB-J binding to SV2A; and Ki or Ki R to cerebellum for [18F]FDG metabolism. [11C]UCB-J binding and [18F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD –compared to CN participants. However, the magnitude of reduction of [11C]UCB-J binding in neocortical regions was less than that observed with [18F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [11C]UCB-J perfusion showed a similar pattern to [18F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.

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Lower MR-indexed locus coeruleus integrity in autosomal-dominant Alzheimer’s disease is related to cortical tau burden and memory deficits

10.1101/2020.11.16.20232561 ◽

2020 ◽

Author(s):

Martin J. Dahl ◽

Mara Mather ◽

Markus Werkle-Bergner ◽

Briana L. Kennedy ◽

Yuchuan Qiao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Resolution ◽

Locus Coeruleus ◽

Autosomal Dominant ◽

Brain Regions ◽

Cognitive Testing ◽

Autosomal Dominant Alzheimer’S Disease

AbstractAbnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

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COMBINING MACHINE LEARNING WITH AUTOMATED NEMATODE LIFESPAN ANALYSIS TO IDENTIFY MODIFIERS OF ALZHEIMER’S DISEASE

Innovation in Aging ◽

10.1093/geroni/igz038.361 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S96-S96

Author(s):

Joshua Russell ◽

Matt Kaeberlein

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Meta Analysis ◽

Brain Regions ◽

Data Sets ◽

Data Types ◽

C Elegans

Abstract Here we present new computational and experimental methods to leverage the gene expression and neuropathology data collected from several large-scale studies of Alzheimer’s disease . These data sets include diverse data types, including transcriptomics, neuropathology phenotypes such as quantification of amyloid beta plaques and tau tangles in different brain regions, as well as assessments of dementia prior to death. This meta-analysis is a complex undertaking because the available data are from different studies and/or brain regions involving study-specific confounders and/or region-specific biological processes. We have therefore taken neural network and probabilistic computational approaches that reduce the data dimensionality, allowing statistical comparison across all brain samples. These approaches identify gene expression changes that are significantly associated with clinical and neuropathological assessment of Alzheimer’s disease. We then conduct in vivo validation of the genes through genetic screening of C. elegans models of Alzheimer's disease utilizing our automated robotic lifespan analysis platform. This approach allows for the greater leverage of existing Alzheimer’s disease biobank data to identify deep genetic signatures that could help identify new clinical gene-expression markers and pharmacological targets for Alzheimer’s disease.

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