scholarly journals Asymmetric Amyloid-β Burden and Neurodegeneration in Late-Onset Alzheimer’s Disease Dementia

2021 ◽  
Vol 39 (3) ◽  
pp. 197-201
Author(s):  
Joonho Lee ◽  
Hong Nam Kim ◽  
Min Hye Kim ◽  
In Ja Shin ◽  
Keun Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Amyloid Deposition ◽  
Positron Emission ◽  
Amyloid Load ◽  
Cortical Regions ◽  
The Right

We report herein a 78-year-old woman with insidiously progressive cognitive impairment and asymmetric amyloid deposition and neurodegeneration. Brain magnetic resonance imaging revealed remarkable atrophy in the right-sided temporal lobe and hippocampus. Early dynamic <sup>18</sup>F-flutemetamol brain amyloid positron-emission tomography images showed decreased uptake in the right temporoparietal regions. Delayed images revealed amyloid deposition which was most remarkable in the right frontotemporoparietal regions. Asymmetries of amyloid burden and neuronal dysfunction are positively correlated in Alzheimer’s disease in cortical regions with high amyloid load.

Associations of Neprilysin Activity in CSF with Biomarkers for Alzheimer’s Disease

2019 ◽  
Vol 19 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Timo Grimmer ◽  
Oliver Goldhardt ◽  
Igor Yakushev ◽  
Marion Ortner ◽  
Christian Sorg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fdg Pet ◽  
Amyloid Β ◽  
Neuronal Injury ◽  
Pittsburgh Compound B ◽  
Positron Emission ◽  
Amyloid Load ◽  
Alzheimer’S Pathology

Background: Neprilysin (NEP) cleaves amyloid-β 1–42 (Aβ42) in the brain. Hence, we aimed to elucidate the effect of NEP on Aβ42 in cerebrospinal fluid (CSF) and on in vivo brain amyloid load using amyloid positron emission tomography (PET) with [11C]PiB (Pittsburgh compound B). In addition, associations with the biomarkers for neuronal injury, CSF-tau and FDG-PET, were investigated. Methods: Associations were calculated using global and voxel-based (SPM8) linear regression analyses in the same cohort of 23 highly characterized Alzheimer’s disease patients. Results: CSF-NEP was significantly inversely associated with CSF-Aβ42 and positively with the extent of neuronal injury as measured by CSF-tau and FDG-PET. Conclusions: Our results on CSF-NEP are compatible with the assumption that local degradation, amongst other mechanisms of amyloid clearance, plays a role in the development of Alzheimer’s pathology. In addition, CSF-NEP is associated with the extent and the rate of neurodegeneration.

scholarly journals Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

2021 ◽  
Vol 39 (3) ◽  
pp. 214-218
Author(s):  
Min Hye Kim ◽  
Joonho Lee ◽  
Hong Nam Kim ◽  
In Ja Shin ◽  
Keun Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Early Onset ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Emission Tomography ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Positron Emission

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed <sup>18</sup>F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

scholarly journals Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load

2021 ◽  
Author(s):  
Valeria Calsolaro ◽  
Paul M. Matthews ◽  
Cornelius K. Donat ◽  
Nicholas R. Livingston ◽  
Grazia D. Femminella ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Late Onset ◽  
Visual Assessment ◽  
Glial Fibrillary Acid Protein ◽  
Pet Tracer ◽  
Positron Emission ◽  
Cortical Regions

Abstract11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

scholarly journals Principal components of tau positron emission tomography and longitudinal tau accumulation in Alzheimer’s disease

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Hanna Cho ◽  
Min Seok Baek ◽  
Hye Sun Lee ◽  
Jae Hoon Lee ◽  
Young Hoon Ryu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Distribution Pattern ◽  
Principal Components ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Emission Tomography ◽  
Longitudinal Changes ◽  
Positron Emission

Abstract Background We aimed to investigate the clinical correlates of principal components (PCs) of tau positron emission tomography (PET) and their predictability for longitudinal changes in tau accumulation in Alzheimer’s disease (AD). Methods We enrolled 272 participants who underwent two PET scans [18F-flortaucipir for tau and 18F-florbetaben for amyloid-β (Aβ)], brain magnetic resonance imaging, and neuropsychological tests as baseline assessments. Among them, 187 participants underwent the same follow-up assessments after an average of 2 years. Using Aβ-positive AD dementia-specific PCs obtained from the baseline scans of 56 Aβ-positive patients with AD dementia, we determined the expression of the first two PCs (PC1 and PC2) in all participants. We assessed the correlation of PC expression with baseline clinical characteristics and tau accumulation rates. Moreover, we investigated the predictability of PCs for the longitudinal tau accumulation in training and test sets. Results PC1 corresponded to the tau distribution pattern in AD, while the two PC2 extremes reflected the parietal or temporal predominance of tau distribution. PC1 expression increased with tau burden and decreased with cognitive impairment, while PC2 expression decreased with advanced age and visuospatial and attention function deterioration. The tau accumulation rate was positively correlated with PC1 expression (greater tau burden) and negatively correlated with PC2 expression (temporal predominance). A regression model using both PCs could predict longitudinal changes in the tau burden (intraclass correlation coefficient = 0.775, R2 = 0.456 in test set). Conclusions PC analysis of tau PET could be useful for evaluating disease progression, characterizing the tau distribution pattern, and predicting longitudinal tau accumulation.

Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

2018 ◽  
Vol 15 (4) ◽  
pp. 386-398 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Cognitive Decline ◽  
Enzyme Inhibitors ◽  
Late Onset ◽  
Amyloid Β ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

scholarly journals Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

GeroScience ◽  
2021 ◽  
Author(s):  
Caitlin S. Latimer ◽  
Nicole F. Liachko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Hippocampal Sclerosis ◽  
Model Organism ◽  
Amyloid Β ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Biology ◽  
Rapid Cognitive Decline

AbstractAlzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

scholarly journals Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

2021 ◽  
Vol 11 (2) ◽  
pp. 215
Author(s):  
Donovan A. McGrowder ◽  
Fabian Miller ◽  
Kurt Vaz ◽  
Chukwuemeka Nwokocha ◽  
Cameil Wilson-Clarke ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Late Onset ◽  
Amyloid Β ◽  
Current Evidence ◽  
Csf Biomarkers ◽  
Diagnostic Efficacy ◽  
Neurofilament Light ◽  
New Biomarkers

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

scholarly journals Comparison of Amyloid β and Tau Spread Models in Alzheimer’s Disease

2018 ◽  
Vol 29 (10) ◽  
pp. 4291-4302 ◽  
Author(s):  
Hang-Rai Kim ◽  
Peter Lee ◽  
Sang Won Seo ◽  
Jee Hoon Roh ◽  
Minyoung Oh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Amyloid Β ◽  
Brain Network ◽  
Amyloid Positron Emission Tomography ◽  
Local Spread ◽  
Positron Emission ◽  
Spread Model ◽  
Graph Theoretical Approach

Abstract Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer’s disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models’ performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.

The Trajectory of Cerebrospinal Fluid Growth-Associated Protein 43 in the Alzheimer’s Disease Continuum: A Longitudinal Study

2021 ◽  
pp. 1-12
Author(s):  
Heng Zhang ◽  
Diyang Lyu ◽  
Jianping Jia ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Dementia Patients ◽  
Positron Emission ◽  
Potential Biomarker ◽  
Synaptic Degeneration ◽  
Over Time

Background: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods: CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

scholarly journals Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

2020 ◽  
Vol 12 (534) ◽  
pp. eaaz4069 ◽  
Author(s):  
Kamalini G. Ranasinghe ◽  
Jungho Cha ◽  
Leonardo Iaccarino ◽  
Leighton B. Hinkley ◽  
Alexander J. Beagle ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Tracer Uptake ◽  
Therapeutic Approaches ◽  
Regional Patterns ◽  
Positron Emission ◽  
Network Synchrony ◽  
Network Disruptions

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer’s disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

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