Karl Herholz

Karl Herholz
The University of Manchester · Wolfson Molecular Imaging Centre

About

565
Publications
35,421
Reads
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28,506
Citations
Citations since 2016
50 Research Items
8443 Citations
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201620172018201920202021202202004006008001,0001,200
201620172018201920202021202202004006008001,0001,200
Additional affiliations
June 2005 - present
The University of Manchester
Position
  • Professor (Full)

Publications

Publications (565)
Article
Full-text available
Amyloid-beta (Aβ) deposition is common in cognitively unimpaired (CU) elderly >85 years. This study investigated amyloid distribution and evaluated three published in vivo amyloid-PET staging schemes from a cognitively unimpaired (CU) cohort aged 84.9 ± 4.3 years (n = 75). SUV-based principal component analysis (PCA) was applied to 18F-flutemetamol...
Article
Full-text available
There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of...
Article
Full-text available
A 65-year-old man was referred to a local memory clinic with memory complaints but clinical assessment found no abnormalities. When he presented two years later to our clinic social disinhibition, reduced empathy, poor judgment and hoarding had become obvious. He showed no insight. He had ischemic heart disease and was on preventive treatment. His...
Chapter
Positron emission tomography (PET) is increasingly contributing to diagnosis and management decision in patients with brain tumours and especially gliomas. Through the use of FDG, amino acid tracers ([¹¹C]-methionine, [¹⁸F]-fluoro-ethyl-tyrosine and [¹⁸F]-fluorodopa) and [¹⁸F]-fluorothymidine, PET contributes to diagnosis as well as planning and mo...
Article
Previous studies have shown that systemic TNFα is associated with increased disease progression in AD and that this may be modulated by the anti‐TNFα agent Etanercept. The effect of Etanercept on microglial activation in patients with MCI due to AD is unknown. A total of 13 patients (from a planned 46 patients) with a clinical diagnosis of MCI due...
Article
Neuroinflammation, a key early pathomechanistic alteration of Alzheimer's disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a l...
Article
Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However,...
Article
Full-text available
β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer's disease (AD). A robust body of evidence demonstrates an associ...
Preprint
Full-text available
Purpose: The combination of positron emission tomography (PET) with magnetic resonance imaging (MRI) may enable novel research in the field of dementia. MR data is commonly used in the analysis of PET data for dementia due to its anatomical information and good soft tissue contrast. PET image reconstruction is currently performed independently of M...
Article
Once first Alzheimer's disease (AD) disease-modifying therapies will become available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers needs to be advanced. Besides establ...
Article
Background Activated microglia play a complex role in neuroinflammation associated with acute ischaemic stroke. As a potential target for anti-inflammatory therapy, it is crucial to understand the association between intensity, extent and the clinical outcome of a stroke. The 18-kDa translocator protein is a marker of cerebral microglial activation...
Article
p>Almost 50 million people worldwide are affected by Alzheimer’s disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. T...
Article
Full-text available
Introduction: Successful development of effective β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudi...
Article
Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative protei...
Article
Introduction: Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. / Methods: We investigated whether plasma concentrations of the Aβ1–40/Aβ1–42 ratio, assessed using t...
Article
Introduction: Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the Aβ1-40/Aβ1-42 ratio, assessed using...
Article
Full-text available
Introduction: Molecular, functional, and structural neuroimaging biomarkers are largely used to study neurodegenerative diseases, but their benefits to patients/science might be greatly enhanced by improving standardization and cross-validation. In this EU Joint Programme-Neurodegenerative Diseases Research-funded project, we surveyed the neuroima...
Article
Full-text available
Objectives With the tools available currently, confirming the diagnosis of inclusion body myositis (IBM) can be difficult. Many patients are initially misdiagnosed with polymyositis (PM). In this observational study at a UK adult neuromuscular centre, we investigated whether amyloid positron emission tomography could differentiate between IBM and P...
Article
Full-text available
Purpose The PET tracer [18F]florbetapir is a specific fibrillar amyloid-beta (Aβ) biomarker. During the late scan phase (> 40 min), it provides pathological information about Aβ status. Early scan phase (0–10 min) can provide FDG-‘like’ information. The current investigation tested the feasibility of using florbetapir as a dual-phase biomarker in b...
Article
Astrocytic contributions to Alzheimer's disease (AD) progression were, until recently, largely overlooked. Astrocytes are integral to normal brain function and astrocyte reactivity is an early feature of AD, potentially providing a promising target for preclinical diagnosis and treatment. Several in vivo AD biomarkers already exist, but presently t...
Article
Full-text available
Background The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilienc...
Article
Full-text available
Background: Amyloid pathology is the pathological hallmark in Alzheimer's disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to fi...
Article
Full-text available
The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the...
Poster
Full-text available
Validation of a realistic simulation of the HRRT using SimSET
Conference Paper
Full-text available
Monte-Carlo simulations of the High Resolution Research Tomograph (HRRT) (Siemens/CTI HRRT PET brain scanner) were developed and conducted using SimSET. We were interested in conducting simulations with comparable resolution to that of a real HRRT in order to investigate partial volume correction. A series of test objects were simulated including p...
Article
The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. Ho...
Article
The use of biomarkers has been proposed for diagnosing Alzheimer's disease in recent criteria, but some biomarkers have not been sufficiently investigated to justify their routine clinical use. Here, we evaluate in a literature review the clinical validity of amyloid positron emission tomography (PET) imaging using a structured framework developed...
Article
The use of biomarkers (BMs) for accurate diagnosis of Alzheimer's disease (AD) has been proposed by recent diagnostic criteria; however, their maturity is not sufficient to grant implementation in the clinical routine. A proper diagnostic process requires not only confirmation of the disease but also the exclusion of similar disorders entering diff...
Article
The use of Alzheimer's disease (AD) biomarkers is supported in diagnostic criteria, but their maturity for clinical routine is still debated. Here, we evaluate brain fluorodeoxyglucose positron emission tomography (FDG PET), a measure of cerebral glucose metabolism, as a biomarker to identify clinical and prodromal AD according to the framework sug...
Article
Full-text available
Objective: To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early-onset Alzheimer's disease. Background: Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language s...
Conference Paper
Background Translocator protein (TSPO) is overexpressed mainly in activated microglia under disease conditions. [11C]-(R)PK11195 is a radioligand for TSPO widely applied in PET studies. Previously we have found upregulated TSPO in neoplastic cells and its correlation with malignant transformation in human gliomas using [11C]-(R)PK11195 PET and neur...
Article
Clinical variants of Alzheimer's disease (AD) include the common amnestic subtype as well as subtypes characterised by leading visual processing impairments or by multimodal neurocognitive deficits. We investigated regional metabolic patterns and networks between AD subtypes. The study comprised 9 age-matched controls and 25 patients with mild to m...
Article
A previous review published in 2012 demonstrated the role of clinical PET for diagnosis and management of brain tumors using mainly FDG, amino acid tracers, and ¹⁸F-fluorothymidine. This review provides an update on clinical PET studies, most of which are motivated by prediction of prognosis and planning and monitoring of therapy in gliomas. For FD...
Article
Full-text available
Impairment of brain-glucose uptake and brain-copper regulation occurs in Alzheimer's disease (AD). Here we sought to further elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage. We employed mass spectrometry (MS) to measure metabolites and...
Article
Full-text available
Positron emission tomography (PET) alone or in combination with MRI is increasingly assuming a central role in the development of diagnostic and therapeutic strategies for brain tumours with the aim of addressing tumour heterogeneity, assisting in patient stratification, and contributing to predicting treatment response. The 18 kDa translocator pro...
Conference Paper
Aim: The analysis of human brain PET scans with tracers binding to the 18-kDa mitochondrial translocator protein (TSPO) is hampered by the absence of an anatomical brain region free of specific binding. We previously reported a comparison between two referencing approaches, cerebellar grey matter (GM) reference input function and supervised cluster...
Article
Full-text available
There is evolving evidence that individuals categorized with subjective cognitive decline (SCD) are potentially at higher risk for developing objective and progressive cognitive impairment compared to cognitively healthy individuals without apparent subjective complaints. Interestingly, SCD, during advancing preclinical Alzheimer's disease (AD), ma...
Article
Full-text available
In vivo imaging of brain amyloid using positron emission tomography (PET) scanning is widely used in research studies of dementia, with three amyloid PET ligands being licenced for clinical use. The main clinical use of PET is to help confirm or exclude the likely diagnosis of Alzheimer's disease in challenging cases, where diagnostic uncertainty r...
Article
Full-text available
Background Imaging biomarkers for Alzheimer's disease include medial temporal lobe atrophy (MTLA) depicted on computed tomography (CT) or magnetic resonance imaging (MRI) and patterns of reduced metabolism on fluorodeoxyglucose positron emission tomography (FDG-PET).AimsTo investigate whether MTLA on head CT predicts the diagnostic usefulness of an...
Article
Full-text available
The 18-kDa mitochondrial translocator protein (TSPO) is up-regulated in high grade astrocytomas and can be imaged by positron emission tomography (PET) using the selective radiotracer (11)C-(R)PK11195. We investigated (11)C-(R)PK11195 binding in human gliomas and its relationship with TSPO expression in tumor tissue and glioma associated microglia/...
Article
Pathological deposition of amyloid β (Aβ) protein is a key component in the pathogenesis of Alzheimer's disease (AD), but not a feature of frontotemporal dementia (FTD). PET ligands for Aβ protein are increasingly used in diagnosis and research of dementia syndromes. Here we report a PET study using (18)F-florbetapir in healthy control subjects and...
Chapter
Neurodegenerative disorders represent a substantial and growing burden on patients and healthcare systems worldwide. Most neurodegenerative disorders are associated with intracellular or extracellular inclusions consisting of pathological protein deposits, which accumulate in specific brain regions. These pathological changes are associated with di...
Article
Brain imaging with glucose ((18)F-FDG) PET or blood flow (hexamethylpropyleneamine oxime) SPECT is widely used for the differential diagnosis of dementia, though direct comparisons to clearly establish superiority of one method have not been undertaken. Subjects with Alzheimer disease (AD; n = 38) and dementia with Lewy bodies (DLB; n = 30) and con...
Article
Full-text available
Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication...
Article
Aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subsca...
Article
FDG PET is a powerful method for detection of disease---related impairment of cerebral glucose metabolism in neurodegenerative diseases. It is of particular interest for early and differential diagnosis of dementia. Reading FDG PET scans requires training to recognise deviations from normal functional brain anatomy and its variations. This paper pr...
Article
Positron emission tomography (PET) with FDG or amyloid tracers is an important diagnostic tool, which also provides imaging biomarkers for patient selection in therapeutic trials in Alzheimer’s disease. PET is also a quantitative technique with the potential to measure disease severity and progression. Limitations in spatial resolution result in pa...
Article
Unlabelled: There are specific dose recommendations for diagnostic amyloid PET imaging with 18F-florbetapir, but they may not apply to research studies using regional quantitative analysis. We, therefore, studied the effect of tracer dose reduction on the discriminative power of regional analysis. Methods: Using bootstrap resampling of list-mode...
Chapter
Positron emission tomography (PET) is increasingly contributing to diagnosis and management decision in patients with brain tumours and especially gliomas. Through the use of FDG, amino acid tracers (11C-methionine, 18F-fluoroethyltyrosine and 18F-fluorodopa) and 18F-fluoro-thymidine, PET can contribute to accurate tumour grading and targeting of b...
Article
The severe cognitive deficits in Alzheimer disease are associated with structural lesions in gray and white matter in addition to changes in synaptic function. The current investigation studied the breakdown of the structure and function in regional networks involving the Papez circuit and extended neocortical association areas. Cortical volumetric...