Publications by authors named "Alexander Gerhard"

52 Publications

Differential early subcortical involvement in genetic FTD within the GENFI cohort.

Neuroimage Clin 2021 Mar 29;30:102646. Epub 2021 Mar 29.

Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.

Background: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups.

Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more).

Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9-10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2-3%), hippocampus (particularly presubiculum and CA1, 2-3%), amygdala (all subregions, 2-6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3-4%) and amygdala (accessory basal and superficial nuclei, 2-4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%).

Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.
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http://dx.doi.org/10.1016/j.nicl.2021.102646DOI Listing
March 2021

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

Neurology 2021 Apr 7. Epub 2021 Apr 7.

Julio C. Rojas, University of California, San Francisco, San Francisco, CA, USA Ping Wang, University of California, San Francisco, San Francisco, CA, USA Adam M. Staffaroni, University of California, San Francisco, San Francisco, CA, USA Carolin Heller, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Yann Cobigo University of California, San Francisco, San Francisco, CA, USA Amy Wolf, University of California, San Francisco, San Francisco, CA, USA Sheng-Yang M. Goh, University of California, San Francisco, San Francisco, CA, USA Peter A. Ljubenkov, University of California, San Francisco, San Francisco, CA, USA Hilary W. Heuer, University of California, San Francisco, San Francisco, CA, USA Jamie C. Fong, University of California, San Francisco, San Francisco, CA, USA Joanne B. Taylor, University of California, San Francisco, San Francisco, CA, USA Eliseo Veras, Quanterix Corporation, Lexington, MA, USA Linan Song, Quanterix Corporation, Lexington, MA, USA Andreas Jeromin, Quanterix Corporation, Lexington, MA, USA David Hanlon, Quanterix Corporation, Lexington, MA, USA Lili Yu, Novartis Institutes for Biomedical Research Inc, Cambridge, MA, USA Arvind Kinhikar, Novartis Institutes for Biomedical Research Inc, Cambridge, MA, USA Rajeev Sivasankaran, Novartis Institutes for Biomedical Research Inc, Cambridge, MA, USAAgnieszka Kieloch, Novartis Pharma AG, Basel, Switzerland Marie-Anne Valentin, Novartis Pharma AG, Basel, Switzerland Anna M. Karydas, University of California, San Francisco, San Francisco, CA, USA Laura L. Mitic, University of California, San Francisco, San Francisco, CA, USA and Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA, USA Rodney Pearlman, Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA, USA John Kornak, University of California, San Francisco, San Francisco, CA, USA Joel H. Kramer, University of California, San Francisco, San Francisco, CA, USA Bruce L. Miller, University of California, San Francisco, San Francisco, CA, USA Kejal Kantarci, Mayo Clinic, Rochester, MN, USA David S. Knopman, Mayo Clinic, Rochester, MN, USA Neill Graff-Radford, Mayo Clinic, Jacksonville, FL, USA Leonard Petrucelli, Mayo Clinic, Jacksonville, FL, USA Rosa Rademakers, Mayo Clinic, Jacksonville, FL, USA David J. Irwin, University of Pennsylvania, Philadelphia, PA, USA Murray Grossman, University of Pennsylvania, Philadelphia, PA, USA Eliana Marisa Ramos, University of California, Los Angeles, Los Angeles, CA, USA Giovanni Coppola, University of California, Los Angeles, Los Angeles, CA, USA Mario F. Mendez, University of California, Los Angeles, Los Angeles, CA, USA Yvette Bordelon, University of California, Los Angeles, Los Angeles, CA, USA Bradford C. Dickerson, Harvard University/Massachusetts General Hospital, Boston, MA, USA Nupur Ghoshal, Washington University, St. Louis, MO, US Edward D. Huey, Columbia University, New York, NY, USA Ian R. Mackenzie, University of British Columbia, Vancouver, British Columbia, Canada Brian S. Appleby, Case Western Reserve University, Cleveland, OH, USA Kimiko Domoto-Reilly, University of Washington, Seattle, WA, USA Ging-Yuek R. Hsiung, University of British Columbia, Vancouver, British Columbia, Canada Arthur W. Toga, Laboratory of Neuroimaging, University of Southern California, Los Angeles, CA, USA Sandra Weintraub, Northwestern University, Chicago, IL, USA Daniel I. Kaufer, University of North Carolina, Chapel Hill, NC, USA Diana Kerwin, Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA Irene Litvan, University of California, San Diego, San Diego, CA, USA Chiadikaobi U. Onyike, Johns Hopkins Hospital, Baltimore, MD, USA Alexander Pantelyat, Johns Hopkins Hospital, Baltimore, MD, USA Erik D. Roberson, University of Alabama, Birmingham, AL, USA Maria C. Tartaglia, University of Toronto, ON, Canada Tatiana Foroud, Indiana University School of Medicine, Indianapolis, IN, USA Weiping Chen, Biogen Inc., Cambridge, MA, USA Julie Czerkowicz, Biogen Inc., Cambridge, MA, USA Danielle L. Graham, Biogen Inc., Cambridge, MA, USA John C. van Swieten, Erasmus Medical Centre, Rotterdam, Netherlands Barbara Borroni, University of Brescia, Brescia, Italy Raquel Sanchez-Valle, University of Barcelona, Barcelona, Spain Fermin Moreno, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain Robert Laforce, Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, QC, Canada Caroline Graff, Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden and Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden Matthis Synofzik, University of Tübingen, Tübingen, Germany and Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany Daniela Galimberti, Fondazione IRCCS Ospedale Policlinico, Milan, Italy and University of Milan, Centro Dino Ferrari, Milan, Italy James B. Rowe, Department of Clinical Neurosciences and Cambridge University Hospital, University of Cambridge, Cambridge, UK Mario Masellis, University of Toronto, ON, Canada Elizabeth Finger, University of Western Ontario, London, ON, Canada Rik Vandenberghe, KU Leuven, Leuven, Belgium and Neurology Service, University Hospitals Leuven, BelgiumAlexandre de Mendonça, University of Lisbon, Lisbon, Portugal Fabrizio Tagliavini, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyIsabel Santana, University of Coimbra, Coimbra, Portugal Simon Ducharme, McGill University, Montreal, Québec, Canada Chris R. Butler, University of Oxford, Oxford, UK Alexander Gerhard, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK and University of Duisburg-Essen, Germany Johannes Levin, Ludwig-Maximilians-Universität München, Munich, Germany and German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Adrian Danek, Ludwig-Maximilians-Universität München, Munich, Germany Markus Otto, University of Ulm, Ulm, Germany Sandro Sorbi, University of Florence, Florence, Italy David M. Cash, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Rhian S. Convery, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Martina Bocchetta, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Martha Foiani, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Caroline V. Greaves, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Georgia Peakman, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Lucy Russell, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Imogen Swift, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Emily Todd, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Jonathan D. Rohrer, UK Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK Bradley F. Boeve, Mayo Clinic, Rochester, MN, USA Howard J. Rosen, University of California, San Francisco, San Francisco, CA, USA Adam L. Boxer, MD, University of California, San Francisco, San Francisco, CA, USA.

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with Simoa in original (n = 277) and validation (n = 297) cohorts. , and mutation carriers and non-carriers from the same families were classified by disease severity [asymptomatic, prodromal and full phenotype] using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to non-progressors (original: 11.4 ± 7 pg/mL vs. 6.7 ± 5 pg/mL, = 0.002; validation: 14.1 ± 12 pg/mL vs. 8.7 ± 6 pg/mL, = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression, and is a potential tool to select participants for prevention clinical trials.

Classification Of Evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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http://dx.doi.org/10.1212/WNL.0000000000011848DOI Listing
April 2021

Does increased microglial activation lead to faster progression in PSP?

J Neurol Neurosurg Psychiatry 2021 Mar 17. Epub 2021 Mar 17.

Wolfson Molecular Imaging Centre, Division of Neuroscience and Experimental Psychology, The University of Manchester, Manchester, Manchester, UK

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http://dx.doi.org/10.1136/jnnp-2020-325980DOI Listing
March 2021

Pharyngeal Pumping and Tissue-Specific Transgenic P-Glycoprotein Expression Influence Macrocyclic Lactone Susceptibility in .

Pharmaceuticals (Basel) 2021 Feb 13;14(2). Epub 2021 Feb 13.

Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, 14163 Berlin, Germany.

Macrocyclic lactones (MLs) are widely used drugs to treat and prevent parasitic nematode infections. In many nematode species including a major pathogen of foals, , resistance against MLs is widespread, but the underlying resistance mechanisms and ML penetration routes into nematodes remain unknown. Here, we examined how the -glycoprotein efflux pumps, candidate genes for ML resistance, can modulate drug susceptibility and investigated the role of active drug ingestion for ML susceptibility in the model nematode . Wildtype or transgenic worms, modified to overexpress PGP-9 (-PGP-9) at the intestine or epidermis, were incubated with ivermectin or moxidectin in the presence (bacteria or serotonin) or absence (no specific stimulus) of pharyngeal pumping (PP). Active drug ingestion by PP was identified as an important factor for ivermectin susceptibility, while moxidectin susceptibility was only moderately affected. Intestinal -PGP-9 expression elicited a protective effect against ivermectin and moxidectin only in the presence of PP stimulation. Conversely, epidermal -PGP-9 expression protected against moxidectin regardless of PP and against ivermectin only in the absence of active drug ingestion. Our results demonstrate the role of active drug ingestion by nematodes for susceptibility and provide functional evidence for the contribution of -glycoproteins to ML resistance in a tissue-specific manner.
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http://dx.doi.org/10.3390/ph14020153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917992PMC
February 2021

Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia.

JAMA Netw Open 2021 01 4;4(1):e2030194. Epub 2021 Jan 4.

Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD.

Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD.

Design, Setting, And Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic.

Main Outcomes And Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation.

Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease course (51.7%-100% of patients). Patients with MAPT variants showed the highest frequency and severity of most behavioral symptoms, particularly disinhibition (79.3%-100% of patients) and compulsive behavior (64.3%-100% of patients), compared with C9orf72 carriers (51.7%-95.8% of patients with disinhibition and 34.5%-75.0% with compulsive behavior) and GRN carriers (38.2%-100% with disinhibition and 20.6%-100% with compulsive behavior). Alongside behavioral symptoms, neuropsychiatric symptoms were very frequently reported in patients with genetic FTD: anxiety and depression were most common in GRN carriers (23.8%-100% of patients) and MAPT carriers (26.1%-77.8% of patients); hallucinations, particularly auditory and visual, were most common in C9orf72 carriers (10.3%-54.5% of patients). Most behavioral and neuropsychiatric symptoms increased in the early-intermediate phases and plateaued in the late stages of disease, except for depression, which steadily declined in C9orf72 carriers, and depression and anxiety, which surged only in the late stages in GRN carriers.

Conclusions And Relevance: This cohort study suggests that behavioral and neuropsychiatric disturbances differ between the common FTD gene variants and have different trajectories throughout the course of disease. These findings have crucial implications for counseling patients and caregivers and for the design of disease-modifying treatment trials in genetic FTD.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788468PMC
January 2021

Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes.

Alzheimers Dement 2020 Dec 14. Epub 2020 Dec 14.

Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.

Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy.

Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling.

Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions.

Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.
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http://dx.doi.org/10.1002/alz.12252DOI Listing
December 2020

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia.

Alzheimers Dement 2021 03 20;17(3):500-514. Epub 2020 Nov 20.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Introduction: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD).

Methods: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset.

Results: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease.

Discussion: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.
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http://dx.doi.org/10.1002/alz.12209DOI Listing
March 2021

The P-glycoprotein repertoire of the equine parasitic nematode Parascaris univalens.

Sci Rep 2020 08 12;10(1):13586. Epub 2020 Aug 12.

Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.

P-glycoproteins (Pgp) have been proposed as contributors to the widespread macrocyclic lactone (ML) resistance in several nematode species including a major pathogen of foals, Parascaris univalens. Using new and available RNA-seq data, ten different genomic loci encoding Pgps were identified and characterized by transcriptome-guided RT-PCRs and Sanger sequencing. Phylogenetic analysis revealed an ascarid-specific Pgp lineage, Pgp-18, as well as two paralogues of Pgp-11 and Pgp-16. Comparative gene expression analyses in P. univalens and Caenorhabditis elegans show that the intestine is the major site of expression but individual gene expression patterns were not conserved between the two nematodes. In P. univalens, PunPgp-9, PunPgp-11.1 and PunPgp-16.2 consistently exhibited the highest expression level in two independent transcriptome data sets. Using RNA-Seq, no significant upregulation of any Pgp was detected following in vitro incubation of adult P. univalens with ivermectin suggesting that drug-induced upregulation is not the mechanism of Pgp-mediated ML resistance. Expression and functional analyses of PunPgp-2 and PunPgp-9 in Saccharomyces cerevisiae provide evidence for an interaction with ketoconazole and ivermectin, but not thiabendazole. Overall, this study established reliable reference gene models with significantly improved annotation for the P. univalens Pgp repertoire and provides a foundation for a better understanding of Pgp-mediated anthelmintic resistance.
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http://dx.doi.org/10.1038/s41598-020-70529-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423980PMC
August 2020

Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration.

J Neurol Neurosurg Psychiatry 2020 09 7;91(9):975-984. Epub 2020 Aug 7.

Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.

Objectives: The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers.

Methods: The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (), progranulin () or microtubule-associated protein tau () and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales.

Results: The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical carriers endorsed worse mood and sleep symptoms, and carriers endorsed marginally greater abnormal behaviours. Preclinical carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.

Conclusion: Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.
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http://dx.doi.org/10.1136/jnnp-2020-322987DOI Listing
September 2020

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome.

JAMA Neurol 2020 03;77(3):377-387

Department of Neuroscience, Brighton and Sussex Medical School, Brighton, United Kingdom.

Importance: Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied.

Objective: To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.

Design, Setting, Participants: This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019.

Main Outcomes And Measures: Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures.

Results: A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05).

Conclusions And Relevance: These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.
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http://dx.doi.org/10.1001/jamaneurol.2019.4347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990759PMC
March 2020

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.

Lancet Neurol 2020 02 3;19(2):145-156. Epub 2019 Dec 3.

Institut du Cerveau et de la Moelle épinière & Centre de Référence des Démences Rares ou précoces, Institut de la Mémoire et de la Maladie d'Alzheimer, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France.

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.

Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.

Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.

Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.

Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.
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http://dx.doi.org/10.1016/S1474-4422(19)30394-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007771PMC
February 2020

Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer's disease.

Eur J Nucl Med Mol Imaging 2019 Dec 8;46(13):2831-2847. Epub 2019 Aug 8.

Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.

Neuroinflammation, as defined by the activation of microglia and astrocytes, has emerged in the last years as a key element of the pathogenesis of neurodegenerative diseases based on genetic findings and preclinical and human studies. This has raised the need for new methodologies to assess and follow glial activation in patients, prompting the development of PET ligands for molecular imaging of glial cells and novel structural MRI and DTI tools leading to a multimodal approach. The present review describes the recent advancements in microglia and astrocyte biology in the context of health, ageing, and Alzheimer's disease, the most common dementia worldwide. The review further delves in molecular imaging discussing the challenges associated with past and present targets, including conflicting findings, and finally, presenting novel methodologies currently explored to improve our in vivo knowledge of the neuroinflammatory patterns in Alzheimer's disease. With glial cell activation as a potential therapeutic target in neurodegenerative diseases, the translational research between cell biologists, chemists, physicists, radiologists, and neurologists should be strengthened.
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http://dx.doi.org/10.1007/s00259-019-04462-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879435PMC
December 2019

Widespread microglial activation in multiple system atrophy.

Mov Disord 2019 04 6;34(4):564-568. Epub 2019 Feb 6.

Departments of Nulcear Medicine and Geriatric Medicine, University Hospital Essen, Germany.

Background: The pattern and role of microglial activation in multiple system atrophy is largely unclear. The objective of this study was to use [ C](R)-PK11195 PET to determine the extent and correlation of activated microglia with clinical parameters in MSA patients.

Methods: Fourteen patients with the parkinsonian phenotype of MSA (MSA-P) with a mean disease duration of 2.9 years (range 2-5 years) were examined with [ C](R)-PK11195 PET and compared with 10 healthy controls.

Results: Patients with the parkinsonian phenotype of MSA showed a significant (P ≤ 0.01) mean increase in binding potentials compared with healthy controls in the caudate nucleus, putamen, pallidum, precentral gyrus, orbitofrontal cortex, presubgenual anterior cingulate cortex, and the superior parietal gyrus. No correlations between binding potentials and clinical parameters were found.

Conclusions: In early clinical stages of the parkinsonian phenotype of MSA, there is widespread microglial activation as a marker of neuroinflammatory changes without correlation to clinical parameters in our patient population. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659386PMC
April 2019

Microglial activation, white matter tract damage, and disability in MS.

Neurol Neuroimmunol Neuroinflamm 2018 May 6;5(3):e443. Epub 2018 Mar 6.

Turku PET Centre (E.R., J.T., M.S., J.R., J.O.R.), Division of Clinical Neurosciences (E.R., M.S., J.O.R., L.A.), Department of Biostatistics (T.V.), and Medical Imaging Centre of Southwest Finland (T.P., R.P.), Turku University Hospital and University of Turku, Finland; Division of Neuroscience and Experimental Psychology (A.G.), University of Manchester, United Kingdom; Department of Nuclear Medicine and Geriatric Medicine (A.G.), University Hospital Essen, Germany; and Wolfson Molecular Imaging Centre (R.H., P.S.T.), University of Manchester, United Kingdom.

Objective: To investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS.

Methods: Patients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [C]()-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison.

Results: [C]()-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls.

Conclusions: PET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.
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http://dx.doi.org/10.1212/NXI.0000000000000443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840890PMC
May 2018

Microglial activation, white matter tract damage, and disability in MS.

Neurol Neuroimmunol Neuroinflamm 2018 May 6;5(3):e443. Epub 2018 Mar 6.

Turku PET Centre (E.R., J.T., M.S., J.R., J.O.R.), Division of Clinical Neurosciences (E.R., M.S., J.O.R., L.A.), Department of Biostatistics (T.V.), and Medical Imaging Centre of Southwest Finland (T.P., R.P.), Turku University Hospital and University of Turku, Finland; Division of Neuroscience and Experimental Psychology (A.G.), University of Manchester, United Kingdom; Department of Nuclear Medicine and Geriatric Medicine (A.G.), University Hospital Essen, Germany; and Wolfson Molecular Imaging Centre (R.H., P.S.T.), University of Manchester, United Kingdom.

Objective: To investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS.

Methods: Patients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [C]()-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison.

Results: [C]()-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls.

Conclusions: PET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.
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http://dx.doi.org/10.1212/NXI.0000000000000443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840890PMC
May 2018

Frontotemporal lobar degeneration and social behaviour: Dissociation between the knowledge of its consequences and its conceptual meaning.

Cortex 2017 08 3;93:107-118. Epub 2017 Jun 3.

Neuroscience and Aphasia Research Unit, Division of Neuroscience and Experimental Psychology, The University of Manchester, Manchester, UK.

Inappropriate social behaviour is an early symptom of frontotemporal lobar degeneration (FTLD) in both behavioural variant frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Knowledge of social behaviour is essential for appropriate social conduct. The superior anterior temporal lobe (ATL) has been identified as one key neural component for the conceptual knowledge of social behaviour, but it is unknown whether this is dissociable from knowledge of the consequences of social behaviour. Here, we used a newly-developed test of knowledge about long-term and short-term consequences of social behaviour to investigate its impairment in patients with FTLD relative to a previously-developed test of social conceptual knowledge. We included 19 healthy elderly control participants and 19 consecutive patients with features of bvFTD or SD and defined dissociations as performance differences between tasks for each patient (Bonferroni-corrected p < .05). Knowledge of long-term consequences was selectively impaired relative to short-term consequences in five patients and the reverse dissociation occurred in one patient. Six patients showed a selective impairment of social concepts relative to long-term consequences with the reverse dissociation occurring in one patient. These results corroborate the hypothesis that knowledge of long-term consequences of social behaviour is dissociable from knowledge of short-term consequences, as well as of social conceptual knowledge. Confirming our hypothesis, we found that patients with more marked grey matter (GM) volume loss in frontopolar relative to right superior ATL regions of interest exhibited poorer knowledge of the long-term consequences of social behaviour relative to the knowledge of its conceptual meaning and vice versa (n = 15). These findings support the hypothesis that frontopolar and ATL regions represent distinct aspects of social knowledge. This suggests that rather than being unable to suppress urges to behave inappropriately, FTLD patients often lose the knowledge of what appropriate social behaviour is and can therefore not be expected to behave accordingly.
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http://dx.doi.org/10.1016/j.cortex.2017.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542070PMC
August 2017

Functional neuroanatomical associations of working memory in early-onset Alzheimer's disease.

Int J Geriatr Psychiatry 2018 Jan 16;33(1):176-184. Epub 2017 Mar 16.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

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 symptoms suggests that temporoparietal neocortical dysfunction may be responsible.

Methods: Twenty-four patients with predominantly early-onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1-weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region-of-interest approach.

Results: Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left-sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers.

Conclusions: Our findings support the hypothesis that working memory changes in early-onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/gps.4703DOI Listing
January 2018

Comparative Evaluation of Three TSPO PET Radiotracers in a LPS-Induced Model of Mild Neuroinflammation in Rats.

Mol Imaging Biol 2017 02;19(1):77-89

Wolfson Molecular Imaging Centre, University of Manchester, 27 Palatine Road, Manchester, M20 3LJ, UK.

Purpose: Over the past 20 years, neuroinflammation (NI) has increasingly been recognised as having an important role in  many neurodegenerative diseases, including Alzheimer's disease. As such, being able to image NI non-invasively in patients is critical to monitor pathological processes and potential therapies targeting neuroinflammation. The translocator protein (TSPO) has proven a reliable NI biomarker for positron emission tomography (PET) imaging. However, if TSPO imaging in acute conditions such as stroke provides strong and reliable signals, TSPO imaging in neurodegenerative diseases has proven more challenging. Here, we report results comparing the recently developed TSPO tracers [F]GE-180 and [F]DPA-714 with (R)-[C]PK11195 in a rodent model of subtle focal inflammation.

Procedures: Adult male Wistar rats were stereotactically injected with 1 μg lipopolysaccharide in the right striatum. Three days later, animals underwent a 60-min PET scan with (R)-[C]PK11195 and [F]GE-180 (n = 6) or [F]DPA-714 (n = 6). Ten animals were scanned with either [F]GE-180 (n = 5) or [F]DPA-714 (n = 5) only. Kinetic analysis of PET data was performed using the simplified reference tissue model (SRTM) with a contralateral reference region or a novel data-driven input to estimate binding potential BP. Autoradiography and immunohistochemistry were performed to confirm in vivo results.

Results: At 40-60 min post-injection, [F]GE-180 dual-scanned animals showed a significantly increased core/contralateral uptake ratio vs. the same animals scanned with (R)-[C]PK11195 (3.41 ± 1.09 vs. 2.43 ± 0.39, p = 0.03); []DPA-714 did not (2.80 ± 0.69 vs. 2.26 ± 0.41). Kinetic modelling with a contralateral reference region identified significantly higher binding potential (BP) in the core of the LPS injection site with [F]GE-180 but not with [F]DPA-714 vs. (R)-[C]PK11195. A cerebellar reference region and novel data-driven input to the SRTM were unable to distinguish differences in tracer BP.

Conclusions: Second-generation TSPO-PET tracers are able to accurately detect mild-level NI. In this model, [F]GE-180 shows a higher core/contralateral ratio and BP when compared to (R)-[C]PK11195, while [F]DPA-714 did not.
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http://dx.doi.org/10.1007/s11307-016-0984-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209405PMC
February 2017

TSPO imaging in parkinsonian disorders.

Clin Transl Imaging 2016;4:183-190. Epub 2016 Apr 11.

Wolfson Molecular Imaging Centre, Institute of Brain, Behaviour and Mental Health, The University of Manchester, 27 Palatine Road, Withington, Manchester, M20 3LJ UK.

Microglial activation is a key aspect of the neuroinflammatory process in neurodegenerative disorders including idiopathic and atypical parkinsonian disorders. With positron emission tomography (PET) it has become possible to image this phenomenon in vivo and over the last years patterns of microglia activation corresponding with the known distribution of neuropathological changes in these disorders have been demonstrated using this technique. In addition the effects of interventions aimed at suppressing microglia activation as part of interventional trials have successfully been demonstrated. Current research aims at evaluating PET tracers for microglial activation with more favorable properties than the prototypical [C]-()-PK11195, as well as developing tracers targeting additional parameters of the neuroinflammatory process like astroglial function.
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http://dx.doi.org/10.1007/s40336-016-0171-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870295PMC
April 2016

TSPO expression in brain tumours: is TSPO a target for brain tumour imaging?

Clin Transl Imaging 2016;4:145-156. Epub 2016 Mar 22.

Department of Neuroimaging, IoPPN, King's College London, London, UK.

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 protein (TSPO) is expressed in high-grade gliomas, while its expression is comparatively low in normal brain. In addition, the evidence of elevated TSPO in neoplastic cells has led to studies investigating TSPO as a transporter of anticancer drugs for brain delivery and a selective target for tumour tissue. The TSPO therefore represents an ideal candidate for molecular imaging studies. Knowledge of the biology of TSPO in normal brain cells, in-depth understanding of TSPO functions and biodistribution in neoplastic cells, accurate methods for quantification of uptake of TSPO tracers and pharmacokinetic data regarding TSPO-targeted drugs are required before introducing TSPO PET and TSPO-targeted treatment in clinical practice. In this review, we will discuss the impact of preclinical PET studies and the application of TSPO imaging in human brain tumours, the advantages and disadvantages of TSPO imaging compared to other imaging modalities and other PET tracers, and pathology studies on the extent and distribution of TSPO in gliomas. The suitability of TSPO as molecular target for treatment of brain tumours will also be the appraised.
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http://dx.doi.org/10.1007/s40336-016-0168-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820497PMC
March 2016

The 18-kDa mitochondrial translocator protein in gliomas: from the bench to bedside.

Biochem Soc Trans 2015 Aug 3;43(4):579-85. Epub 2015 Aug 3.

Division of Brain Science, Wolfson Neuroscience Laboratories, Imperial College London, Du Cane Road, London W12 0NN, U.K.

The 18-kDa mitochondrial translocator protein (TSPO) is known to be highly expressed in several types of cancer, including gliomas, whereas expression in normal brain is low. TSPO functions in glioma are still incompletely understood. The TSPO can be quantified pre-operatively with molecular imaging making it an ideal candidate for personalized treatment of patient with glioma. Studies have proposed to exploit the TSPO as a transporter of chemotherapics to selectively target tumour cells in the brain. Our studies proved that positron emission tomography (PET)-imaging can contribute to predict progression of patients with glioma and that molecular imaging with TSPO-specific ligands is suitable to stratify patients in view of TSPO-targeted treatment. Finally, we proved that TSPO in gliomas is predominantly expressed by tumour cells.
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http://dx.doi.org/10.1042/BST20150064DOI Listing
August 2015

Fluid biomarkers in multiple system atrophy: A review of the MSA Biomarker Initiative.

Neurobiol Dis 2015 Aug 15;80:29-41. Epub 2015 May 15.

Service de Neurologie, CHU de Bordeaux, F-33076 Bordeaux, France; Centre de référence atrophie multisystématisée, CHU de Bordeaux, F-33076 Bordeaux, France; Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33076 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33076 Bordeaux, France. Electronic address:

Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.
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http://dx.doi.org/10.1016/j.nbd.2015.05.004DOI Listing
August 2015

Pain in multiple system atrophy and progressive supranuclear palsy compared to Parkinson's disease.

Brain Behav 2015 May 25;5(5):e00320. Epub 2015 Mar 25.

Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust Stott Lane, M6 8HD, Salford, U.K ; Centre for Clinical and Cognitive Neurosciences, Institute of Brain Behaviour and Mental Health, University of Manchester Manchester, U.K.

Background: Pain is a common nonmotor symptom in Parkinson's disease (PD). The pathophysiology of pain in PD is not well understood. Pain characteristics have rarely been studied in atypical parkinsonian disorders such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP).

Aim Of The Study: We aimed to evaluate pain intensity, location, and associated symptoms in atypical parkinsonian disorders compared to PD.

Methods: Twenty-one patients with MSA, 16 patients with PSP, and 65 patients with PD were screened for pain using question 1.9 of the MDS-UPDRS. Pain intensity was quantified using the short form McGill Pain Questionnaire (SFMPQ). Pain locations were documented. Motor disability was measured using UPDRS-III. Affective symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS).

Results: Pain was significantly more common and more severe in PD and MSA compared to PSP (P < 0.01). Pain locations were similar with limb pain being the most common followed by neck and back pain. Pain intensity correlated with HADS scores but not motor severity.

Conclusions: Pain is more common and more intense in PD and MSA than PSP. Differences in distribution of neurodegenerative pathologies may underlie these differential pain profiles.
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http://dx.doi.org/10.1002/brb3.320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389053PMC
May 2015

The 18-kDa mitochondrial translocator protein in human gliomas: an 11C-(R)PK11195 PET imaging and neuropathology study.

J Nucl Med 2015 Apr 26;56(4):512-7. Epub 2015 Feb 26.

Wolfson Molecular Imaging Center, University of Manchester, Manchester, United Kingdom

Unlabelled: The 18-kDa mitochondrial translocator protein (TSPO) is upregulated in high-grade astrocytomas and can be imaged by 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/macrophages (GAMs) within the tumors.

Methods: Twenty-two glioma patients underwent dynamic (11)C-(R)PK11195 PET scans and perfusion MR imaging acquisition. Parametric maps of (11)C-(R)PK11195 binding potential (BPND) were generated. Coregistered MR/PET images were used to guide tumor biopsy. The tumor tissue was quantitatively assessed for TSPO expression and infiltration of GAMs using immunohistochemistry and double immunofluorescence. The imaging and histopathologic parameters were compared among different histotypes and grades and correlated with each other.

Results: BPND of (11)C-(R)PK11195 in high-grade gliomas was significantly higher than in low-grade astrocytomas and low-grade oligodendrogliomas. TSPO in gliomas was expressed predominantly by neoplastic cells, and its expression correlated positively with BPND in the tumors. GAMs only partially contributed to the overall TSPO expression within the tumors, and TSPO expression in GAMs did not correlate with tumor BPND.

Conclusion: PET with (11)C-(R)PK11195 in human gliomas predominantly reflects TSPO expression in tumor cells. It therefore has the potential to effectively stratify patients who are suitable for TSPO-targeted treatment.
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http://dx.doi.org/10.2967/jnumed.114.151621DOI Listing
April 2015

Cognitive-behavioural features of progressive supranuclear palsy syndrome overlap with frontotemporal dementia.

J Neurol 2015 7;262(4):916-22. Epub 2015 Feb 7.

Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK,

Cognitive impairment is common in patients with the neurodegenerative tauopathy progressive supranuclear palsy (PSP). Although a pattern of 'subcortical' cognitive impairment is considered prototypical in PSP, pathological and clinical observations suggest an overlap with frontotemporal dementia (FTD). Our objective was to evaluate behavioural and cognitive symptoms in a retrospective study of patients with PSP syndrome (PSPS) and their relationship to features seen in behavioural variant FTD. We reviewed the records of 62 patients (29 male, 33 female, median age 65.5 years) evaluated at a tertiary cognitive clinic who met NINDS-SPSP criteria for probable or possible PSP, and collected clinical details of their presenting history, cognitive and behavioural features. We also evaluated the proportion of patients fulfilling FTD Consensus criteria. Cognitive and behavioural symptoms were a predominant presenting feature in 58% of patients evaluated. Cognitive slowing, executive impairments, and inefficient memory recall, consistent with 'subcortical' impairment, were identified in the majority of patients. Twenty patients (32%) fulfilled cognitive and behavioural criteria for possible FTD at initial assessment, whereas behavioural changes not meeting formal diagnostic criteria were present in a greater proportion of the patients. Our findings support the existence of a spectrum of cognitive-behavioural features in PSPS, with significant clinical overlap with behavioural variant FTD. Cognitive and behavioural profiling should be an integral part of the assessment of patients with PSPS.
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http://dx.doi.org/10.1007/s00415-015-7657-zDOI Listing
January 2016

18F-florbetapir PET in patients with frontotemporal dementia and Alzheimer disease.

J Nucl Med 2015 Mar 5;56(3):386-91. Epub 2015 Feb 5.

Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, United Kingdom

Unlabelled: Pathologic deposition of amyloid β (Aβ) protein is a key component in the pathogenesis of Alzheimer 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 controls and patients with AD and FTD.

Methods: Ten healthy controls (mean age ± SD, 62.5 ± 5.2 y), 10 AD patients (mean age ± SD, 62.6 ± 4.5), and 8 FTD patients (mean age ± SD, 62.5 ± 9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychologic assessment and T1-weighted MR imaging and were genotyped for apolipoprotein E status. All participants underwent dynamic (18)F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent (18)F-FDG PET scans. Standardized uptake value ratios (SUVRs) were extracted for predefined gray and white matter regions of interest using cerebellar gray matter as a reference region. Static PET images were evaluated by trained raters masked to clinical status and regional analysis.

Results: Total cortical gray matter (18)F-florbetapir uptake values were significantly higher in AD patients (median SUVR, 1.73) than FTD patients (SUVR, 1.13, P = 0.002) and controls (SUVR, 1.26, P = 0.04). (18)F-Florbetapir uptake was also higher in AD patients than FTD patients and controls in the frontal, parietal, occipital, and cingulate cortices and in the central subcortical regions. Only 1 FTD patient (homozygous for apolipoprotein E ε4) displayed high cortical (18)F-florbetapir retention, whereas (18)F-FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. Most visual raters classified 1 control (10%) and 8 AD (80%) and 2 FTD (25%) patients as amyloid-positive, whereas ratings were tied in another 2 FTD patients and 1 healthy control.

Conclusion: Cortical (18)F-florbetapir uptake is low in most FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging, with a higher rate of discordance between interpreters than in AD and control subjects.
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http://dx.doi.org/10.2967/jnumed.114.147454DOI Listing
March 2015

18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke.

Eur J Nucl Med Mol Imaging 2015 Mar 29;42(3):503-11. Epub 2014 Oct 29.

Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK,

Purpose: Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer (11)C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer (18)F-GE-180 in a rat model of stroke.

Methods: Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with (11)C-R-PK11195 and (18)F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of (18)F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP).

Results: (18)F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of (11)C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BPND = 3.5 ± 0.4 and 2.4 ± 0.5 for (18)F-GE-180 and (11)C-R-PK11195, respectively, with R 1 = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of (18)F-GE-180 significantly displaced (18)F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry.

Conclusion: The in vivo binding characteristics of (18)F-GE-180 demonstrate a better signal to noise ratio than (11)C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in healthy tissue. These results provide evidence that (18)F-GE-180 is a strong candidate to replace (11)C-R-PK11195.
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http://dx.doi.org/10.1007/s00259-014-2939-8DOI Listing
March 2015

Frontotemporal dementia and its subtypes: a genome-wide association study.

Lancet Neurol 2014 Jul;13(7):686-99

University of Milan, Milan, Italy; Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.

Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms.

Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis.

Interpretation: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD.

Funding: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.
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http://dx.doi.org/10.1016/S1474-4422(14)70065-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112126PMC
July 2014

Imaging of neuroinflammation in parkinsonian syndromes with positron emission tomography.

Curr Neurol Neurosci Rep 2013 Dec;13(12):405

Wolfson Molecular Imaging Center, Institute of Brain, Behaviour and Mental Health, The University of Manchester, 27 Palatine Road, Withington, Manchester, M20 3LJ, UK,

Microglial activation is a key aspect of the neuroinflammatory process in neurodegenerative disorders including idiopathic and atypical parkinsonian disorders. Using positron emission tomography, it has become possible to image this phenomenon in vivo and over the last years patterns of microglia activation corresponding well known distribution of neuropathologic changes in these disorders have successfully been demonstrated using this technique. It has also been possible to measure the effects of interventions aimed at suppressing microglia activation as part interventional trials. Current research aims at evaluating positron emission tomography tracers for microglial activation with more favorable properties than the prototypical [(11)C]-(R)-PK11195, as well as developing tracers targeting additional parameters of the neuroinflammatory process like astroglial function or the cannabinoid receptor type 2.
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http://dx.doi.org/10.1007/s11910-013-0405-9DOI Listing
December 2013