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Article ; Online: Defining the presymptomatic phase of frontotemporal dementia.

Russell, Lucy L / Rohrer, Jonathan D

2023 Volume 36, Issue 4, Page(s) 276–282

Abstract: Purpose of review: Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Whilst disease modifying therapy trials are mostly focused on the symptomatic phase, future studies will move earlier in the disease ...

Abstract	Purpose of review: Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Whilst disease modifying therapy trials are mostly focused on the symptomatic phase, future studies will move earlier in the disease aiming to prevent symptom onset. This review summarizes the recent work to better understand this presymptomatic period. Recent findings: The presymptomatic phase can be split into preclinical and prodromal stages. The onset of the preclinical phase is defined by the first presence of pathological inclusions of tau, TDP-43 or fused in sarcoma in the brain. Definitive biomarkers of these pathologies do not yet exist for FTD. The prodromal phase is defined by the onset of mild symptoms. Recent work has highlighted the wide phenotypic spectrum that occurs, with the concept of mild cognitive ± behavioural ± motor impairment (MCBMI) being put forward, and additions to scales such as the CDR plus NACC FTLD now incorporating neuropsychiatric and motor symptoms. Summary: It will be important to better characterize the presymptomatic period moving forward and develop robust biomarkers that can be used both for stratification and outcome measures in prevention trials. The work of the FTD Prevention Initiative aims to facilitate this by bringing together data from natural history studies across the world.
MeSH term(s)	Humans ; Frontotemporal Dementia/diagnosis ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/pathology ; Brain/pathology ; Biomarkers ; Mutation ; tau Proteins
Chemical Substances	Biomarkers ; tau Proteins
Language	English
Publishing date	2023-06-23
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1182686-1
ISSN	1473-6551 ; 1350-7540
ISSN (online)	1473-6551
ISSN	1350-7540
DOI	10.1097/WCO.0000000000001174
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Article ; Online: Novel instructionless eye tracking tasks identify emotion recognition deficits in frontotemporal dementia.

Russell, Lucy L / Greaves, Caroline V / Convery, Rhian S / Nicholas, Jennifer / Warren, Jason D / Kaski, Diego / Rohrer, Jonathan D

Alzheimer's research & therapy

2021 Volume 13, Issue 1, Page(s) 39

Abstract: Background: Current tasks measuring social cognition are usually 'pen and paper' tasks, have ceiling effects and include complicated test instructions that may be difficult to understand for those with cognitive impairment. We therefore aimed to develop ...

Abstract	Background: Current tasks measuring social cognition are usually 'pen and paper' tasks, have ceiling effects and include complicated test instructions that may be difficult to understand for those with cognitive impairment. We therefore aimed to develop a set of simple, instructionless, quantitative, tasks of emotion recognition using the methodology of eye tracking, with the subsequent aim of assessing their utility in individuals with behavioural variant frontotemporal dementia (bvFTD). Methods: Using the Eyelink 1000 Plus eye tracker, 18 bvFTD and 22 controls completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and the others non-target) followed by a target emotion word and lastly the original four images alongside the emotion word. A dwell time change score was then calculated as the main outcome measure by subtracting the percentage dwell time for the target image before the emotion word appeared away from the percentage dwell time for the target image after the emotion word appeared. All participants also underwent a standard cognitive battery and volumetric T1-weighted magnetic resonance imaging. Results: Analysis using a mixed effects model showed that the average (standard deviation) mean dwell time change score in the target interest area was 35 (27)% for the control group compared with only 4 (18)% for the bvFTD group (p < 0.05) for the simple emotion recognition task, and 15 (26)% for the control group compared with only 2 (18)% for the bvFTD group (p < 0.05) for the complex emotion recognition task. Worse performance in the bvFTD group correlated with atrophy in the right ventromedial prefrontal and orbitofrontal cortices, brain regions previously implicated in social cognition. Conclusions: In summary, eye tracking is a viable tool for assessing social cognition in individuals with bvFTD, being well-tolerated and able to overcome some of the problems associated with standard psychometric tasks.
MeSH term(s)	Brain/diagnostic imaging ; Emotions ; Eye-Tracking Technology ; Frontotemporal Dementia/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Neuropsychological Tests
Language	English
Publishing date	2021-02-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-021-00775-x
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Article ; Online: Eye movements in frontotemporal dementia: Abnormalities of fixation, saccades and anti-saccades.

Russell, Lucy L / Greaves, Caroline V / Convery, Rhian S / Bocchetta, Martina / Warren, Jason D / Kaski, Diego / Rohrer, Jonathan D

Alzheimer's & dementia (New York, N. Y.)

2021 Volume 7, Issue 1, Page(s) e12218

Abstract: Introduction: Oculomotor function has not been systematically studied in frontotemporal dementia (FTD) and yet may offer a simple target to monitor disease activity.: Methods: We assessed fixation stability, smooth pursuit, pro-saccades, and anti- ... ...

Abstract	Introduction: Oculomotor function has not been systematically studied in frontotemporal dementia (FTD) and yet may offer a simple target to monitor disease activity. Methods: We assessed fixation stability, smooth pursuit, pro-saccades, and anti-saccades using the Eyelink 1000-plus eye-tracker in 19 individuals with behavioral variant FTD (bvFTD) and 22 controls. Neuroanatomical correlates were assessed using a region of interest magnetic resonance imaging (MRI) analysis. Results: Measures of fixation stability were impaired in the bvFTD group compared with controls. However, performance did not differ from controls in the pro-saccade tasks except in the vertical overlap condition. The bvFTD group performed worse in the anti-saccade task, which correlated strongly with executive function. Neural correlates included the orbitofrontal and ventromedial prefrontal cortices and striatum for fixation stability, and the dorsolateral prefrontal and parietal cortices and striatum for anti-saccades. Discussion: Overall, oculomotor function is abnormal in bvFTD, with performance likely related to impairment of inhibitory control and executive dysfunction.
Language	English
Publishing date	2021-12-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832891-7
ISSN	2352-8737 ; 2352-8737
ISSN (online)	2352-8737
ISSN	2352-8737
DOI	10.1002/trc2.12218
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Article ; Online: Addition of the FTD Module to the Neuropsychiatric Inventory improves classification of frontotemporal dementia spectrum disorders.

Jiskoot, Lize C / Russell, Lucy L / Greaves, Caroline V / van Schaik, Esther / van den Berg, Esther / Poos, Jackie M / de Boer, Liset / Donker Kaat, Laura / Seelaar, Harro / Pijnenburg, Yolande A L / van Swieten, John C / Rohrer, Jonathan D

Journal of neurology

2023 Volume 270, Issue 5, Page(s) 2674–2687

Abstract: Most neuropsychiatric symptoms (NPS) common in frontotemporal dementia (FTD) are currently not part of the Neuropsychiatric Inventory (NPI). We piloted an FTD Module that included eight extra items to be used in conjunction with the NPI. Caregivers of ... ...

Abstract	Most neuropsychiatric symptoms (NPS) common in frontotemporal dementia (FTD) are currently not part of the Neuropsychiatric Inventory (NPI). We piloted an FTD Module that included eight extra items to be used in conjunction with the NPI. Caregivers of patients with behavioural variant FTD (n = 49), primary progressive aphasia (PPA; n = 52), Alzheimer's dementia (AD; n = 41), psychiatric disorders (n = 18), presymptomatic mutation carriers (n = 58) and controls (n = 58) completed the NPI and FTD Module. We investigated (concurrent and construct) validity, factor structure and internal consistency of the NPI and FTD Module. We performed group comparisons on item prevalence, mean item and total NPI and NPI with FTD Module scores, and multinomial logistic regression to determine its classification abilities. We extracted four components, together explaining 64.1% of the total variance, of which the largest indicated the underlying dimension 'frontal-behavioural symptoms'. Whilst apathy (original NPI) occurred most frequently in AD, logopenic and non-fluent variant PPA, the most common NPS in behavioural variant FTD and semantic variant PPA were loss of sympathy/empathy and poor response to social/emotional cues (part of FTD Module). Patients with primary psychiatric disorders and behavioural variant FTD showed the most severe behavioural problems on both the NPI as well as the NPI with FTD Module. The NPI with FTD Module correctly classified more FTD patients than the NPI alone. By quantifying common NPS in FTD the NPI with FTD Module has large diagnostic potential. Future studies should investigate whether it can also prove a useful addition to the NPI in therapeutic trials.
MeSH term(s)	Humans ; Frontotemporal Dementia/diagnosis ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/psychology ; Alzheimer Disease/diagnosis ; Behavioral Symptoms ; Caregivers
Language	English
Publishing date	2023-02-22
Publishing country	Germany
Document type	Journal Article
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-023-11596-3
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Article ; Online: The architecture of abnormal reward behaviour in dementia: multimodal hedonic phenotypes and brain substrate.

Chokesuwattanaskul, Anthipa / Jiang, Harmony / Bond, Rebecca L / Jimenez, Daniel A / Russell, Lucy L / Sivasathiaseelan, Harri / Johnson, Jeremy C S / Benhamou, Elia / Agustus, Jennifer L / van Leeuwen, Janneke E P / Chokesuwattanaskul, Peerapat / Hardy, Chris J D / Marshall, Charles R / Rohrer, Jonathan D / Warren, Jason D

Brain communications

2023 Volume 5, Issue 2, Page(s) fcad027

Abstract: Abnormal reward processing is a hallmark of neurodegenerative diseases, most strikingly in frontotemporal dementia. However, the phenotypic repertoire and neuroanatomical substrates of abnormal reward behaviour in these diseases remain incompletely ... ...

Abstract	Abnormal reward processing is a hallmark of neurodegenerative diseases, most strikingly in frontotemporal dementia. However, the phenotypic repertoire and neuroanatomical substrates of abnormal reward behaviour in these diseases remain incompletely characterized and poorly understood. Here we addressed these issues in a large, intensively phenotyped patient cohort representing all major syndromes of sporadic frontotemporal dementia and Alzheimer's disease. We studied 27 patients with behavioural variant frontotemporal dementia, 58 with primary progressive aphasia (22 semantic variant, 24 non-fluent/agrammatic variant and 12 logopenic) and 34 with typical amnestic Alzheimer's disease, in relation to 42 healthy older individuals. Changes in behavioural responsiveness were assessed for canonical primary rewards (appetite, sweet tooth, sexual activity) and non-primary rewards (music, religion, art, colours), using a semi-structured survey completed by patients' primary caregivers. Changes in more general socio-emotional behaviours were also recorded. We applied multiple correspondence analysis and
Language	English
Publishing date	2023-02-09
Publishing country	England
Document type	Journal Article ; Comment
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcad027
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Article: Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia.

Samra, Kiran / Peakman, Georgia / MacDougall, Amy M / Bouzigues, Arabella / Greaves, Caroline V / Convery, Rhian S / van Swieten, John C / Jiskoot, Lize / Seelaar, Harro / Moreno, Fermin / Sanchez-Valle, Raquel / Laforce, Robert / Graff, Caroline / Masellis, Mario / Tartaglia, Maria Carmela / Rowe, James B / Borroni, Barbara / Finger, Elizabeth / Synofzik, Matthis /

Galimberti, Daniela / Vandenberghe, Rik / de Mendonça, Alexandre / Butler, Chris R / Gerhard, Alexander / Ducharme, Simon / Ber, Isabelle Le / Tiraboschi, Pietro / Santana, Isabel / Pasquier, Florence / Levin, Johannes / Otto, Markus / Sorbi, Sandro / Rohrer, Jonathan D / Russell, Lucy L

Alzheimer's & dementia (Amsterdam, Netherlands)

2024 Volume 16, Issue 2, Page(s) e12571

Abstract: Introduction: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC ... ...

Abstract	Introduction: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). Methods: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). Results: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. Discussion: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale.Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.
Language	English
Publishing date	2024-04-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832898-X
ISSN	2352-8729
ISSN	2352-8729
DOI	10.1002/dad2.12571
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Article ; Online: Agnosia for bird calls.

Muhammed, Louwai / Hardy, Chris J D / Russell, Lucy L / Marshall, Charles R / Clark, Camilla N / Bond, Rebecca L / Warrington, Elizabeth K / Warren, Jason D

Neuropsychologia

2018 Volume 113, Page(s) 61–67

Abstract: The cognitive organisation of nonverbal auditory knowledge remains poorly defined. Deficits of environmental sound as well as word and visual object knowledge are well-recognised in semantic dementia. However, it is unclear how auditory cognition breaks ... ...

Abstract	The cognitive organisation of nonverbal auditory knowledge remains poorly defined. Deficits of environmental sound as well as word and visual object knowledge are well-recognised in semantic dementia. However, it is unclear how auditory cognition breaks down in this disorder and how this relates to deficits in other knowledge modalities. We had the opportunity to study a patient with a typical syndrome of semantic dementia who had extensive premorbid knowledge of birds, allowing us to assess the impact of the disease on the processing of auditory in relation to visual and verbal attributes of this specific knowledge category. We designed a novel neuropsychological test to probe knowledge of particular avian characteristics (size, behaviour [migratory or nonmigratory], habitat [whether or not primarily water-dwelling]) in the nonverbal auditory, visual and verbal modalities, based on a uniform two-alternative-forced-choice procedure. The patient's performance was compared to healthy older individuals of similar birding experience. We further compared his performance on this test of bird knowledge with his knowledge of familiar human voices and faces. Relative to healthy birder controls, the patient showed marked deficits of bird call and bird name knowledge but relatively preserved knowledge of avian visual attributes and retained knowledge of human voices and faces. In both the auditory and visual modalities, his knowledge of the avian characteristics of size and behaviour was intact whereas his knowledge of the associated characteristic of habitat was deficient. This case provides further evidence that nonverbal auditory knowledge has a fractionated organisation that can be differentially targeted in semantic dementia.
MeSH term(s)	Acoustic Stimulation/methods ; Aged ; Agnosia/physiopathology ; Animals ; Auditory Perception/physiology ; Birds ; Female ; Humans ; Knowledge ; Male ; Middle Aged ; Photic Stimulation ; Recognition (Psychology)/physiology ; Semantics ; Sound
Language	English
Publishing date	2018-03-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207151-4
ISSN	1873-3514 ; 0028-3932
ISSN (online)	1873-3514
ISSN	0028-3932
DOI	10.1016/j.neuropsychologia.2018.03.024
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Article ; Online: Cerebrospinal Fluid YKL-40 and Chitotriosidase Levels in Frontotemporal Dementia Vary by Clinical, Genetic and Pathological Subtype.

Woollacott, Ione O C / Nicholas, Jennifer M / Heller, Carolin / Foiani, Martha S / Moore, Katrina M / Russell, Lucy L / Paterson, Ross W / Keshavan, Ashvini / Schott, Jonathan M / Warren, Jason D / Heslegrave, Amanda / Zetterberg, Henrik / Rohrer, Jonathan D

Dementia and geriatric cognitive disorders

2020 Volume 49, Issue 1, Page(s) 56–76

Abstract: Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are increased in Alzheimer's disease (AD) but have not been ... ...

Abstract	Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are increased in Alzheimer's disease (AD) but have not been explored in detail across the spectrum of FTD. Methods: We investigated whether CSF YKL-40 and chitotriosidase levels differed between FTD patients and controls, across different clinical and genetic subtypes of FTD, and between individuals with a clinical FTD syndrome due to AD versus non-AD (frontotemporal lobar degeneration, FTLD) pathology (based on CSF neurodegenerative biomarkers). Eighteen healthy controls and 64 people with FTD (behavioural variant FTD, n = 20; primary progressive aphasia [PPA], n = 44: nfvPPA, n = 16, svPPA, n = 11, lvPPA, n = 14, PPA-NOS, n = 3) were included. 10/64 had familial FTD, with mutations in GRN(n = 3), MAPT(n = 4), or C9orf72 (n = 3). 15/64 had neurodegenerative biomarkers consistent with AD pathology. Levels were measured by immunoassay and compared using multiple linear regressions. We also examined relationships of YKL-40 and chitotriosidase with CSF total tau (T-tau), phosphorylated tau 181 (P-tau) and β-amyloid 1-42 (Aβ42), with each other, and with age and disease du-ration. Results: CSF YKL-40 and chitotriosidase levels were higher in FTD, particularly lvPPA (both) and nfvPPA (YKL-40), compared with controls. GRN mutation carriers had higher levels of both proteins than controls and C9orf72 expansion carriers, and YKL-40 was higher in MAPT mutation carriers than controls. Individuals with underlying AD pathology had higher YKL-40 and chitotriosidase levels than both controls and those with likely FTLD pathology. CSF YKL-40 and chitotriosidase levels were variably associated with levels of T-tau, P-tau and Aβ42, and with each other, depending on clinical syndrome and underlying pathology. CSF YKL-40 but not chitotriosidase was associated with age, but not disease duration. Conclusion: CSF YKL-40 and chitotriosidase levels are increased in individuals with clinical FTD syndromes, particularly due to AD pathology. In a preliminary analysis of genetic groups, levels of both proteins are found to be highly elevated in FTD due to GRN mutations, while YKL-40 is increased in individuals with MAPT mutations. As glia-derived protein levels generally correlate with T-tau and P-tau levels, they may reflect the glial response to neurodegeneration in FTLD.
MeSH term(s)	Aged ; Biomarkers/cerebrospinal fluid ; C9orf72 Protein/genetics ; Chitinase-3-Like Protein 1/cerebrospinal fluid ; Female ; Frontotemporal Dementia/cerebrospinal fluid ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/pathology ; Frontotemporal Lobar Degeneration/cerebrospinal fluid ; Frontotemporal Lobar Degeneration/metabolism ; Frontotemporal Lobar Degeneration/pathology ; Hexosaminidases/cerebrospinal fluid ; Humans ; Male ; Microglia/metabolism ; Microglia/pathology ; Neurodegenerative Diseases/cerebrospinal fluid ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/pathology ; Progranulins/genetics ; tau Proteins/genetics
Chemical Substances	Biomarkers ; C9orf72 Protein ; C9orf72 protein, human ; CHI3L1 protein, human ; Chitinase-3-Like Protein 1 ; GRN protein, human ; MAPT protein, human ; Progranulins ; tau Proteins ; Hexosaminidases (EC 3.2.1.-) ; chitotriosidase (EC 3.2.1.-)
Language	English
Publishing date	2020-04-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1026007-9
ISSN	1421-9824 ; 1013-7424
ISSN (online)	1421-9824
ISSN	1013-7424
DOI	10.1159/000506282
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Article: Altered Time Awareness in Dementia.

Requena-Komuro, Maï-Carmen / Marshall, Charles R / Bond, Rebecca L / Russell, Lucy L / Greaves, Caroline / Moore, Katrina M / Agustus, Jennifer L / Benhamou, Elia / Sivasathiaseelan, Harri / Hardy, Chris J D / Rohrer, Jonathan D / Warren, Jason D

Frontiers in neurology

2020 Volume 11, Page(s) 291

Abstract: Our awareness of time, specifically of longer intervals spanning hours, days, months, and years, is critical for ensuring our sense of self-continuity. Disrupted time awareness over such intervals is a clinical feature in a number of frontotemporal ... ...

Abstract	Our awareness of time, specifically of longer intervals spanning hours, days, months, and years, is critical for ensuring our sense of self-continuity. Disrupted time awareness over such intervals is a clinical feature in a number of frontotemporal dementia syndromes and Alzheimer's disease, but has not been studied and compared systematically in these diseases. We used a semi-structured caregiver survey to capture time-related behavioral alterations in 71 patients representing all major sporadic and genetic syndromes of frontotemporal dementia, in comparison to 28 patients with typical Alzheimer's disease and nine with logopenic aphasia, and 32 healthy older individuals. Survey items pertained to apparent difficulties ordering past personal events or estimating time intervals between events, temporal rigidity and clockwatching, and propensity to relive past events. We used a logistic regression model including diagnosis, age, gender, and disease severity as regressors to compare the proportions of individuals exhibiting each temporal awareness symptom between diagnostic groups. Gray matter associations of altered time awareness were assessed using voxel-based morphometry. All patient groups were significantly more prone to exhibit temporal awareness symptoms than healthy older individuals. Clinical syndromic signatures were identified. While patients with typical and logopenic Alzheimer's disease most frequently exhibited disturbed event ordering or interval estimation, patients with semantic dementia were most prone to temporal rigidity and clockwatching and those with behavioral variant frontotemporal dementia commonly exhibited all these temporal symptoms as well as a propensity to relive past events. On voxel-based morphometry, the tendency to relive past events was associated with relative preservation of a distributed left-sided temporo-parietal gray matter network including hippocampus. These findings reveal a rich and complex picture of disturbed temporal awareness in major dementia syndromes, with stratification of frontotemporal dementia syndromes from Alzheimer's disease. This is the first study to assess symptoms of altered temporal awareness across frontotemporal dementia syndromes and provides a motivation for future work directed to the development of validated clinical questionnaires, analysis of underlying neurobiological mechanisms and design of interventions.
Language	English
Publishing date	2020-04-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2020.00291
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Article ; Online: The neurophysiological architecture of semantic dementia: spectral dynamic causal modelling of a neurodegenerative proteinopathy.

Benhamou, Elia / Marshall, Charles R / Russell, Lucy L / Hardy, Chris J D / Bond, Rebecca L / Sivasathiaseelan, Harri / Greaves, Caroline V / Friston, Karl J / Rohrer, Jonathan D / Warren, Jason D / Razi, Adeel

Scientific reports

2020 Volume 10, Issue 1, Page(s) 16321

Abstract: The selective destruction of large-scale brain networks by pathogenic protein spread is a ubiquitous theme in neurodegenerative disease. Characterising the circuit architecture of these diseases could illuminate both their pathophysiology and the ... ...

Abstract	The selective destruction of large-scale brain networks by pathogenic protein spread is a ubiquitous theme in neurodegenerative disease. Characterising the circuit architecture of these diseases could illuminate both their pathophysiology and the computational architecture of the cognitive processes they target. However, this is challenging using standard neuroimaging techniques. Here we addressed this issue using a novel technique-spectral dynamic causal modelling-that estimates the effective connectivity between brain regions from resting-state fMRI data. We studied patients with semantic dementia-the paradigmatic disorder of the brain system mediating world knowledge-relative to healthy older individuals. We assessed how the effective connectivity of the semantic appraisal network targeted by this disease was modulated by pathogenic protein deposition and by two key phenotypic factors, semantic impairment and behavioural disinhibition. The presence of pathogenic protein in SD weakened the normal inhibitory self-coupling of network hubs in both antero-mesial temporal lobes, with development of an abnormal excitatory fronto-temporal projection in the left cerebral hemisphere. Semantic impairment and social disinhibition were linked to a similar but more extensive profile of abnormally attenuated inhibitory self-coupling within temporal lobe regions and excitatory projections between temporal and inferior frontal regions. Our findings demonstrate that population-level dynamic causal modelling can disclose a core pathophysiological feature of proteinopathic network architecture-attenuation of inhibitory connectivity-and the key elements of distributed neuronal processing that underwrite semantic memory.
MeSH term(s)	Aged ; Female ; Frontotemporal Dementia/diagnostic imaging ; Frontotemporal Dementia/metabolism ; Frontotemporal Dementia/physiopathology ; Functional Neuroimaging ; Humans ; Magnetic Resonance Imaging ; Male ; Models, Neurological ; Nerve Tissue Proteins/metabolism ; Neural Pathways/physiopathology ; Neuropsychological Tests
Chemical Substances	Nerve Tissue Proteins
Language	English
Publishing date	2020-10-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-72847-1
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