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  • 1
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    Radiogenomics of C9orf72 Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment
    Society for Neuroscience ; 2023
    In:  The Journal of Neuroscience Vol. 43, No. 2 ( 2023-01-11), p. 333-345
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 43, No. 2 ( 2023-01-11), p. 333-345
    Kurzfassung: Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis ( n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity ( n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS . L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS , which predicted atrophy of FTD-relevant thalamic nuclei. SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements—genetic elements typically repressed in the human genome—in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.
    Materialart: Online-Ressource
    ISSN: 0270-6474 , 1529-2401
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    DOI: 10.1523/JNEUROSCI.1448-22.2022
    DOI: 10.1523/JNEUROSCI.1448-22.2022.f1-1
    DOI: 10.1523/JNEUROSCI.1448-22.2022.f2-1
    DOI: 10.1523/JNEUROSCI.1448-22.2022.f3-1
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    DOI: 10.1523/JNEUROSCI.1448-22.2022.f3-3
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    DOI: 10.1523/JNEUROSCI.1448-22.2022.f3-5
    DOI: 10.1523/JNEUROSCI.1448-22.2022.f4-1
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    DOI: 10.1523/JNEUROSCI.1448-22.2022.f4-3
    DOI: 10.1523/JNEUROSCI.1448-22.2022.f5-1
    DOI: 10.1523/JNEUROSCI.1448-22.2022.f5-2
    Sprache: Englisch
    Verlag: Society for Neuroscience
    Publikationsdatum: 2023
    ZDB Id: 1475274-8
    SSG: 12
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  • 2
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    Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia
    American Medical Association (AMA) ; 2023
    In:  JAMA Neurology Vol. 80, No. 4 ( 2023-04-01), p. 377-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 80, No. 4 ( 2023-04-01), p. 377-
    Kurzfassung: The neurological substrates of visual artistic creativity (VAC) are unknown. VAC is demonstrated here to occur early in frontotemporal dementia (FTD), and multimodal neuroimaging is used to generate a novel mechanistic hypothesis involving dorsomedial occipital cortex enhancement. These findings may illuminate a novel mechanism underlying human visual creativity. Objective To determine the anatomical and physiological underpinnings of VAC in FTD. Design, Setting, and Participants This case-control study analyzed records of 689 patients who met research criteria for an FTD spectrum disorder between 2002 and 2019. Individuals with FTD and emergence of visual artistic creativity (VAC-FTD) were matched to 2 control groups based on demographic and clinical parameters: (1) not visually artistic FTD (NVA-FTD) and (2) healthy controls (HC). Analysis took place between September 2019 to December 2021. Main Outcomes and Measures Clinical, neuropsychological, genetic, and neuroimaging data were analyzed to characterize VAC-FTD and compare VAC-FTD with control groups. Results Of 689 patients with FTD, 17 (2.5%) met VAC-FTD inclusion criteria (mean [SD] age, 65 [9.7] years; 10 [58.8%] female). NVA-FTD (n = 51; mean [SD] age, 64.8 [7] years; 25 [49.0%] female) and HC (n = 51; mean [SD] age, 64.5 [7.2] years; 25 [49%] female) groups were well matched to VAC-FTD demographically. Emergence of VAC occurred around the time of onset of symptoms and was disproportionately seen in patients with temporal lobe predominant degeneration (8 of 17 [47.1%] ). Atrophy network mapping identified a dorsomedial occipital region whose activity inversely correlated, in healthy brains, with activity in regions found within the patient-specific atrophy patterns in VAC-FTD (17 of 17) and NVA-FTD (45 of 51 [88.2%]). Structural covariance analysis revealed that the volume of this dorsal occipital region was strongly correlated in VAC-FTD, but not in NVA-FTD or HC, with a volume in the primary motor cortex corresponding to the right-hand representation. Conclusions and Relevance This study generated a novel hypothesis about the mechanisms underlying the emergence of VAC in FTD. These findings suggest that early lesion-induced activation of dorsal visual association areas may predispose some patients to the emergence of VAC under certain environmental or genetic conditions. This work sets the stage for further exploration of enhanced capacities arising early in the course of neurodegeneration.
    Materialart: Online-Ressource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2023.0001
    Sprache: Englisch
    Verlag: American Medical Association (AMA)
    Publikationsdatum: 2023
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  • 3
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    Diagnostic Utility of Measuring Cerebral Atrophy in the Behavioral Variant of Frontotemporal Dementia and Association With Clinical Deterioration
    American Medical Association (AMA) ; 2021
    In:  JAMA Network Open Vol. 4, No. 3 ( 2021-03-11), p. e211290-
    Details
    In: JAMA Network Open, American Medical Association (AMA), Vol. 4, No. 3 ( 2021-03-11), p. e211290-
    Materialart: Online-Ressource
    ISSN: 2574-3805
    URL: Article
    DOI: 10.1001/jamanetworkopen.2021.1290
    Sprache: Englisch
    Verlag: American Medical Association (AMA)
    Publikationsdatum: 2021
    ZDB Id: 2931249-8
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  • 4
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    Emergence of visual artistic creativity in frontotemporal dementia
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S9 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S9 ( 2022-12)
    Kurzfassung: Emergence of novel visual artistic skills has been described in neurodegenerative disorders, particularly in the frontotemporal dementia – amyotrophic lateral sclerosis (FTD‐ALS) spectrum, but associated clinical and genetic features and the underlying neural mechanisms have not been systematically examined. We aimed to address these gaps. Method We performed comprehensive chart review of all 734 participants in the University of California San Francisco FTD Program Project Grant who had a clinical syndrome within the FTD‐ALS spectrum. This review allowed us to ascertain subjects meeting current FTD‐ALS clinical research criteria who had: (1) an emergence of novel visual artistic skills or (2) a change in the style of visual art produced or (3) a significant increase in quantity of visual art produced. Clinical data, imaging studies, and genetic information were collected and analyzed. Result Among the 734 patients screened, 45 were excluded due to lack of available research notes. We identified a change in visual artistic creativity in 17/689 patients (prevalence 2.5%). Mean age of FTD symptom onset was 57.4 (±10.4), and the visual artistic creativity (VAC) change was reported an average of 0.7 years (±10.1) prior to FTD symptom onset. Of the 17 patients with VAC, 8 exhibited no prior interest in art, 2 were professional visual artists who experienced a change in artistic style, and 7 reported some prior interest in art but a substantial change of style or quantity. Artistic output was diverse however bright colors and non‐human subjects were prominent. VAC occurred in patients with semantic variant primary progressive aphasia (8), behavioral variant FTD (3), nonfluent variant primary progressive aphasia (2), progressive supranuclear palsy ‐ Richardson’s syndrome (2), corticobasal syndrome (1), and ALS (1). None carried a common pathogenic variant in a FTD gene. Conclusion Change in VAC is an uncommon but early positive symptom that occurs in patients across the FTD‐ALS clinical spectrum but appears most common in patients with anterior temporal lobe degeneration. We are pursuing the neural mechanisms of VAC through structural and functional neuroimaging studies.
    Materialart: Online-Ressource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S9
    DOI: 10.1002/alz.065202
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2022
    ZDB Id: 2201940-6
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  • 5
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    Case Report: Novel CSF1R Variant in a Patient With Behavioral Variant Frontotemporal Dementia Syndrome With Prodromal Repetitive Scratching Behavior
    Frontiers Media SA ; 2022
    In:  Frontiers in Neurology Vol. 13 ( 2022-6-22)
    Details
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 13 ( 2022-6-22)
    Kurzfassung: CSF1R -related leukoencephalopathy is an autosomal dominant neurodegenerative disease caused by mutations in the tyrosine kinase domain of the colony stimulating factor 1 receptor (CSF1R). Several studies have found that hematogenic stem cell transplantation is an effective disease modifying therapy however the literature regarding prodromal and early symptoms CSF1R -related leukoencephalopathy is limited. We describe a 63-year-old patient with 4 years of repetitive scratching and skin picking behavior followed by 10 years of progressive behavioral, cognitive, and motor decline in a pattern suggesting behavioral variant of frontotemporal dementia. Brain MRI demonstrated prominent frontal and parietal atrophy accompanied by underlying bilateral patchy white matter hyperintensities sparing the U fibers and cavum septum pellucidum. Whole-exome sequencing revealed a novel, predicted deleterious missense variant in a highly conserved amino acid in the tyrosine kinase domain of CSF1R (p.Gly872Arg). Given this evidence and the characteristic clinical and radiological findings this novel variant was classified as likely pathogenic according to the American College of Medical Genetics standard guidelines. Detailed description of the prodromal scratching and skin picking behavior and possible underlying mechanisms in this case furthers knowledge about early manifestations of CSF1R -related leukoencephalopathy with the hope that early detection and timely administration of disease modifying therapies becomes possible.
    Materialart: Online-Ressource
    ISSN: 1664-2295
    URL: Article
    DOI: 10.3389/fneur.2022.909944
    Sprache: Unbekannt
    Verlag: Frontiers Media SA
    Publikationsdatum: 2022
    ZDB Id: 2564214-5
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  • 6
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    Efficacy of Parenteral Amantadine Therapy in the Treatment of Multiple System Atrophy With Predominant Parkinsonism
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Clinical Neuropharmacology Vol. 41, No. 5 ( 2018-9), p. 160-163
    Details
    In: Clinical Neuropharmacology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 5 ( 2018-9), p. 160-163
    Kurzfassung: The aim of this study was to assess clinical response to a high-dose intravenous (IV) amantadine given for 5 consecutive days in patients with multiple system atrophy parkinsonism (MSA-P). Methods Subjects with a diagnosis of MSA-P treated with IV amantadine were included. Patients' disease severity before and after therapy was evaluated using the Unified Multiple System Atrophy Rating Scale (UMSARS). Results Fourteen subjects (8 females) were included. In 10 subjects (71.4%), clinical improvement was noted. The UMSARS score after treatment decreased by 2 points (median [interquartile range, 0–3]) when compared with UMSARS score at baseline ( P = 0.0020). Upon examining the walking parameter, a trend of improvement was shown ( P = 0.0625) (range, 0–1 points). Neither specific demographic parameters nor occurrence of adverse effects was found to be a predictive factor for improvement. Adverse events were mild and transient except for one patient who experienced acute psychosis prompting treatment cessation, upon which psychosis resolved. Conclusions Our preliminary data show that IV amantadine may be a safe and effective therapy in MSA-P. A double-blind placebo-controlled trial is needed to establish the true benefit of amantadine therapy.
    Materialart: Online-Ressource
    ISSN: 1537-162X , 0362-5664
    URL: Article
    DOI: 10.1097/WNF.0000000000000291
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2018
    ZDB Id: 2048796-4
    SSG: 15,3
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  • 7
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    Impact of cortical and subcortical atrophy in the diagnosis and prognosis of bvFTD: A multicenter longitudinal study : Neuroimaging / Optimal neuroimaging measures for tracking disease progression
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S5 ( 2020-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S5 ( 2020-12)
    Kurzfassung: The behavioral variant of frontotemporal dementia (bvFTD) presents with variable patterns of cortical and subcortical atrophy on Magnetic Resonance Imaging (MRI). We aimed to assess the clinical utility of two reproducible measurements of cerebral atrophy (Harper's visual atrophy scale [HVAS], and the Magnetic Resonance Parkinsonism Index [MRPI] ) in a large multicenter sample of bvFTD with longitudinal follow‐up. Methods We included 466 participants from three centers: 241 bvFTD (according to the International bvFTD Criteria Consortium), and 225 healthy controls (HC). Clinical deterioration was assessed with Mini‐Mental State Examination (MMSE) and the Clinical Deterioration Scale Sum‐of‐boxes (CDR‐sb). bvFTD participants were considered to have an increased certainty of underlying Frontotemporal Lobar Degeneration (+FTLD) when: (i) FTLD was confirmed at autopsy (n=72); (ii) a secondary FTLD‐related phenotype was identified during follow‐up (n=47) or (iii) a FTLD‐related mutation was found (n=49). Six raters blinded to clinical data were first asked to dichotomize participants according to the presence of "a clear pattern of atrophy suggestive of probable bvFTD", and then applied the HVAS (ICC(2,k)=.86 to .96). The MRPI was calculated with a fully automated algorithm. Results Mean age of bvFTD participants was 63.3 ± 10, 68% were male (MMSE=23 ± 7 and CDR‐sb=6.7 ± 3.5). Blinded raters had 52% sensitivity and 97% specificity for the identification of bvFTD participants (AUC=.74, p =.001). All HVAS measures with the exception of posterior atrophy discriminated between bvFTD and HC (AUC=.77 to .83, p 〈 .001). The composite bvFTD score (average score of orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe and frontal insula regions) showed the best diagnostic accuracy for the differentiation of bvFTD from HC (AUC=.91, p 〈 .001 in +FTLD). This composite score also differentiated between bvFTD participants that were not considered to have a clear pattern of atrophy suggestive of probable bvFTD (blinded raters) and HC ( p 〈 .001). We hypothesized that HVAS and MRPI scores may be independent predictors of clinical deterioration and survival in bvFTD (definitive results pending). Conclusion The combination of HVAS and MRPI may provide valuable diagnostic and prognostic information in the behavioral syndromes verifying bvFTD criteria. These measures represent reliable, reproducible and affordable imaging biomarkers.
    Materialart: Online-Ressource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S5
    DOI: 10.1002/alz.044984
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2020
    ZDB Id: 2201940-6
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  • 8
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    Local neurodegeneration and global connectivity adaptation across the FTD‐AD spectrum
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S6 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S6 ( 2021-12)
    Kurzfassung: Neurodegenerative diseases involve weakened functional connectivity in disease‐targeted brain areas. Equally important but overlooked is the hyperconnectivity that appears in other brain areas (Hillary and Grafman, TICS 2017). Hyperconnectivity has been attributed to processes like disinhibition, imbalance, compensation, and reserve. It is critical to understand the neuroanatomical mechanism underlying hyperconnectivity because this functional process may accelerate subsequent disease progression. We performed structure‐function mapping for patients across subtypes and stages of the frontotemporal dementia‐Alzheimer’s disease atrophy spectrum. Our goal is to develop a comprehensive model relating diverse focal atrophy patterns to corresponding brain‐wide functional connectivity reconfigurations. Method We studied patients with Alzheimer’s disease (AD), behavioral variant FTD (bvFTD), semantic and nonfluent variant primary progressive aphasia (svPPA/nfvPPA), cortical basal syndrome (CBS), and healthy controls (HC). We included subjects who received a clinical diagnosis at the UCSF Memory and Aging Center and had structural and task‐free functional MRI scans (n=281). Each subject’s gray matter atrophy map was measured using voxel‐based morphometry volume loss in 273 ROIs. Functional connectivity matrices (273x273) were derived for each subject. We combined data for all patients and controls into a structural data matrix (281x273) and a functional data matrix (281x37128). We then performed partial least squares regression to find components that maximized the covariance between structure and function. Result The first PLS component captured the relationship between global atrophy burden and a distributed pattern of functional connectivity loss in unimodal cortical areas and enhancement in subcortical‐cortical pathways (r=0.64; Figure 1 ). The second PLS component showed svPPA‐like anterior temporal atrophy corresponding to atrophy‐proximal connectivity deficits, with enhancements in contralateral frontoparietal areas (r=0.67). The third PLS component revealed a spectrum from anterior (bvFTD) to posterior (AD), contrasting frontal‐insular atrophy, connectivity deficits, and parietal connectivity enhancements versus parietal atrophy, connectivity deficits, and frontal connectivity enhancements (r=0.51). Conclusion Specific atrophy subtypes across the FTD‐AD spectrum associate with proximal functional connectivity reductions. Intriguingly, these subtypes also exhibit concomitant functional connectivity enhancements in more distal areas. The enhancements are of the same magnitude as the deficits and may represent a general principle of functional “load‐shifting” (Jones et al, Brain 2016) away from disease‐targeted areas.
    Materialart: Online-Ressource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S6
    DOI: 10.1002/alz.055308
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2021
    ZDB Id: 2201940-6
    Standort Signatur Einschränkungen Verfügbarkeit
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