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  • 1
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    Online Resource
    Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning : Dementia Praecox Revisited
    American Medical Association (AMA) ; 2022
    In:  JAMA Psychiatry Vol. 79, No. 9 ( 2022-09-01), p. 907-
    Details
    In: JAMA Psychiatry, American Medical Association (AMA), Vol. 79, No. 9 ( 2022-09-01), p. 907-
    Type of Medium: Online Resource
    ISSN: 2168-622X
    URL: Article
    DOI: 10.1001/jamapsychiatry.2022.2075
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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  • 2
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    Factors influencing atrophy progression in primary progressive aphasia
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Primary progressive aphasia (PPA) is a rare primarily language‐related neurodegenerative disorder that subdivides into the non‐fluent (nfvPPA) and the semantic variant (svPPA). Atrophy progression shows variant‐specific patterns, however, its extent seems highly individual and thus difficult to predict. Method We investigated volumetric changes in patients with nfvPPA (n=18) and svPPA (n=15) with an MRI scan (3D T1 MPRAGE sequence, 3T) at baseline and 2‐years follow‐up that were recruited from the prospective German FTLD‐consortium study. According to the LONI Probabilistic Brain Atlas (Shattuck et al., 2009), 56 brain regions were assessed with automated atlas‐based volumetry (Huppertz et al., 2010). Longitudinal volumetric changes were analyzed by means of the R software ( www.r‐project.org ). A possible impact of group, adjusted for age and sex, had been investigated using a linear mixed effect model. Atrophy progression for each region over two years was correlated (Pearson or Kendall rank correlation; 95% BCa bootstrap CI with 1000 replicates) with age at symptom onset, years of education, and disease duration to review a possible relation. Result Volume change within 2‐years revealed parts of the left frontal lobe (up to ‐10%) and subcortical regions in nfvPPA and parts of the left temporal lobe (up to ‐15%) and the hippocampus/amygdala complex in svPPA as most progressive. A correlation analysis with age at symptom onset rendered no relevant results. Higher educated patients showed more atrophy in the right parahippocampal gyrus in nfvPPA and less atrophy in white matter portions of the left superior frontal, the bilateral middle and inferior frontal, the right middle and bilateral lateral orbitofrontal and the bilateral cingulate gyrus in svPPA. Shorter disease duration correlated with higher atrophy in the caudate and putamen in nfvPPA, and in the left middle and inferior temporal gyrus, the right superior and bilateral middle occipital gyrus, the left cuneus, and left angular gyrus in svPPA. Conclusion Age at symptom onset showed no interrelation with atrophy progression in PPA. Higher education levels seem to slow white matter decrease of frontal areas in svPPA. Shorter disease duration is related to increased volume loss in some primarily affected regions in both nfvPPA and svPPA.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S4
    DOI: 10.1002/alz.052567
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 3
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    Utility of the Repeat and Point Test for Subtyping Patients With Primary Progressive Aphasia
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Alzheimer Disease & Associated Disorders Vol. 36, No. 1 ( 2022-01), p. 44-51
    Details
    In: Alzheimer Disease & Associated Disorders, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 1 ( 2022-01), p. 44-51
    Abstract: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). Objective: The aim was to examine the utility of the German version of the Repeat and Point (R & P) Test for subtyping patients with PPA. Method: During the R & P Test, the examiner reads out aloud a noun and the participants are asked to repeat the word and subsequently point to the corresponding picture. Data from 204 patients (68 svPPA, 85 nfvPPA, and 51 lvPPA) and 33 healthy controls were analyzed. Results: Controls completed both tasks with 〉 90% accuracy. Patients with svPPA had high scores in repetition (mean=9.2±1.32) but low scores in pointing (mean=6±2.52). In contrast, patients with nfvPPA and lvPPA performed comparably in both tasks with lower scores in repetition (mean=7.4±2.7 for nfvPPA and 8.2±2.34 for lvPPA) but higher scores in pointing (mean=8.9±1.41 for nfvPPA and 8.6±1.62 for lvPPA). The R & P Test had high accuracy discriminating svPPA from nfvPPA (83% accuracy) and lvPPA (79% accuracy). However, there was low accuracy discriminating nfvPPA from lvPPA ( 〈 60%). Conclusion: The R & P Test helps to differentiate svPPA from 2 nonsemantic variants (nfvPPA and lvPPA). However, additional tests are required for the differentiation of nfvPPA and lvPPA.
    Type of Medium: Online Resource
    ISSN: 0893-0341
    URL: Article
    DOI: 10.1097/WAD.0000000000000482
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2048789-7
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  • 4
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    Quantifying progression in primary progressive aphasia with structural neuroimaging
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. 10 ( 2021-10), p. 1595-1609
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. 10 ( 2021-10), p. 1595-1609
    Abstract: The term primary progressive aphasia (PPA) sums up the non‐fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression. Methods Structural brain imaging and an extensive assessment were applied at baseline and up to 4‐year(s) follow‐up in 269 participants. With automated atlas‐based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials. Results At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (–17%) and of the left temporal lobe for svPPA (–34%) and lvPPA (–24%). Severest progression within 1‐year follow‐up occurred in the basal ganglia in nfvPPA (–7%), in the hippocampus/amygdala in svPPA (–9%), and in (medial) temporal regions in lvPPA (–6%). Conclusion PPA presents as a left‐dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant‐specific.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.10
    DOI: 10.1002/alz.12323
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 5
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    Kosten der Diagnostik kognitiver Störungen in deutschen Gedächtnisambulanzen
    Georg Thieme Verlag KG ; 2022
    In:  Fortschritte der Neurologie · Psychiatrie Vol. 90, No. 07/08 ( 2022-07), p. 361-367
    Details
    In: Fortschritte der Neurologie · Psychiatrie, Georg Thieme Verlag KG, Vol. 90, No. 07/08 ( 2022-07), p. 361-367
    Abstract: Demenzen sind teure Erkrankungen: die jährlichen Kosten betragen in europäischen Versorgungssystemen etwa 28.000 €/Fall mit einer starken Stadien-Abhängigkeit, davon entfallen etwa 19% auf die medizinische Versorgung. Die diagnostischen Kosten hingegen verursachen davon nur einen geringen Teil. Mit Wandel des konzeptuellen Verständnisses von Demenzerkrankungen, der Behandlungsmöglichkeiten und der Leitlinien spielen zunehmend auch Biomarker-Untersuchungen eine wichtige Rolle. Die ökonomischen Auswirkungen der Biomarker-basierten Diagnostik sind derzeit nicht sicher abschätzbar. Zur Erhebung der Kosten einer leitlinien-orientierten ätiologischen Erst-Diagnostik von kognitiven Störungen wurde eine Umfrage im Deutschen Netzwerk Gedächtnisambulanzen (DNG) durchgeführt. An 15 Expertenzentren des DNG wurden systematisch die Personalbindungszeiten für alle Prozeduren und alle beteiligten Berufsgruppen erhoben und die Personalkosten basierend auf den tarifvertraglichen Arbeitgeberkosten berechnet. Zusammen mit den Kosten für technische Untersuchungen wurden Gesamtkosten der Diagnostik für drei Szenarien abgeschätzt: Diagnostik ohne Biomarker € 633,97 €, Diagnostik mit Liquoruntersuchungen € 1.214,90 und Diagnostik mit FDG- plus Amyloid-PET € 4.740,58. Zusätzlich erfolgte eine Analyse der derzeitigen realen Kostensituation in Gedächtnisambulanzen, wobei die Personalbindungszeiten für einzelne Leistungen und die apparativen Kosten ins Verhältnis zur Häufigkeit ihrer Anwendung gesetzt wurden. Als Mittelwert aller Zentren ergeben sich dabei Gesamtkosten von € 1.394,43/Fall (Mittelwert der Personalkosten € 351,72, Mittelwert der Kosten für apparative Diagnostik € 1.042,71). Die Ergebnisse zeigen, dass eine ätiologische Diagnostik von kognitiven Störungen (Demenzen und leichte kognitive Störung) einen Ressourceneinsatz erfordert, welcher derzeit weder durch die Vergütungssysteme von Ambulanzen noch durch die vertragsärztliche Vergütung kostendeckend erstattet wird. Die Biomarker-gestützte Diagnostik dementieller und prädementieller Syndrome wird häufiger werden, wenn sie zur Indikationsstellung vor einer krankheits-modifizierenden Therapie erforderlich ist. Deshalb müssen neue Finanzierungsmodelle entwickelt werden, um die gegenwärtige Lücke in der Kostenerstattung für die ätiologische Diagnostik kognitiver Störungen zu schließen.
    Type of Medium: Online Resource
    ISSN: 0720-4299 , 1439-3522
    URL: Article
    DOI: 10.1055/a-1871-9889
    RVK:
    XA 10000
    Language: German
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2022
    detail.hit.zdb_id: 2037701-0
    SSG: 2,1
    SSG: 5,2
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  • 6
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    A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study
    Springer Science and Business Media LLC ; 2021
    In:  Molecular Neurodegeneration Vol. 16, No. 1 ( 2021-12)
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 16, No. 1 ( 2021-12)
    Abstract: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/s13024-021-00499-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2244557-2
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  • 7
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    Faster Cortical Thinning and Surface Area Loss in Presymptomatic and Symptomatic C9orf72 Repeat Expansion Adult Carriers
    Wiley ; 2020
    In:  Annals of Neurology Vol. 88, No. 1 ( 2020-07), p. 113-122
    Details
    In: Annals of Neurology, Wiley, Vol. 88, No. 1 ( 2020-07), p. 113-122
    Abstract: C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD). We examined aging trajectories of cortical thickness (CTh) and surface area in C9orf72 expansion adult carriers compared to healthy controls to characterize preclinical cerebral changes leading to symptoms. Methods Data were obtained from the Genetic Frontotemporal Dementia Initiative. T1‐weighted magnetic resonance imaging scans were processed with CIVET 2.1 to extract vertex‐wide CTh and cortical surface area (CSA). Symptomatic and presymptomatic subjects were compared to age‐matched controls using mixed‐effects models, controlling for demographic variables. Aging trajectories were compared between carriers and noncarriers by testing the “age by genetic status” interaction. False discovery rate corrections were applied to all vertex‐wide analyses. Results The sample included 640 scans from 386 subjects, including 54 symptomatic C9orf72 carriers (72.2% behavioral variant FTD), 83 asymptomatic carriers, and 249 controls (age range = 18–86 years). Symptomatic carriers showed fairly symmetric reduction in CTh/CSA in most of the frontal lobes, in addition to large temporoparietal areas. Presymptomatic subjects had reduced CTh/CSA in more restricted areas of the medial frontoparietal lobes, in addition to scattered lateral frontal, parietal, and temporal areas. These differences were explained by faster cortical thinning linearly throughout adulthood in a similar anatomical distribution, with differences emerging in the early 30s. CSA reduction was also faster in mutation carriers predominantly in the ventrofrontal regions. Interpretation C9orf72 mutation carriers have faster cortical thinning and surface loss throughout adulthood in regions that show atrophy in symptomatic subjects. This suggests that the pathogenic effects of the mutation lead to structural cerebral changes decades prior to symptoms. ANN NEUROL 2020 ANN NEUROL 2020;88:113–122
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v88.1
    DOI: 10.1002/ana.25748
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2037912-2
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  • 8
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    Data‐driven staging of genetic frontotemporal dementia using multi‐modal MRI
    Wiley ; 2022
    In:  Human Brain Mapping Vol. 43, No. 6 ( 2022-04-15), p. 1821-1835
    Details
    In: Human Brain Mapping, Wiley, Vol. 43, No. 6 ( 2022-04-15), p. 1821-1835
    Abstract: Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high‐dimensional large‐scale population datasets to obtain individual scores of disease stage. We used cross‐sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting‐state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI‐obtained disease scores to the estimated years to onset (age—mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre‐dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data‐driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.
    Type of Medium: Online Resource
    ISSN: 1065-9471 , 1097-0193
    URL: Issue
    URL: Article
    DOI: 10.1002/hbm.v43.6
    DOI: 10.1002/hbm.25727
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1492703-2
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  • 9
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    Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia
    BMJ ; 2020
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, No. 6 ( 2020-06), p. 612-621
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 91, No. 6 ( 2020-06), p. 612-621
    Abstract: Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD. Methods We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN , C9orf72 or MAPT , and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses. Results Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301–872)) than presymptomatic carriers (1003 pg/mL (624–1358), p 〈 0.001) and non-carriers (990 pg/mL (597–1373), p 〈 0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage. Discussion We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-322493
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1480429-3
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  • 10
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    Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia
    BMJ ; 2020
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, No. 3 ( 2020-03), p. 263-270
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 91, No. 3 ( 2020-03), p. 263-270
    Abstract: There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, –61.3 to 54.6), MAPT mutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions Raised GFAP concentrations appear to be unique to GRN -related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-321954
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1480429-3
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