Publications by authors named "Daniela Galimberti"

360 Publications

A multicentre validation study of the diagnostic value of plasma neurofilament light.

Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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http://dx.doi.org/10.1038/s41467-021-23620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185001PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study.

Alzheimers Dement (Amst) 2021 13;13(1):e12185. Epub 2021 May 13.

Douglas Mental Health University Institute Department of Psychiatry McGill University Montreal Canada.

Introduction: We aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT).

Methods: The FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [], 163 progranulin [], and 73 microtubule-associated protein tau []) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel-based morphometry to investigate the underlying neural substrates of the FCSRT.

Results: All symptomatic mutation carrier groups and presymptomatic mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic mutation carriers. Performance on the FCSRT correlated with executive function, particularly in mutation carriers, but also with memory and naming tasks in the group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in and , but mainly temporal areas in mutation carriers.

Discussion: The FCSRT detects presymptomatic deficits in - and -associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD.
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http://dx.doi.org/10.1002/dad2.12185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116844PMC
May 2021

Analysis of C9orf72 Intermediate Alleles in a Retrospective Cohort of Neurological Patients: Risk Factors for Alzheimer's Disease?

J Alzheimers Dis 2021 Apr 28. Epub 2021 Apr 28.

Fondazione IRCCS Ca' Granda, Ospedale Policlinico, Milan, Italy.

Background: C9orf72 hexanucleotide GGGGCC (G4C2) large repeat expansions within the first intron of the gene are a major cause of familial frontotemporal dementia, but also of apparently sporadic cases. Alleles with >  30 repeats are often considered pathogenic, but the repeat length threshold is still undefined. It is also unclear if C9orf72 intermediate alleles (9-30 repeats) have clinically significant effects.

Objectives: We correlated the presence of C9orf72 intermediate alleles with clinical diagnoses in a perspective cohort referred to a secondary memory clinic.

Methods: All samples were genotyped with AmplideXPCR/CE C9ORF72 Kit (Asuragen, Inc), an optimized C9orf72 PCR amplification reagent.

Results: We showed that in patients with Alzheimer's disease (AD) the frequency of the intermediate repeat allele was significantly increased versus controls (34/54, 63%AD versus 16/39, 41%CTRLs,  *p = 0.01, OR 2.91 CI 95%1.230-6.077), whereas no significant differences (p >  0.05) were observed when comparing all other dementias with non-demented individuals.

Conclusion: Our findings suggest that C9orf72 intermediate repeat units may represent a genetic risk factor, contributing to the occurrence of AD. Nevertheless, further longitudinal studies, including larger cohort of subjects with intermediate alleles with long-term follow-up, would be needed to confirm these results.
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http://dx.doi.org/10.3233/JAD-210249DOI Listing
April 2021

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

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

Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich German Center for Neurodegenerative Diseases (DZNE), Munich Munich Cluster of Systems Neurology, Munich, Germany.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099608PMC
March 2021

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

Neurology 2021 05 7;96(18):e2296-e2312. Epub 2021 Apr 7.

From the University of California, San Francisco (J.C.R., P.W., A.M.S., Y.C., A.W., S.-Y.M.G., P.A.L., H.W.H., J.C.F., J.B.T., A.M.K., L.L.M., J.K., J.H.K., B.L.M., H.J.S., A.L.B.); UK Dementia Research Centre (C.H., D.M.C., R.S.C., M.B., M.F., C.V.G., G.P., L.R., I.S., E.T., J.D.R.), UCL Institute of Neurology, Queen Square, London; Quanterix Corp (E.V., L.S., A.J., D.H.), Lexington; Novartis Institutes for Biomedical Research Inc (L.Y., A. Khinikar, R.S.), Cambridge, MA; Novartis Pharma AG (A. Kieloch, M.-A.V.), Basel, Switzerland; Bluefield Project to Cure Frontotemporal Dementia (L.L.M., R.P.), San Francisco, CA; Mayo Clinic (K.K., D.S.K., B.F.B.), Rochester, MN; Mayo Clinic (N.G.-R., L.P., R.R.), Jacksonville, FL; University of Pennsylvania (D.J.I., M.G.), Philadelphia; University of California, Los Angeles (E.M.R., G.C., M.F.M., Y.B.); Harvard University/Massachusetts General Hospital (B.D.C.), Boston, MA; Washington University (N.G.), St. Louis, MO; Columbia University (E.D.H.), New York, NY; University of British Columbia (I.R.M., G.-Y.R.H.), Vancouver, Canada; Case Western Reserve University (B.S.A.), Cleveland, OH; University of Washington (K.D.-R.), Seattle; Laboratory of Neuroimaging (A.W.T.), University of Southern California, Los Angeles; Northwestern University (S.W.), Chicago, IL; University of North Carolina (D.I.K.), Chapel Hill; Texas Health Presbyterian Hospital Dallas (D.K.); University of California, San Diego (I.L.); Johns Hopkins Hospital (C.U.O., A.P.), Baltimore, MD; University of Alabama at Birmingham (E.D.R.); University of Toronto (M.C.T., M.M.), Ontario, Canada; Indiana University School of Medicine (T.F.), Indianapolis; Biogen Inc (W.C., J.C., D.L.G.), Cambridge, MA; Erasmus Medical Centre (J.C.v.S.), Rotterdam, the Netherlands; University of Brescia (B.B.), Italy; University of Barcelona (R.S.-V.); Donostia University Hospital (F.M.), San Sebastian, Gipuzkoa, Spain; Clinique Interdisciplinaire de Mémoire (R.L.), Département des Sciences Neurologiques, CHU de Québec; Faculté de Médecine (R.L.), Université Laval, Quebec, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; University of Tübingen (M.S.); Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Fondazione IRCCS Ospedale Policlinico (D.G.); University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospital (J.B.R.), University of Cambridge, UK; University of Western Ontario (E.F.), London, Canada; KU Leuven (R.V.), Belgium; Neurology Service (R.V.), University Hospitals Leuven, Belgium; University of Lisbon (A.d.M.), Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University of Coimbra (I.S.), Portugal; McGill University (S.D.), Montreal, Québec, Canada; University of Oxford (C.R.B.); Wolfson Molecular Imaging Centre (A.G.), University of Manchester, UK; University of Duisburg-Essen (A.G.), Duisberg; Ludwig-Maximilians-Universität München (J.L., A.D.); German Center for Neurodegenerative Diseases (J.L.), Munich Cluster for Systems Neurology (SyNergy); University of Ulm (M.O.), Germany; and Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence, and IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

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 single-molecule array in original (n = 277) and validation (n = 297) cohorts. , , and mutation carriers and noncarriers 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 nonprogressors (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 those with 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.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166434PMC
May 2021

MRI data-driven algorithm for the diagnosis of behavioural variant frontotemporal dementia.

J Neurol Neurosurg Psychiatry 2021 Mar 15. Epub 2021 Mar 15.

McConnell Brain Imaging Center, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Introduction: Structural brain imaging is paramount for the diagnosis of behavioural variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis.

Methods: A total of 515 subjects from two different bvFTD cohorts (training and independent validation cohorts) were used to perform voxel-wise morphometric analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from deformation-based morphometry differences in isolation and together with semantic fluency. Tenfold cross validation was used to assess the performance of the classifier within the training cohort. A second held-out cohort of genetically confirmed bvFTD cases was used for additional validation.

Results: Average 10-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In the separate validation cohort of definite bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added semantic fluency scores.

Conclusion: Our results show that structural MRI and semantic fluency can accurately predict bvFTD at the individual subject level within a completely independent validation cohort coming from a different and independent database.
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http://dx.doi.org/10.1136/jnnp-2020-324106DOI Listing
March 2021

The distinct roles of monoamines in multiple sclerosis: A bridge between the immune and nervous systems?

Brain Behav Immun 2021 05 2;94:381-391. Epub 2021 Mar 2.

Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, UK; Rita Levi Montalcini Department of Neuroscience, University of Torino, Turin, Italy.

The monoaminergic neurotransmitters dopamine, noradrenaline, and serotonin are pivotal actors of the interplay between the nervous and the immune system due to their ability of binding to cell-receptors of both systems, crucially regulating their function within the central nervous system and the periphery. As monoamines are dysfunctional in many neurological and psychiatric diseases, they have been successfully used as pharmacological targets. Multiple sclerosis (MS) is one of the best examples of neurological disease caused by an altered interaction between the nervous and immune system and emerging evidence supports a dysregulation of monoaminergic systems in the pathogenesis of MS, secondary to both inflammation-induced reduction of monoamines' synthesis and structural damage to monoaminergic pathways within the brain. Here we review the evidence for monoamines being key mediators of neuroimmune interaction, affecting MS pathogenesis and course. Moreover, we discuss how the reduction/dysfunction of monoamines in MS may contribute to some clinical features typical of the disease, particularly fatigue and depression. Finally, we summarize different drugs targeting monoamines that are currently under evaluation for their potential efficacy to treat MS, as well as to alleviate fatigue and depression in MS.
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http://dx.doi.org/10.1016/j.bbi.2021.02.030DOI Listing
May 2021

Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis.

Neuroimage Clin 2021 12;30:102587. Epub 2021 Feb 12.

Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, UK; Neuroimaging Laboratory, Santa Lucia Foundation IRCCS, Rome, Italy.

In multiple sclerosis (MS), monoaminergic systems are altered as a result of both inflammation-dependent reduced synthesis and direct structural damage. Aberrant monoaminergic neurotransmission is increasingly considered a major contributor to fatigue pathophysiology. In this study, we aimed to compare the integrity of the monoaminergic white matter fibre tracts projecting from brainstem nuclei in a group of patients with MS (n = 68) and healthy controls (n = 34), and to investigate its association with fatigue. Fibre tracts integrity was assessed with the novel fixel-based analysis that simultaneously estimates axonal density, by means of 'fibre density', and white matter atrophy, by means of fibre 'cross section'. We focused on ventral tegmental area, locus coeruleus, and raphe nuclei as the main source of dopaminergic, noradrenergic, and serotoninergic fibres within the brainstem, respectively. Fourteen tracts of interest projecting from these brainstem nuclei were reconstructed using diffusion tractography, and compared by means of the product of fibre-density and cross-section (FDC). Finally, correlations of monoaminergic axonal damage with the modified fatigue impact scale scores were evaluated in MS. Fixel-based analysis revealed significant axonal damage - as measured by FDC reduction - within selective monoaminergic fibre-tracts projecting from brainstem nuclei in MS patients, in comparison to healthy controls; particularly within the dopaminergic-mesolimbic pathway, the noradrenergic-projections to prefrontal cortex, and serotoninergic-projections to cerebellum. Moreover, we observed significant correlations between severity of cognitive fatigue and axonal damage within the mesocorticolimbic tracts projecting from ventral tegmental area, as well as within the locus coeruleus projections to prefrontal cortex, suggesting a potential contribution of dopaminergic and noradrenergic pathways to central fatigue in MS. Our findings support the hypothesis that axonal damage along monoaminergic pathways contributes to the reduction/dysfunction of monoamines in MS and add new information on the mechanisms by which monoaminergic systems contribute to MS pathogenesis and fatigue. This supports the need for further research into monoamines as therapeutic targets aiming to combat and alleviate fatigue in MS.
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http://dx.doi.org/10.1016/j.nicl.2021.102587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903010PMC
February 2021

Case Report: Efficacy of Rituximab in a Patient With Familial Mediterranean Fever and Multiple Sclerosis.

Front Neurol 2020 6;11:591395. Epub 2021 Jan 6.

Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Donato, Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit & MS Centre, Milan, Italy.

Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disease characterized by recurrent episodes of fever and serositis caused by mutations in the MEFV gene, while Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the CNS with genetic and environmental etiology. The two diseases rarely occur in association with relevant implications for clinical management and drug choice. In this paper, we present the case of a 53-year-old male with an autosomal dominant FMF since childhood who presented acute paresthesia at the right part of the body. He performed a brain and spinal cord MRI, which showed multiple brain lesions and a gd-enhancing lesion in the cervical spinal cord, and then received a diagnosis of MS. He then started Interferonβ-1a which was effective but not tolerated and caused hepatotoxicity, and then shifted to Rituximab with 3-month clinical and neuroradiological efficacy.
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http://dx.doi.org/10.3389/fneur.2020.591395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874168PMC
January 2021

Clinical features and disease course of patients with acute ischaemic stroke just before the Italian index case: Was COVID-19 already there?

Intern Emerg Med 2021 Feb 10. Epub 2021 Feb 10.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Since the end of February 2020, Italy has suffered one of the most severe outbreaks of coronavirus disease 2019 (COVID-19). However, what happened just before the Italian index case has not yet been investigated. To answer this question, we evaluated the potential impact of COVID-19 on the clinical features of a cohort of neurological inpatients admitted right before the Italian index case, as compared to the same period of the previous year. Demographic, clinical, treatment and laboratory data were extracted from medical records. The data collected included all inpatients who had been admitted to the Neurology and Stroke Units of the Ospedale Maggiore Policlinico, Milan, Italy, from December 15, 2018 to February 20, 2019 and from December 15, 2019 to February 20, 2020. Of the 248 patients, 97 subjects (39.1%) were admitted for an acute cerebrovascular event: 46 in the 2018/2019 period (mean [SD] age, 72.3 [15.6] years; 22 men [47.8%]), and 51 in the 2019/2020 interval (mean [SD] age, 72.8 [12.4] years; 24 men [47.1%]). The number of cryptogenic strokes has increased during the 2019-2020 year, as compared to the previous year (30 [58.8%] vs. 18 [39.1%], p = 0.05). These patients had a longer hospitalization (mean [SD] day, 15.7 [10.5] days vs. mean [SD] day, 11.7 [7.2] days, p = 0.03) and more frequent cerebrovascular complications (9 [30.0%] vs. 2 [11.1%]), but presented a lower incidence of cardiocerebral risk factors (18 [60.0%] vs. 14 [77.8%]). Right before the Italian index case, an increase in cryptogenic strokes has occurred, possibly due to the concomitant COVID-19.
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http://dx.doi.org/10.1007/s11739-021-02634-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872881PMC
February 2021

Retinoblastoma Is Characterized by a Cold, CD8+ Cell Poor, PD-L1- Microenvironment, Which Turns Into Hot, CD8+ Cell Rich, PD-L1+ After Chemotherapy.

Invest Ophthalmol Vis Sci 2021 Feb;62(2)

Department of Medicine, Surgery and Neuroscience, Ophthalmology Unit, University Hospital of Siena, Siena, Italy.

Purpose: To investigate the impact of chemotherapy (CHT) on human retinoblastoma (RB) tumor microenvironment (TME).

Cases And Methods: Ninety-four RBs were studied, including 44 primary RBs treated by upfront surgery (Group 1) and 50 primary RBs enucleated after CHT (CHT), either intra-arterial (IAC; Group 2, 33 cases) or systemic (S-CHT; Group 3, 17 cases). Conventional and multiplexed immunohistochemistry were performed to make quantitative comparisons among the three groups, for the following parameters: tumor-infiltrating inflammatory cells (TI-ICs); programmed cell death protein 1 (PD-1) positive TI-ICs; Ki67 proliferation index; gliosis; PD-1 ligand (PD-L1) protein expression; vessel number. We also correlated these TME factors with the presence of histological high-risk factors (HHRF+) and RB anaplasia grade (AG).

Results: After CHT, a decrease in both RB burden and Ki67 positivity was observed. In parallel, most subsets of TI-ICs, PD-1+ TI-ICs, gliosis, and PD-L1 protein expression significantly increased (P < 0.001, P = 0.02, P < 0.001, respectively). Vessel number did not significantly vary. Age, HHRFs+ and AG were significantly different between primary and chemoreduced RBs (P < 0.001, P = 0.006, P = 0.001, respectively) and were correlated with most TME factors.

Conclusions: CHT modulates host antitumor immunity by reorienting the RB TME from anergic into an active, CD8+, PD-L1+ hot state. Furthermore, some clinicopathological characteristics of RB correlate with several factors of TME. Our study adds data in favor of the possibility of a new therapeutic scenario in human RB.
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http://dx.doi.org/10.1167/iovs.62.2.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862737PMC
February 2021

Diogenes syndrome in dementia: a case report.

BJPsych Open 2021 Feb 2;7(2):e43. Epub 2021 Feb 2.

Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Diogenes syndrome is a neurobehavioural syndrome characterised by domestic squalor, hoarding and lack of insight. It is an uncommon but high-mortality condition, often associated with dementia.

Aims: To describe the clinical features and treatment of Diogenes syndrome secondary to behavioural variant frontotemporal dementia (bvFTD).

Method: We describe a case of bvFTD in a 77-year-old man presenting with Diogenes syndrome.

Results: The patient's medical and psychiatric histories were unremarkable, but in recent years he had begun packing his flat with 'art pieces'. Mental state examination revealed confabulation and more structured delusions. Neuropsychological evaluation outlined an impairment in selective attention and letter verbal fluency, but no semantic impairment, in the context of an overall preserved mental functioning. Brain magnetic resonance imaging and positron emission tomography (PET) with fluorodeoxyglucose showed mild bilateral temporo-insular atrophy and hypometabolism in the left-superior temporal gyrus respectively. An amyloid PET scan and genetic analysis covering the dementia spectrum were normal. A diagnosis of bvFTD was made.

Conclusions: The clinical framing of behavioural symptoms of dementia such as hoarding poses a diagnostic challenge. This case illustrates the importance of a deeper understanding of Diogenes syndrome, leading to timelier diagnosis and effective therapeutic strategies.
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http://dx.doi.org/10.1192/bjo.2020.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058863PMC
February 2021

Facing the digital divide into a dementia clinic during COVID-19 pandemic: caregiver age matters.

Neurol Sci 2021 Apr 18;42(4):1247-1251. Epub 2021 Jan 18.

Neurodegenerative Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.

Background: The coronavirus disease 2019 (COVID-19) pandemic has dramatically stressed the health care system and has provoked changes in population use of digital technologies. Digital divide is any uneven distribution in Information and Communications Technologies between people.

Aims: The purpose of this work was to describe the digital divide of a population of patients with dementia contacted by telemedicine during Italian lockdown for COVID-19 pandemic.

Method: One hundred eight patients with cognitive impairment were contacted by video call to perform a telemedicine neurological evaluation. Information on patients and caregivers attending the televisit were recorded.

Results: Seventy-four patients connected with neurologist (successful televisit, 68.5%) and 34 patients were not able to perform televisit and were contacted by phone (failed televisit, 31.5%). No significant differences were observed among the two groups concerning age, gender, and education, but the prevalence of successful televisit was higher in the presence of younger caregivers: televisits performed in the presence of subjects of younger generation (sons and grandsons) had a successful rate higher (86% successful, 14% failed) than the group without younger generation caregiver (49% successful, 51% failed). This difference is mainly due to the ability of technological use among younger people.

Discussion: The most impacting factors on digital divide in our population are the social support networks and the experience with the technology: the presence of a digital native caregiver. The COVID-19 pandemic is unmasking an emerging form of technology-related social inequalities: political and community interventions are needed to support the most socially vulnerable population and prevent social health inequalities.
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http://dx.doi.org/10.1007/s10072-020-05009-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811944PMC
April 2021

Disease-related cortical thinning in presymptomatic granulin mutation carriers.

Neuroimage Clin 2021 29;29:102540. Epub 2020 Dec 29.

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

Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.
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http://dx.doi.org/10.1016/j.nicl.2020.102540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804836PMC
December 2020

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Front Neurol 2020 17;11:579438. Epub 2020 Dec 17.

Department of Neurology, NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.
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http://dx.doi.org/10.3389/fneur.2020.579438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780851PMC
December 2020

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

Detection of the SQSTM1 Mutation in a Patient with Early-Onset Hippocampal Amnestic Syndrome.

J Alzheimers Dis 2021 ;79(2):477-481

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Genetics has a major role in early-onset dementia, but the correspondence between genotype and phenotype is largely tentative. We describe a 54-year-old with familial early-onset slowly-progressive episodic memory impairment with the P392L-variant in SQSTM1. The patient showed cortical atrophy and hypometabolism in the temporal lobes, but no amyloidosis biomarkers. As symptoms/neuroimaging were suggestive for Alzheimer's disease-but biomarkers were not-and considering the family-history, genetic analysis was performed, revealing the P392L-variant in SQSTM1, which encodes for sequestosome-1/p62. Increasing evidence suggests a p62 involvement in neurodegeneration and SQSTM1 mutations have been found to cause amyotrophic lateral sclerosis/frontotemporal dementia. Our report suggests that the clinical spectrum of SQSTM1 variants is wider.
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http://dx.doi.org/10.3233/JAD-201231DOI Listing
January 2021

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

Alzheimers Dement 2021 Jun 14;17(6):969-983. 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
June 2021

Cerebrospinal fluid glutamate changes in functional movement disorders.

NPJ Parkinsons Dis 2020 Dec 4;6(1):37. Epub 2020 Dec 4.

Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.

The aim of this study was to assess cerebrospinal fluid (CSF) concentrations of specific amino acids using a high-performance liquid chromatography system in a sample of patients with functional movement disorders (FMDs) and in a sample of controls. CSF levels of glutamate were significantly lower in patients with FMD than in controls. This finding argues in favor of glutamatergic dysfunction in the pathophysiology of FMD.
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http://dx.doi.org/10.1038/s41531-020-00140-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718900PMC
December 2020

Psychiatric Disorders in Alzheimer Disease With the Presenilin-1 L226F Mutation.

Cogn Behav Neurol 2020 12;33(4):278-282

Aldo Ravelli Center for Neurotechnology and Experimental Neurotherapeutics, University of Milan, Milan, Italy.

The presenilin-1 (PSEN1) L226F mutation has been linked to very early onset of prominent behavioral and psychiatric disturbances followed by cognitive decline within a few years. We report a novel case of early-onset Alzheimer disease that was originally diagnosed as psychotic depression in a patient with this gene mutation. We also compare our patient's clinical data to those of other cases of this mutation that have been described in the literature. Because atypical behavioral and psychiatric disturbances in young (<40 years) individuals can herald Alzheimer disease, a tight collaboration between psychiatrists and neurologists is crucial for an early diagnosis.
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http://dx.doi.org/10.1097/WNN.0000000000000249DOI Listing
December 2020

White Matter Hyperintensities Are No Major Confounder for Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

J Alzheimers Dis 2021 ;79(1):163-175

Department of Geriatrics, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer's disease (AD). However, CSF biomarker levels can be affected by confounding factors.

Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels.

Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis.

Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group.

Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.
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http://dx.doi.org/10.3233/JAD-200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902951PMC
January 2021

Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort.

Cortex 2020 12 26;133:384-398. Epub 2020 Sep 26.

Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.

A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.
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http://dx.doi.org/10.1016/j.cortex.2020.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754789PMC
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

Biomarkers and phenotypic expression in Alzheimer's disease: exploring the contribution of frailty in the Alzheimer's Disease Neuroimaging Initiative.

Geroscience 2021 04 19;43(2):1039-1051. Epub 2020 Nov 19.

Department of Human Neuroscience, "Sapienza" University of Rome, Rome, Italy.

The present study aimed at investigating if the main biomarkers of Alzheimer's disease (AD) neuropathology and their association with cognitive disturbances and dementia are modified by the individual's frailty status. We performed a cross-sectional analysis of data from participants with normal cognition, mild cognitive impairment (MCI), and AD dementia enrolled in the Alzheimer's Disease Neuroimaging Initiative 2 (ADNI2) study. Frailty was operationalized by computing a 40-item Frailty Index (FI). The following AD biomarkers were considered and analyzed according to the participants' frailty status: CSF Aβ, P-tau, and T-tau; MRI-based hippocampus volume; cortical glucose metabolism at the FDG PET imaging; amyloid deposition at the F-AV-45 PET imaging. Logistic regression models, adjusted for age, sex, and education, were performed to explore the association of biomarkers with cognitive status at different FI levels. Subjects with higher FI scores had lower CSF levels of Aβ, hippocampus volumes at the MRI, and glucose metabolism at the FDG PET imaging, and a higher amyloid deposition at the F-AV-45 PET. No significant differences were observed among the two frailty groups concerning ApoE genotype, CSF T-tau, and P-tau. Increasing frailty levels were associated with a weakened relationship between dementia and F-AV-45 uptake and hippocampus volume and with a stronger relationship of dementia with FDG PET. Frailty contributes to the discrepancies between AD pathology and clinical manifestations and influences the association of AD pathological modifications with cognitive changes. AD and dementia should increasingly be conceived as "complex diseases of aging," determined by multiple, simultaneous, and interacting pathophysiological processes.
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http://dx.doi.org/10.1007/s11357-020-00293-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110661PMC
April 2021

Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia.

Brain Commun 2020 Jul 19;2(2). Epub 2020 Aug 19.

Instituto di Recovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work we combined gene expression data for 16,772 genes from the Allen Institute for Brain Science atlas with brain maps of gray matter atrophy in symptomatic and mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between and expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1,000 and 5,000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being and (negative association in and respectively) and , and (positive association in and respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively-associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood-brain barrier respectively.
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http://dx.doi.org/10.1093/braincomms/fcaa122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667525PMC
July 2020

Fluid biomarkers in frontotemporal dementia: past, present and future.

J Neurol Neurosurg Psychiatry 2021 02 13;92(2):204-215. Epub 2020 Nov 13.

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

The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important molecular studies in the early 2000s, major advances have now been made in the understanding of the pathological and genetic underpinnings of the disease. In turn, alongside the development of novel methodologies for measuring proteins and other molecules in biological fluids, the last 10 years have seen a huge increase in biomarker studies within FTD. This recent past has focused on attempting to develop markers that will help differentiate FTD from other dementias (particularly Alzheimer's disease (AD)), as well as from non-neurodegenerative conditions such as primary psychiatric disorders. While cerebrospinal fluid, and more recently blood, markers of AD have been successfully developed, specific markers identifying primary tauopathies or TDP-43 proteinopathies are still lacking. More focus at the moment has been on non-specific markers of neurodegeneration, and in particular, multiple studies of neurofilament light chain have highlighted its importance as a diagnostic, prognostic and staging marker of FTD. As clinical trials get under way in specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids have become important potential measures of therapeutic response. However, understanding of whether drugs restore cellular function will also be important, and studies of key pathophysiological processes, including neuroinflammation, lysosomal function and synaptic health, are also now becoming more common. There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains. Here we provide an overview of the past, present and future of fluid biomarkers within the FTD field.
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http://dx.doi.org/10.1136/jnnp-2020-323520DOI Listing
February 2021

Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer's disease in comparison with healthy aging.

Geroscience 2021 04 31;43(2):985-1001. Epub 2020 Oct 31.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer's disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian' offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.
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http://dx.doi.org/10.1007/s11357-020-00287-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110619PMC
April 2021

Parieto-occipital sulcus widening differentiates posterior cortical atrophy from typical Alzheimer disease.

Neuroimage Clin 2020 28;28:102453. Epub 2020 Sep 28.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, Dino Ferrari Center, CRC Molecular Basis of Neuro-Psycho-Geriatrics Diseases, University of Milan, Milan, Italy.

Objectives: Posterior Cortical Atrophy (PCA) is an atypical presentation of Alzheimer disease (AD) characterized by atrophy of posterior brain regions. This pattern of atrophy is usually evaluated with Koedam visual rating scale, a score developed to enable visual assessment of parietal atrophy on magnetic resonance imaging (MRI). However, Koedam scale is complex to assess and its utility in the differential diagnosis between PCA and typical AD has not been demonstrated yet. The aim of this study is therefore to spot a simple and reliable MRI element able to differentiate between PCA and typical AD using visual rating scales.

Methods: 15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypometabolism on PET-FDG were selected from our centre and compared with 30 typical AD patients and 15 healthy subjects. We used previously validated visual rating scales including Koedam scale, which we divided into three major components: posterior cingulate, precuneus and parieto-occipital. Subsequently we validated the results using the automated software Brainvisa Morphologist and Voxel Based Morphometry (VBM).

Results: Patients with PCA, compared to typical AD, showed higher widening of the parieto-occipital sulcus, assessed both with visual rating scales and Brainvisa. In the corresponding areas, the VBM analysis showed an inverse correlation between the results obtained from the visual evaluation scales with the volume of the grey matter and a direct correlation between the same results with the cerebrospinal fluid volume.

Conclusions: A visually based rating scale for parieto-occipital sulcus can distinguish Posterior Cortical Atrophy from typical Alzheimer disease.
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http://dx.doi.org/10.1016/j.nicl.2020.102453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559336PMC
September 2020

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Neurobiol Aging 2021 03 2;99:99.e15-99.e22. Epub 2020 Sep 2.

Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Fundació Clínic per a la Recerca Biomèdica, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.018DOI Listing
March 2021