Publications by authors named "Mario Masellis"

220 Publications

The CBI-R detects early behavioural impairment in genetic frontotemporal dementia.

Ann Clin Transl Neurol 2022 05 26;9(5):644-658. Epub 2022 Mar 26.

Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.

Introduction: Behavioural dysfunction is a key feature of genetic frontotemporal dementia (FTD) but validated clinical scales measuring behaviour are lacking at present.

Methods: We assessed behaviour using the revised version of the Cambridge Behavioural Inventory (CBI-R) in 733 participants from the Genetic FTD Initiative study: 466 mutation carriers (195 C9orf72, 76 MAPT, 195 GRN) and 267 non-mutation carriers (controls). All mutation carriers were stratified according to their global CDR plus NACC FTLD score into three groups: asymptomatic (CDR = 0), prodromal (CDR = 0.5) and symptomatic (CDR = 1+). Mixed-effects models adjusted for age, education, sex and family clustering were used to compare between the groups. Neuroanatomical correlates of the individual domains were assessed within each genetic group.

Results: CBI-R total scores were significantly higher in all CDR 1+ mutation carrier groups compared with controls [C9orf72 mean 70.5 (standard deviation 27.8), GRN 56.2 (33.5), MAPT 62.1 (36.9)] as well as their respective CDR 0.5 groups [C9orf72 13.5 (14.4), GRN 13.3 (13.5), MAPT 9.4 (10.4)] and CDR 0 groups [C9orf72 6.0 (7.9), GRN 3.6 (6.0), MAPT 8.5 (13.3)]. The C9orf72 and GRN 0.5 groups scored significantly higher than the controls. The greatest impairment was seen in the Motivation domain for the C9orf72 and GRN symptomatic groups, whilst in the symptomatic MAPTgroup, the highest-scoring domains were Stereotypic and Motor Behaviours and Memory and Orientation. Neural correlates of each CBI-R domain largely overlapped across the different mutation carrier groups.

Conclusions: The CBI-R detects early behavioural change in genetic FTD, suggesting that it could be a useful measure within future clinical trials.
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http://dx.doi.org/10.1002/acn3.51544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082390PMC
May 2022

Frequency and Longitudinal Course of Motor Signs In Genetic Frontotemporal Dementia.

Neurology 2022 Aug 10. Epub 2022 Aug 10.

Dementia Research Centre, University College London, London, United Kingdom.

Background And Objectives: Frontotemporal dementia (FTD) is a highly heritable disorder. The majority of genetic cases are caused by autosomal dominant pathogenic variants in the , and gene. As motor disorders are increasingly recognized as part of the clinical spectrum the current study aimed to describe motor phenotypes caused by genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.

Methods: We analyzed baseline visit data of known carriers of a pathogenic variant in the gene from the Genetic Frontotemporal dementia Initiative cohort study. Principal component analysis with varimax rotation was performed to identify motor sign clusters that were compared with respect to frequency and severity between groups. Associations with cross-sectional atrophy patterns were determined using voxel-wise regression. We applied linear mixed effects models to assess whether groups differed in the association between motor signs and estimated time to symptom onset.

Results: 322 pathogenic variant carriers were included in the analysis: 122 (79 presymptomatic) 143 (112 presymptomatic) and 57 (43 presymptomatic) pathogenic variant carriers. Principal component analysis revealed five motor clusters, which we call progressive supranuclear palsy like (PSP-like), bulbar amyotrophic lateral sclerosis (ALS) like, mixed/ALS-like, Parkinson's disease like (PD-like), and corticobasal syndrome like motor phenotypes. There was no significant group difference in the frequency of signs of different motor phenotypes. However, mixed/ALS-like motor signs were most frequent, followed by PD-like motor signs. While the PSP-like phenotype was associated with mesencephalic atrophy, the mixed/ALS-like phenotype was associated with motor cortex and corticospinal tract atrophy. The PD-like phenotype was associated with widespread cortical and subcortical atrophy. Estimated time to onset, genetic group and their interaction, influenced motor signs. In pathogenic variant carriers, motor signs could be detected up to 25 years prior to expected symptom onset.

Discussion: These results indicate the presence of multiple natural clusters of motor signs in genetic FTD, each correlated with specific atrophy patterns. Their motor severity depends on time and the affected gene. These clinico-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.
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http://dx.doi.org/10.1212/WNL.0000000000200828DOI Listing
August 2022

Hierarchical spectral clustering reveals brain size and shape changes in asymptomatic carriers of .

Brain Commun 2022 18;4(4):fcac182. Epub 2022 Jul 18.

Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven 3000, Belgium.

Traditional methods for detecting asymptomatic brain changes in neurodegenerative diseases such as Alzheimer's disease or frontotemporal degeneration typically evaluate changes in volume at a predefined level of granularity, e.g. voxel-wise or in a priori defined cortical volumes of interest. Here, we apply a method based on hierarchical spectral clustering, a graph-based partitioning technique. Our method uses multiple levels of segmentation for detecting changes in a data-driven, unbiased, comprehensive manner within a standard statistical framework. Furthermore, spectral clustering allows for detection of changes in shape along with changes in size. We performed tensor-based morphometry to detect changes in the Genetic Frontotemporal dementia Initiative asymptomatic and symptomatic frontotemporal degeneration mutation carriers using hierarchical spectral clustering and compared the outcome to that obtained with a more conventional voxel-wise tensor- and voxel-based morphometric analysis. In the symptomatic groups, the hierarchical spectral clustering-based method yielded results that were largely in line with those obtained with the voxel-wise approach. In asymptomatic expansion carriers, spectral clustering detected changes in size in medial temporal cortex that voxel-wise methods could only detect in the symptomatic phase. Furthermore, in the asymptomatic and the symptomatic phases, the spectral clustering approach detected changes in shape in the premotor cortex in . In summary, the present study shows the merit of hierarchical spectral clustering for data-driven segmentation and detection of structural changes in the symptomatic and asymptomatic stages of monogenic frontotemporal degeneration.
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http://dx.doi.org/10.1093/braincomms/fcac182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311825PMC
July 2022

Biofluid markers of blood-brain barrier disruption and neurodegeneration in Lewy body spectrum diseases: A systematic review and meta-analysis.

Parkinsonism Relat Disord 2022 Jun 20. Epub 2022 Jun 20.

Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada; KITE UHN Toronto Rehabilitation Institute, Toronto, Ontario, Canada. Electronic address:

Background: Mixed evidence supports blood-brain barrier (BBB) dysfunction in Lewy body spectrum diseases.

Methods: We compare biofluid markers in people with idiopathic Parkinson's disease (PD) and people with PD dementia (PDD) and/or dementia with Lewy bodies (DLB), compared with healthy controls (HC). Seven databases were searched up to May 10, 2021. Outcomes included cerebrospinal fluid to blood albumin ratio (Q), and concentrations of 7 blood protein markers that also reflect BBB disruption and/or neurodegenerative co-pathology. We further explore differences between PD patients with and without evidence of dementia. Random-effects models were used to obtain standardized mean differences (SMD) with 95% confidence interval.

Results: Of 13,949 unique records, 51 studies were meta-analyzed. Compared to HC, Q was higher in PD (N/N = 224/563; SMD = 0.960 [0.227-1.694], p = 0.010; I = 92.2%) and in PDD/DLB (N/N = 265/670; SMD = 1.126 [0.358-1.893], p < 0.001; I = 78.2%). Blood neurofilament light chain (NfL) was higher in PD (N/N = 1848/1130; SMD = 0.747 [0.442-1.052], p < 0.001; I = 91.9%) and PDD/DLB (N/N = 183/469; SMD = 1.051 [0.678-1.423], p = 0.004; I = 92.7%) than in HC. p-tau 181 (N/N = 276/164; SMD = 0.698 [0.149-1.247], p = 0.013; I = 82.7%) was also higher in PD compared to HC. In exploratory analyses, blood NfL was higher in PD without dementia (N/N = 1005/740; SMD = 0.252 [0.042-0.462], p = 0.018; I = 71.8%) and higher in PDD (N/N = 100/111; SMD = 0.780 [0.347-1.214], p < 0.001; I = 46.7%) compared to HC. Q (N/N = 63/191; SMD = 0.482 [0.189-0.774], p = 0.010; I<0.001%) and NfL (N/N = 100/223; SMD = 0.595 [0.346-0.844], p < 0.001; I = 3.4%) were higher in PDD than in PD without dementia.

Conclusions: Biofluid markers suggest BBB disruption and neurodegenerative co-pathology involvement in common Lewy body diseases. Greater evidence of BBB breakdown was seen in Lewy body disease with cognitive impairment.
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http://dx.doi.org/10.1016/j.parkreldis.2022.06.004DOI Listing
June 2022

Elevated regional cerebral blood flow in adults with 22q11.2 deletion syndrome.

World J Biol Psychiatry 2022 Jul 15:1-6. Epub 2022 Jul 15.

Institute of Medical Science, University of Toronto, Toronto, Canada.

Objectives: Recurrent chromosome 22q11.2 deletions cause 22q11 deletion syndrome (22q11DS), a multisystem disorder associated with high rates of schizophrenia. Neuroanatomical changes on brain MRI have been reported in relation to 22q11DS. However, to date no 22q11DS neuroimaging studies have examined cerebral blood flow (CBF). This exploratory case-control study seeks to identify differences in regional cerebral blood flow between 22q11DS subjects and controls, and their association with psychotic symptoms.

Methods: This study of 23 adults used arterial spin labelling MRI to investigate voxel-wise CBF in 22q11DS individuals compared with age- and sex-matched healthy controls.

Results: Four significant clusters, involving the right and left putamen, right fusiform gyrus and left middle temporal gyrus, delineated significantly elevated CBF in individuals with 22q11DS compared to controls. analysis determined that this elevation in CBF trended with psychotic symptom diagnosis within the 22q11DS group.

Conclusions: These findings suggest possible relevance to schizophrenia risk and support further functional neuroimaging studies of 22q11DS with larger sample sizes to improve our understanding of the underlying pathophysiology.
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http://dx.doi.org/10.1080/15622975.2022.2093969DOI Listing
July 2022

Targeted copy number variant identification across the neurodegenerative disease spectrum.

Mol Genet Genomic Med 2022 Aug 3;10(8):e1986. Epub 2022 Jun 3.

Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Background: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied.

Methods: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519).

Results: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1-5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7-11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies.

Conclusion: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.
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http://dx.doi.org/10.1002/mgg3.1986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356547PMC
August 2022

Caregiving concerns and clinical characteristics across neurodegenerative and cerebrovascular disorders in the Ontario neurodegenerative disease research initiative.

Int J Geriatr Psychiatry 2022 06;37(6)

Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada.

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?

Methods/design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery.

Results: We found three components in the ZBI. The first was "overall burden" and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = -0.566, basic ADLs r = -0.43), (2) moderately related to cognition (MoCA r = -0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners.

Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions.
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http://dx.doi.org/10.1002/gps.5727DOI Listing
June 2022

Case of a Man with Hemichorea and Behavioral Changes: "A Red Herring".

Mov Disord Clin Pract 2022 May 30;9(4):501-507. Epub 2022 Mar 30.

Division of Neurology, Department of Medicine University of Toronto Toronto Ontario Canada.

Background: Progressive supranuclear palsy (PSP)-pallido-nigro-luysian atrophy (PNLA) is a neuropathological entity thought to be a variant of classic PSP. Clinical features and pathologic hallmarks are the same in both conditions; however, age and order of symptom onset, disease duration and prognosis, and distribution and density of pathology differentiate the 2 entities.

Objectives: This study presents a PSP-PNLA case confirmed pathologically with a clinical presentation of hemichorea/ballism, spasticity, progressive hemiparesis, and a frontal behavioral syndrome with relative cognitive sparing early in the disease course.

Methods: We describe the clinical progression in this unique case supplemented with video and imaging findings in the form of magnetic resonance imaging and brain single photon emission computed tomography. Final diagnosis is via pathological analysis at autopsy.

Results: We present an elderly gentleman who manifested a clinical syndrome consisting of subacute onset of chorea that at presentation was distinctly unilateral and a frontal behavioral syndrome in the setting of mild thrombocytopenia and elevated anticardiolipin antibodies. Positive antiphospholipid antibodies resulted in an initial antemortem diagnosis of primary antiphospholipid syndrome as a cause of his chorea. Longitudinal follow-up over 5 years demonstrated a progression of clinical features with hemi-motor impersistence/chorea, disinhibition and impulsivity, and eventually corticospinal distribution weakness on the initially affected side. He required nursing home care and falls necessitated wheelchair use. Postmortem neuropathological study revealed a diagnosis of frontotemporal lobar degeneration-tau, PSP-PNLA.

Conclusions: This case broadens the phenotype of PSP-PNLA and to our knowledge is the only case presenting with unilateral chorea.
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http://dx.doi.org/10.1002/mdc3.13433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092749PMC
May 2022

Data-Driven Analyses of Longitudinal Hippocampal Imaging Trajectories: Discrimination and Biomarker Prediction of Change Classes.

J Alzheimers Dis 2022 ;88(1):97-115

Department of Psychology, University of Alberta, Edmonton, AB, Canada.

Background: Hippocampal atrophy is a well-known biomarker of neurodegeneration, such as that observed in Alzheimer's disease (AD). Although distributions of hippocampal volume trajectories for asymptomatic individuals often reveal substantial heterogeneity, it is unclear whether interpretable trajectory classes can be objectively detected and used for prediction analyses.

Objective: To detect and predict hippocampal trajectory classes in a computationally competitive context using established AD-related risk factors/biomarkers.

Methods: We used biomarker/risk factor and longitudinal MRI data in asymptomatic adults from the AD Neuroimaging Initiative (n = 351; Mean = 75 years; 48.7% female). First, we applied latent class growth analyses to left (LHC) and right (RHC) hippocampal trajectory distributions to identify distinct classes. Second, using random forest analyses, we tested 38 multi-modal biomarkers/risk factors for their relative importance in discriminating the lower (potentially elevated atrophy risk) from the higher (potentially reduced risk) class.

Results: For both LHC and RHC trajectory distribution analyses, we observed three distinct trajectory classes. Three biomarkers/risk factors predicted membership in LHC and RHC lower classes: male sex, higher education, and lower plasma Aβ1-42. Four additional factors selectively predicted membership in the lower LHC class: lower plasma tau and Aβ1-40, higher depressive symptomology, and lower body mass index.

Conclusion: Data-driven analyses of LHC and RHC trajectories detected three classes underlying the heterogeneous distributions. Machine learning analyses determined three common and four unique biomarkers/risk factors discriminating the higher and lower LHC/RHC classes. Our sequential analytic approach produced evidence that the dynamics of preclinical hippocampal trajectories can be predicted by AD-related biomarkers/risk factors from multiple modalities.
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http://dx.doi.org/10.3233/JAD-215289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9277685PMC
January 2022

Effects of white matter hyperintensities, neuropsychiatric symptoms, and cognition on activities of daily living: Differences between Alzheimer's disease and dementia with Lewy bodies.

Alzheimers Dement (Amst) 2022 2;14(1):e12306. Epub 2022 May 2.

Division of Neurology, Department of Medicine University of Toronto Toronto Ontario Canada.

Introduction: Disability is common across Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). White matter hyperintensities (WMHs) are prevalent in both diagnoses and associated with disability; both diagnoses show neuropsychiatric symptoms (NPS) and impaired cognition.

Methods: In AD and DLB, we examined if WMHs, NPS, and cognition associate with basic and/or instrumental activities of daily living (BADLs and/or IADLs) cross-sectionally, and longitudinally over ≈1.4 years.

Results: Across both diagnoses, NPS were not only associated with greater disability in performing both BADLs and IADLs, but were also associated with a decline in the ability to perform BADLs in the AD group. In the DLB group only, higher WMH volume was associated with greater disability in performing both BADLs and IADLs, and was associated with a decline in the ability to perform BADL over time.

Discussion: Management of NPS and WMHs, particularly in DLB, might help maintain functionality in dementia patients for longer.
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http://dx.doi.org/10.1002/dad2.12306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9060552PMC
May 2022

Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort.

Neurology 2022 Apr 28. Epub 2022 Apr 28.

Divison of Neuroscience & Experimental Psychology, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, United Kingdom.

Background And Objectives: Disease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating firstly, cognitive decline in a large cohort of genetic FTD pathogenic variant carriers, and secondly, whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal and symptomatic).

Methods: , and pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering eight cognitive domains, as part of the Genetic FTD Initiative (GENFI), a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global CDR® plus NACC FTLD score (0, 0.5 and ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages, as well as the three-way interaction between time, genetic group and disease stage.

Results: 207 , 206 , 86 pathogenic variant carriers and 255 controls were included. pathogenic variant carriers performed lower on attention, executive function and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1.

Discussion: We confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive endpoints for measuring treatment effects as well as characterizing the best time window for starting treatment.
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http://dx.doi.org/10.1212/WNL.0000000000200384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302936PMC
April 2022

Small and Large Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia of Parkinson's Disease Patients.

Mov Disord 2022 06 11;37(6):1304-1309. Epub 2022 Apr 11.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.

Background: Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested.

Objective: The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD.

Methods: We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study.

Results: Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P = 0.008) and II (both P = 0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition.

Conclusions: Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.29010DOI Listing
June 2022

Development of a sensitive trial-ready poly(GP) CSF biomarker assay for -associated frontotemporal dementia and amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2022 07 4;93(7):761-771. Epub 2022 Apr 4.

Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.

Objective: A GGGGCC repeat expansion in the gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. Our objective was to develop such an assay.

Methods: We used the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the repeat expansion in cerebrospinal fluid (CSF) of people with -associated FTD/ALS.

Results And Conclusions: We show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intraplate and interplate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze-thaw and no haemoglobin interference. We used this assay to measure poly(GP) in CSF samples collected through the Genetic FTD Initiative (N=40 and 15 controls). We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the CSF sample with the lowest poly(GP) signal had eightfold higher signal than controls and on average values from samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing repeat-containing transcripts.
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http://dx.doi.org/10.1136/jnnp-2021-328710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279742PMC
July 2022

Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations.

J Neurol 2022 Aug 29;269(8):4322-4332. Epub 2022 Mar 29.

Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Université, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.

Introduction: A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail.

Methods: We investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis.

Results: All symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions.

Conclusion: This study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.
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http://dx.doi.org/10.1007/s00415-022-11068-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294015PMC
August 2022

Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia.

Neurobiol Aging 2022 06 26;114:94-104. Epub 2022 Feb 26.

University Hospital of Coimbra (HUC), Neurology Service, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Frontotemporal dementia associated with granulin (GRN) mutations presents asymmetric brain atrophy. We applied a Minimum Spanning Tree plus an Efficiency Cost Optimization approach to cortical thickness data in order to test whether graph theory measures could identify global or local impairment of connectivity in the presymptomatic phase of pathology, where other techniques failed in demonstrating changes. We included 52 symptomatic GRN mutation carriers (SC), 161 presymptomatic GRN mutation carriers (PSC) and 341 non-carriers relatives from the Genetic Frontotemporal dementia research Initiative cohort. Group differences of global, nodal and edge connectivity in (Minimum Spanning Tree plus an Efficiency Cost Optimization) graph were tested via Structural Equation Models. Global graph perturbation was selectively impaired in SC compared to non-carriers, with no changes in PSC. At the local level, only SC exhibited perturbation of frontotemporal nodes, but edge connectivity revealed a characteristic pattern of interhemispheric disconnection, involving homologous parietal regions, in PSC. Our results suggest that GRN-related frontotemporal dementia resembles a disconnection syndrome, with interhemispheric disconnection between parietal regions in presymptomatic phases that progresses to frontotemporal areas as symptoms emerge.
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http://dx.doi.org/10.1016/j.neurobiolaging.2022.02.009DOI Listing
June 2022

Examining empathy deficits across familial forms of frontotemporal dementia within the GENFI cohort.

Cortex 2022 05 9;150:12-28. Epub 2022 Feb 9.

Univ Lille, France; Inserm 1172, Lille, France; CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, France.

Background: Reduced empathy is a common symptom in frontotemporal dementia (FTD). Although empathy deficits have been extensively researched in sporadic cases, few studies have explored the differences in familial forms of FTD.

Methods: Empathy was examined using a modified version of the Interpersonal Reactivity Index (mIRI) in 676 participants from the Genetic FTD Initiative: 216 mutation-negative controls, 192 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. Using global scores from the CDR® plus NACC FTLD, mutation carriers were divided into three groups, asymptomatic (0), very mildly symptomatic/prodromal (.5), or fully symptomatic (1 or more). The mIRI Total score, as well as the subscores of Empathic Concern (EC) and Perspective Taking (PT) were assessed. Linear regression models with bootstrapping were used to assess empathy ratings across genetic groups, as well as across phenotypes in the symptomatic carriers. Neural correlates of empathy deficits were examined using a voxel-based morphometry (VBM) analysis.

Results: All fully symptomatic groups scored lower on the mIRI Total, EC, and PT when compared to controls and their asymptomatic or prodromal counterparts (all p < .001). Prodromal C9orf72 expansion carriers also scored significantly lower than controls on the mIRI Total score (p = .046). In the phenotype analysis, all groups (behavioural variant FTD, primary progressive aphasia and FTD with amyotrophic lateral sclerosis) scored significantly lower than controls (all p < .007). VBM revealed an overlapping neural correlate of the mIRI Total score across genetic groups in the orbitofrontal lobe but with additional involvement in the temporal lobe, insula and basal ganglia in both the GRN and MAPT groups, and uniquely more posterior regions such as the parietal lobe and thalamus in the GRN group, and medial temporal structures in the MAPT group.

Conclusions: Significant empathy deficits present in genetic FTD, particularly in symptomatic individuals and those with a bvFTD phenotype, while prodromal deficits are only seen using the mIRI in C9orf72 expansion carriers.
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http://dx.doi.org/10.1016/j.cortex.2022.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067453PMC
May 2022

Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases.

Geroscience 2022 Jun 16;44(3):1575-1598. Epub 2022 Mar 16.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson's disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.
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http://dx.doi.org/10.1007/s11357-022-00539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213606PMC
June 2022

Common Data Elements to Facilitate Sharing and Re-use of Participant-Level Data: Assessment of Psychiatric Comorbidity Across Brain Disorders.

Front Psychiatry 2022 7;13:816465. Epub 2022 Feb 7.

Tanz Centre for Research in Neurodegenerative Diseases University of Toronto, Toronto, ON, Canada.

The Ontario Brain Institute's "Brain-CODE" is a large-scale informatics platform designed to support the collection, storage and integration of diverse types of data across several brain disorders as a means to understand underlying causes of brain dysfunction and developing novel approaches to treatment. By providing access to aggregated datasets on participants with and without different brain disorders, Brain-CODE will facilitate analyses both within and across diseases and cover multiple brain disorders and a wide array of data, including clinical, neuroimaging, and molecular. To help achieve these goals, consensus methodology was used to identify a set of core demographic and clinical variables that should be routinely collected across all participating programs. Establishment of Common Data Elements within Brain-CODE is critical to enable a high degree of consistency in data collection across studies and thus optimize the ability of investigators to analyze pooled participant-level data within and across brain disorders. Results are also presented using selected common data elements pooled across three studies to better understand psychiatric comorbidity in neurological disease (Alzheimer's disease/amnesic mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia, and Parkinson's disease).
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http://dx.doi.org/10.3389/fpsyt.2022.816465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859302PMC
February 2022

Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia.

Brain 2022 Feb 21. Epub 2022 Feb 21.

Department of Neurology, Erasmus University Medical Centre, Rotterdam, Netherlands.

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioral variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). We first identify distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally- connected neighbors, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicenter of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. Finally, we find that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.
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http://dx.doi.org/10.1093/brain/awac069DOI Listing
February 2022

Data-driven staging of genetic frontotemporal dementia using multi-modal MRI.

Hum Brain Mapp 2022 04 3;43(6):1821-1835. Epub 2022 Feb 3.

McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

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.
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http://dx.doi.org/10.1002/hbm.25727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933323PMC
April 2022

Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation.

Hum Brain Mapp 2022 05 28;43(7):2089-2108. Epub 2022 Jan 28.

Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.

White matter hyperintensities (WMHs) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D convolutional neural network with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control, and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. Four hundred thirty-two subjects were recruited to train the CNNs from four multisite imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multisite study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on "clinical adversarial cases" simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io.
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http://dx.doi.org/10.1002/hbm.25784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996363PMC
May 2022

An Automated Toolbox to Predict Single Subject Atrophy in Presymptomatic Granulin Mutation Carriers.

J Alzheimers Dis 2022 ;86(1):205-218

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

Background: Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD).

Objectives: To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD.

Methods: 84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded.

Results: Prediction accuracy was high for each considered brain region (i.e., prefrontal region, real CT at follow-up versus predicted CT at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05).

Conclusion: The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself.
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http://dx.doi.org/10.3233/JAD-215447DOI Listing
April 2022

Cognitive composites for genetic frontotemporal dementia: GENFI-Cog.

Alzheimers Res Ther 2022 01 19;14(1):10. Epub 2022 Jan 19.

Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.

Background: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design.

Methods: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be).

Results: The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period.

Discussion: We created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
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http://dx.doi.org/10.1186/s13195-022-00958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772227PMC
January 2022

Consensus Statement Regarding the Application of Biogen to Health Canada for Approval of Aducanumab.

Can Geriatr J 2021 Dec 1;24(4):373-378. Epub 2021 Dec 1.

Faculté de médecine, Université Laval, Laval, QC.

Alzheimer's disease is a major cause of morbidity and mortality. Currently, there are no disease-modifying pharmacotherapies for this condition. Aducanumab, an amyloid beta-directed monoclonal antibody that targets aggregated forms of amyloid-beta in the brains of people with Alzheimer's disease, has raised hopes that such a therapy has been discovered, but its approval by the US Food and Drug Administration has engendered a good deal of controversy. A similar application for approval has been submitted to Health Canada. In response to this, a group of Canadian clinical dementia experts representing a number of organizations, including the Canadian Geriatrics Society, was convened by the Canadian Consortium on Neurodegeneration in Aging (CCNA) to discuss the evidence currently available on this agent and seek consensus on what advice they would offer Health Canada on the application. There was wide-spread agreement that it would be premature for aducanumab to receive approval for the treatment of Alzheimer's disease. It was also noted that the Canadian health-care system is poorly prepared at this time to deal with a disease-modifying therapeutic with targeting, administration, and monitoring characteristics like aducanumab. In this paper, the consensus reached is presented along with its underlying rationale.
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http://dx.doi.org/10.5770/cgj.24.570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629494PMC
December 2021

Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia.

Alzheimers Dement 2022 07 7;18(7):1408-1423. Epub 2021 Dec 7.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

The presymptomatic stages of frontotemporal dementia (FTD) are still poorly defined and encompass a long accrual of progressive biological (preclinical) and then clinical (prodromal) changes, antedating the onset of dementia. The heterogeneity of clinical presentations and the different neuropathological phenotypes have prevented a prior clear description of either preclinical or prodromal FTD. Recent advances in therapeutic approaches, at least in monogenic disease, demand a proper definition of these predementia stages. It has become clear that a consensus lexicon is needed to comprehensively describe the stages that anticipate dementia. The goal of the present work is to review existing literature on the preclinical and prodromal phases of FTD, providing recommendations to address the unmet questions, therefore laying out a strategy for operationalizing and better characterizing these presymptomatic disease stages.
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http://dx.doi.org/10.1002/alz.12485DOI Listing
July 2022

Differential Cognitive Decline in Alzheimer's Disease Is Predicted by Changes in Ventricular Size but Moderated by Apolipoprotein E and Pulse Pressure.

J Alzheimers Dis 2022 ;85(2):545-560

Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Background: Differential cognitive trajectories in Alzheimer's disease (AD) may be predicted by biomarkers from multiple domains.

Objective: In a longitudinal sample of AD and AD-related dementias patients (n = 312), we tested whether 1) change in brain morphometry (ventricular enlargement) predicts differential cognitive trajectories, 2) further risk is contributed by genetic (Apolipoprotein E [APOE] ɛ4+) and vascular (pulse pressure [PP]) factors separately, and 3) the genetic + vascular risk moderates this pattern.

Methods: We applied a dynamic computational approach (parallel process models) to test both concurrent and change-related associations between predictor (ventricular size) and cognition (executive function [EF]/attention). We then tested these associations as stratified by APOE (ɛ4-/ɛ4+), PP (low/high), and APOE+ PP (low/intermediate/high) risk.

Results: First, concurrently, higher ventricular size predicted lower EF/attention performance and, longitudinally, increasing ventricular size predicted steeper EF/attention decline. Second, concurrently, higher ventricular size predicted lower EF/attention performance selectively in APOEɛ4+ carriers, and longitudinally, increasing ventricular size predicted steeper EF/attention decline selectively in the low PP group. Third, ventricular size and EF/attention associations were absent in the high APOE+ PP risk group both concurrently and longitudinally.

Conclusion: As AD progresses, a threshold effect may be present in which ventricular enlargement in the context of exacerbated APOE+ PP risk does not produce further cognitive decline.
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http://dx.doi.org/10.3233/JAD-215068DOI Listing
February 2022

Brain structure and function in people recovering from COVID-19 after hospital discharge or self-isolation: a longitudinal observational study protocol.

CMAJ Open 2021 Oct-Dec;9(4):E1114-E1119. Epub 2021 Nov 30.

Hurvitz Brain Sciences Program (MacIntosh, Gao, Masellis, Goubran, Lam, Heyn, Black, Graham), Physical Sciences Platform (MacIntosh, Jegatheesan, Goubran, Graham), Evaluative Clinical Sciences, Integrated Community Program (Cheng), Harquail Centre for Neuromodulation (Rabin) and Evaluative Clinical Sciences, Trauma, Emergency & Critical Care Research Program (Fowler), Sunnybrook Research Institute; Department of Medical Biophysics (MacIntosh, Chen, Chad, Jegatheesan, Goubran, Graham), University of Toronto; LC Campbell Cognitive Neurology Research Group (Ji, Gao, Masellis, Lam, Black), Sunnybrook Hospital; Rotman Research Institute (Chen, Gilboa, Roudaia, Sekuler, Chad), Baycrest Health Sciences; Division of Neurology (Masellis, Rabin, Lam, Black), Department of Medicine, University of Toronto; Rehabilitation Sciences Institute (Rabin), Department of Medical Imaging (Heyn) and Department of Psychology (Gilboa, Sekuler), University of Toronto; Department of Medicine (Cheng, Fowler), University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ont.; Department of Psychology, Neuroscience & Behaviour (Sekuler), McMaster University, Hamilton, Ont.

Background: The detailed extent of neuroinvasion or deleterious brain changes resulting from COVID-19 and their time courses remain to be determined in relation to "long-haul" COVID-19 symptoms. Our objective is to determine whether there are alterations in functional brain imaging measures among people with COVID-19 after hospital discharge or self-isolation.

Methods: This paper describes a protocol for NeuroCOVID-19, a longitudinal observational study of adults aged 20-75 years at Sunnybrook Health Sciences Centre in Toronto, Ontario, that began in April 2020. We aim to recruit 240 adults, 60 per group: people who contracted COVID-19 and were admitted to hospital (group 1), people who contracted COVID-19 and self-isolated (group 2), people who experienced influenza-like symptoms at acute presentation but tested negative for COVID-19 and self-isolated (group 3, control) and healthy people (group 4, control). Participants are excluded based on premorbid neurologic or severe psychiatric illness, unstable cardiovascular disease, and magnetic resonance imaging (MRI) contraindications. Initial and 3-month follow-up assessments include multiparametric brain MRI and electroencephalography. Sensation and cognition are assessed alongside neuropsychiatric assessments and symptom self-reports. We will test the data from the initial and follow-up assessments for group differences based on 3 outcome measures: MRI cerebral blood flow, MRI resting state fractional amplitude of low-frequency fluctuation and electroencephalography spectral power.

Interpretation: If neurophysiologic alterations are detected in the COVID-19 groups in our NeuroCOVID-19 study, this information could inform future research regarding interventions for long-haul COVID-19. The study results will be disseminated to scientists, clinicians and COVID-19 survivors, as well as the public and private sectors to provide context on how brain measures relate to lingering symptoms.
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http://dx.doi.org/10.9778/cmajo.20210023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8648350PMC
December 2021

A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study.

Mol Neurodegener 2021 11 27;16(1):79. Epub 2021 Nov 27.

Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.

Background: 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.
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http://dx.doi.org/10.1186/s13024-021-00499-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626910PMC
November 2021

VMAT2 availability in Parkinson's disease with probable REM sleep behaviour disorder.

Mol Brain 2021 11 10;14(1):165. Epub 2021 Nov 10.

Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.

REM sleep behaviour disorder (RBD) can be an early non-motor symptom of Parkinson's disease (PD) with pathology involving mainly the pontine nuclei. Beyond the brainstem, it is unclear if RBD patients comorbid with PD have more affected striatal dopamine denervation compared to PD patients unaffected by RBD (PD-RBD-). To elucidate this, we evaluated the availability of vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, in 15 PD patients with probable RBD (PD-RBD+), 15 PD-RBD-, and 15 age-matched healthy controls (HC) using [C]DTBZ PET imaging. This technique measured VMAT2 availability within striatal regions of interest (ROI). A mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive function and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. We observed a significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, our results revealed that PD-RBD+ had lower VMAT2 availability compared to HC in all these regions except for the subthalamus and substantia nigra, while PD-RBD- was significantly lower than HC in all these regions. PD-RBD- showed a negative relationship between motor severity and VMAT2 availability within the left caudate. Our findings reflect that both PD patient subgroups had similar denervation within the nigrostriatal pathway. There were no significant interactions detected between radioligand binding and clinical scores in PD-RBD+. Taken together, VMAT2 and striatal dopamine denervation in general may not be a significant contributor to the pathophysiology of RBD in PD patients. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients.
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http://dx.doi.org/10.1186/s13041-021-00875-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579554PMC
November 2021

Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study.

Ann Neurol 2022 01 29;91(1):33-47. Epub 2021 Nov 29.

Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.

Objective: Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage.

Methods: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls.

Results: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates.

Interpretation: Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. ANN NEUROL 2022;91:33-47.
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http://dx.doi.org/10.1002/ana.26265DOI Listing
January 2022
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