Maria Carmela Tartaglia

• MD
• Professor (Associate) at University of Toronto

Background and Objectives Progressive supranuclear paralysis (PSP) is an atypical parkinsonian disorder associated with oculomotor features, motor disturbances, along with cognitive problems and neuropsychiatric symptoms. Quality of life (QoL) is often assessed in relation to the motor symptoms. Our aim was to investigate the impact of neuropsychia...

This Viewpoint reports on the potential of multimodal approaches that include validation, standardization, and ethical considerations in diagnosing neurodegenerative diseases, many of which have overlapping clinical phenotypes.

The recent development of brain charts for the human lifespan offers an ideal modeling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asympto...

Background Vascular risk factors are common in older adults and contribute to brain damage, can manifest as increased white matter hyperintensities (WMH), and associated with future risk of stroke and dementia. However, their prevalence, effect across different neurodegenerative diseases, and association with WMH remains underexplored. Objective T...

Objectives Cognitive impairment (CI) is common in patients with Systemic Lupus Erythematosus (SLE). Despite its prevalence, the immune mechanisms are not well understood. We previously reported elevated serum levels of S100A8/A9 and MMP‐9 in SLE patients with CI. This study aims to validate those findings by examining the relationship between serum...

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD...

INTRODUCTION Self‐reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear. METHODS We analyzed 394 genetic‐FTD patients and 279 controls from the ALLFTD consortium, assessing annual neuropsychological performance and MRI‐based cortical thickness. Clinical characteristics and cortical thicknes...

INTRODUCTION Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females. METHODS We included genetic and sporadic bvFTD patients from two multicenter cohorts. We co...

Assessment of spoken language is a promising marker for cognitive impairment in individuals with cerebrovascular disease. However, the underlying neurological basis for spoken language beyond single words and sentences remains poorly defined in this cohort, particularly with respect to white matter. This study aimed to examine and compare white mat...

Alzheimer disease (AD) is a life-limiting neurodegenerative disorder that disproportionately affects women. Indeed, sex and gender are emerging as crucial modifiers of diagnostic and therapeutic pathways in AD. This Review provides an overview of the interactions of sex and gender with important developments in AD and offers insights into prioritie...

An extensive library of symptom inventories has been developed over time to measure clinical symptoms of traumatic brain injury (TBI), but this variety has led to several long-standing issues. Most notably, results drawn from different settings and studies are not comparable. This creates a fundamental problem in TBI diagnostics and outcome predict...

INTRODUCTION: Increased white matter hyperintensities (WMHs) have been reported in genetic frontotemporal dementia (FTD) in small studies, but the sequence of WMH abnormalities relative to other biomarkers is unclear. METHODS: Using a large dataset (n=763 GENFI2 participants), we measured WMHs and examined them across genetic FTD variants and stage...

Background and Objectives: Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD), including associations between FTD-causing mutations and neurodevelopmental disorders, and differences in young adult mutation carriers compared to familial non-mutation carriers in total intracranial volume...

A 79‐year‐old former professional football player presented with language deficits and cognitive changes. A year later, he had difficulty completing sentences, and 3 years after onset, was reduced to one‐word answers. He developed severe apathy and agitation, and became more impulsive. He eventually became mute and had difficulty with walking and b...

Background Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomati...

Background and objectives: Plasma biomarkers of Alzheimer disease (AD), neuroinflammation, and neurodegeneration are increasingly being used in clinical trials for diagnosis and monitoring of dementia. However, their association with longitudinal structural brain MRI changes, an important outcome measure across neurodegenerative and cerebrovascula...

Objective Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency in the majority of cases. Caregivers of adults with DS often complain about the loss of previously acquired skills. We set out to explore these perceptions and determine whether abnormalities reported were detectable in validated...

Frontotemporal dementia (FTD) shows autosomal dominant transmission in up to a third of families, enabling the study of presymptomatic and prodromal phases. Despite self-reported well-being and normal daily cognitive functioning, brain structural changes are evident a decade or more before the expected onset of disease. This divergence between cogn...

Background Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72), Microtubule Associated Protein Tau (MAPT), and P...

Background The association of cognitive and motor impairments in Alzheimer’s disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an...

Background The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be dif...

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 scan...

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72 , 38 GRN , and 25 MAPT ) and 55...

Objectives Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen (HLA) locus on chromosome 6 is a polymorphic region with complex linkage patterns that has been implicated in several autoimmune and neurological disorders. The HLA...

The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in...

Background In‐vivo detection of neuropathology is critical for early diagnosis of neurodegenerative diseases. Post‐mortem brain magnetic resonance imaging (MRI) of pathological protein inclusions could further our ability to detect them in vivo and correlate MRI parameters to histopathological substrates. In this post‐mortem study, we aimed to iden...

Background Neuropsychiatric symptoms (NPS) constitute a major challenge for patients with Alzheimer’s disease (AD). We have recently demonstrated that in AD, overall NPS burden is significantly associated with patient function. However, few studies have examined the relationship between specific symptom clusters with neurological biomarkers. Theref...

Background Social cognition is impacted early in the disease progression of many neurodegenerative diseases (ND). The Salience network (SN) is an intrinsically connected brain network responsible for social cognitive function. Keys hubs of this brain network, the anterior insula (AI) and anterior cingulate cortex (ACC), are reported to incorporate...

Background As new anti‐amyloid immunotherapies emerge for Alzheimer’s disease (AD), it is clear that early diagnosis of AD pathology is crucial for treatment success. This can be challenging in atypical presentations of AD and, together with our reliance on CSF or PET scans, can, at times, lead to delayed diagnosis. Here, we further explore the pos...

Cognitive changes associated with PASC may not be uniform across populations. We conducted individual-level pooled analyses and meta-analyses of cognitive assessments from eight prospective cohorts, comprising 2,105 patients and 1,432 controls from Argentina, Canada, Chile, Greece, India, Italy, Russia, and the UK. The meta-analysis found no differ...

Background Mild Behavioral Impairment (MBI) is a condition characterized by neuropsychiatric symptoms (NPS) in older adults without dementia, serving as a precursor to various forms of dementia. This study explores the association between NPS and functional connectivity (FC) within the default mode network (DMN), executive control network (ECN), an...

Background Language impairment is common in progressive supranuclear palsy (PSP) and is often overlooked due to the severity of the motor symptoms. We investigated whether language can be used to predict PSP prognosis. Methods One hundred‐forty‐six patients with a diagnosis of possible or probable PSP from the Tilavonemab (ABBV‐8E12) clinical tria...

Background Frontotemporal dementia (FTD) presents with heterogeneous neuropsychiatric symptoms (NPS). These symptoms often begin prior to the onset of FTD, and progress throughout the prodromal stages of FTD. Particularly, familial FTD due to autosomal dominant genetic mutations might display mutation‐specific NPS profiles. We hypothesized distinct...

Background The Clinical Dementia Rating Sum of Boxes (CDR‐SB) is a widely used measurement score to stage dementia severity; it has become one of the most common outcome measurements in Alzheimer’s Disease (AD) research. The CDR‐SB requires an informant to provide information to stage a patient’s dementia severity. The effect of the informant’s cha...

Background Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit th...

Background: There are no approved oral disease-modifying treatments for Alzheimer's disease (AD). Objectives: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including...

White matter hyperintensities (WMH) of presumed vascular origin are a magnetic resonance imaging (MRI)‐based biomarker of cerebral small vessel disease (CSVD). WMH are associated with cognitive decline and increased risk of stroke and dementia, and are commonly observed in aging, vascular cognitive impairment, and neurodegenerative diseases. The re...

INTRODUCTION Psychotropic medication (PM) use in behavioral‐variant frontotemporal dementia (bvFTD) is higher than in other dementias. However, no information exists on whether PM use differs between sporadic and genetic bvFTD. METHODS We analyzed data from sporadic and genetic bvFTD participants with PM prescriptions in the Advancing Research and...

Background Although there is growing evidence of the association between gender and early diagnosis of preclinical Alzheimer's disease, little attention has been given to the enrolment ratio of men and women in clinical trials and data reporting. Methods This study aims to analyze gender differences in sociodemographic factors associated with the...

Background The Montreal Cognitive assessment (MoCA) is a well-validated global cognitive screening instrument. Its validity in progressive supranuclear palsy (PSP) has not been assessed. Objectives To evaluate the MoCA as an outcome measure in PSP clinical trials. Methods Cognitive data from 162 participants in the placebo arm of the Biogen PASSP...

At the Canadian Concussion Centre, we treated 136 patients from 2000 to 2020 who sustained concussion plus persisting concussion symptoms (C+PCS) as motor vehicle occupants involved in motor vehicle crashes (MVCs). This center specializes in the treatment of patients with C+PCS. The objective of the present study was to identify strategies for prev...

INTRODUCTION Elevated plasma homocysteine (Hcy) is associated with an increased risk of developing neurodegenerative diseases; however, its relationship with the apolipoprotein E (APOE) ε4 allele has not been well characterized. METHODS Participants clinically diagnosed with Alzheimer's disease or mild cognitive impairment (AD/MCI), frontotemporal...

Background and objectives: Sleep dysfunction is common in patients with neurodegenerative disorders; however, its neural underpinnings remain poorly characterized in genetic frontotemporal dementia (FTD). Hypothalamic nuclei important for sleep regulation may be related to this dysfunction. Thus, we examined changes in hypothalamic structure acros...

Background and objectives: Pathogenic variants in the GRN gene cause frontotemporal dementia (FTD-GRN) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD-GRN depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease. Methods: Retr...

The Clinical Dementia Rating Sum of Boxes (CDR-SB) is a staging scale for Alzheimer’s disease (AD)¹ and is commonly used as an outcome in clinical trials². It relies on information provided by the patient and an informant³. The CDR-SB should reflect only the patient’s disease severity. However, we explored whether informant characteristics were ass...

INTRODUCTION Genetic mutation carriers of frontotemporal dementia can remain cognitively well despite neurodegeneration. A better understanding of brain structural, perfusion, and functional patterns in the pre‐symptomatic stage could inform accurate staging and potential mechanisms. METHODS We included 207 pre‐symptomatic genetic mutation carrier...

INTRODUCTION: Sex differences are apparent in neurodegenerative diseases, but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to six years. Linear mixed...

MRI-detected white matter hyperintensities (WMH) are often recognized as markers of cerebrovascular abnormalities and an index of vascular brain injury. The literature establishes a strong link between WMH burden and cognitive decline, and suggests that the anatomical distribution of WMH mediates cognitive dysfunction. Pathological remodeling of ma...

Background and objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare t...

Until recently, only symptomatic therapies, in the form of acetylcholine esterase inhibitors and NMDA-receptor antagonists, have been available for the treatment of Alzheimer’s disease. However, advancements in our understanding of the amyloid cascade hypothesis have led to a development of disease-modifying therapeutic strategies. These include im...

This study discusses 4-repeat tau seeding in the skin of patients with progressive supranuclear palsy.

Background and Objective: Frontotemporal dementia (FTD) is a highly heritable disorder. The majority of genetic cases are caused by autosomal dominant pathogenic variants in the c9orf72, GRN and MAPT gene. Behavioural and neuropsychiatric symptoms are frequent in genetic FTD. We aimed to describe behavioural and neuropsychiatric phenotypes in genet...

INTRODUCTION Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTL...

Falls in older adults and those with neurodegenerative disease (ND) are a current public health hazard and the primary cause of sustaining a mild traumatic brain injury (mTBI)/concussion. Little is known regarding how post-concussion symptoms present in older adults and patients with ND, even though they are the demographic at highest risk. A combi...

Background and objectives: There is no disease-modifying treatment of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), 2 disorders characterized by their striking phenotypic, and, in CBS, pathologic heterogeneity. Seed amplification assays (SAAs) could enable the detection of neuropathologic processes, such as α-synuclein (αSy...

Background The long-term consequences of concussions may include pathological neurodegeneration as seen in Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Tau-PET showed promise as a method to detect tau pathology of CTE, but more studies are needed Objective This study aimed (1) to assess the association of imaging evidence o...

Aims Astrocytic tau pathology is a major feature of tauopathies and ageing‐related tau astrogliopathy (ARTAG). The substantia nigra (SN) is one of the important degenerative areas in tauopathies with parkinsonism. Nigral tau pathology is usually reported as neuronal predominant with less prominent astrocytic involvement. We aimed to identify cases...

Objective To determine if self-reported fatigue, anxiety, depression, cognitive difficulties, health-related quality of life, disease activity scores and neuropsychological battery (NB) cluster into distinct groups in patients with SLE based on symptom intensity and if they change at 1-year follow-up. Methods This is a retrospective analysis of co...

INTRODUCTION We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS A mediation analysis was performed to assess the relationship between neuroimaging marker...

Background and objectives: Identification of fluid biomarkers for progressive supranuclear palsy (PSP) is critical to enhance therapeutic development. We implemented unbiased DNA aptamer (SOMAmer) proteomics to identify novel CSF PSP biomarkers. Methods: This is a cross-sectional study in original (18 clinically diagnosed PSP-Richardson syndrome...

Introduction Persistent symptoms after mild traumatic brain injury (mTBI) negatively affect daily functioning and quality of life. Fear avoidance behaviour, a coping style in which people avoid or escape from activities or situations that they expect will exacerbate their symptoms, maybe a particularly potent and modifiable risk factor for chronic...

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and...

White matter hyperintensities (WMH) of presumed vascular origin are an MRI-based biomarker of cerebral small vessel disease (CSVD). WMH are associated with accelerated cognitive decline and increased risk of stroke and dementia, and are commonly observed in aging, vascular cognitive impairment, Alzheimer's and Parkinson's disease, and related demen...

The glymphatic system is an emerging target in neurodegenerative disorders. Here, we investigated the activity of the glymphatic system in genetic frontotemporal dementia with a diffusion-based technique called diffusion tensor image analysis along the perivascular space. We investigated 291 subjects with symptomatic or presymptomatic frontotempora...

Background: Frontotemporal dementia (FTD) often presents with varying neuropsychiatric symptoms (NPS), which may differ based on genetic mutations. We hypothesized distinct NPS trajectories in FTD progression among carriers of chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) mutations. M...

Background Executive dysfunction is a core feature of frontotemporal dementia (FTD). Whilst there has been extensive research into such impairments in sporadic FTD, there has been little research in the familial forms. Methods 752 individuals were recruited in total: 214 C9orf72 , 205 GRN and 86 MAPT mutation carriers, stratified into asymptomatic...

Objectives To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI). Methods 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness w...

Background/Aims Cognitive impairment (CI) is common in people with systemic lupus erythematosus (pwSLE). Treatment options are limited and the effects upon the brain is unclear. Differences in brain structure seen in SLE do not always associate with CI, however significant associations have been found with functional magnetic resonance imaging (fMR...

INTRODUCTION Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. METHODS We investigated longitudinal profiles of cerebral perfusi...

INTRODUCTION We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD gen...

Objectives To evaluate the effect of Alzheimer's disease (AD) ‐related biomarker change on clinical features, brain atrophy and functional connectivity of patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). Methods Data from patients with a clinical diagnosis of CBS, PSP, and AD and healthy controls were obtained fr...

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of...

Importance Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated fo...

Aims Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. Methods This cross‐sectional study systematically evaluated HBs in a co...

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mut...

INTRODUCTION: Cerebrovascular reactivity (CVR) is an indicator of cerebrovascular health and its signature in hereditary frontotemporal dementia (FTD) remains unknown. We investigated CVR in genetic FTD and its relationship to cognition. METHODS: CVR differences were assessed between 284 pre-symptomatic and 124 symptomatic mutation carriers, and 26...

Background Headache is a prevalent and debilitating symptom following traumatic brain injury (TBI). Large-scale, prospective cohort studies are needed to establish long-term headache prevalence and associated factors after TBI. This study aimed to assess the frequency and severity of headache after TBI and determine whether sociodemographic factors...

Background The Mini-Cog is a rapid screening tool that can be administered to older adults to detect cognitive impairment (CI); however, the accuracy of the Mini-Cog to detect CI for older patients in various healthcare settings is unclear. Objectives To evaluate the diagnostic accuracy of the Mini-Cog to screen for cognitive impairment in older p...