Sandra E. Black

Bio: Sandra E. Black is an academic researcher from Sunnybrook Health Sciences Centre. The author has contributed to research in topics: Hyperintensity & Frontotemporal dementia. The author has an hindex of 10, co-authored 15 publications receiving 777 citations. Previous affiliations of Sandra E. Black include Heart and Stroke Foundation of Canada & Sunnybrook Research Institute.

Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis

Abstract: Summary Background Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin ( GRN ), microtubule-associated protein tau ( MAPT ), or chromosome 9 open reading frame 72 ( C9orf72 ). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. Methods We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT , or C9orf72 , or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Findings Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test −0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all −0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference −0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference −0·2, SE 0·1). Interpretation Structural imaging and cognitive changes can be identified 5–10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Funding Centres of Excellence in Neurodegeneration.

Prevalence of amyloid-β pathology in distinct variants of primary progressive aphasia

Abstract: OBJECTIVE: To estimate the prevalence of amyloid-positivity, defined by PET/CSF biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n=443], non-fluent [nfvPPA, n=333], semantic [svPPA, n=401] and mixed/unclassifiable [PPA-M/U, n=74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n=600]), PET [n=366] and/or autopsy [n=378]) available. The estimated prevalence of amyloid-positivity according to PPA variant, age and apolipoprotein E (APOE) e4 status was determined using generalized estimating equation models. RESULTS: Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%) (p<0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 to 27% at age 80, p<0.01) and svPPA (from 6% at age 50 to 32% at age 80, p<0.001), but not in lvPPA (p=0.94). Across PPA variants, APOE e4 carriers were more often amyloid-β positive (58.0%) than non-carriers (35.0%, p<0.001). Autopsy data revealed Alzheimer's disease (AD) pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration - TDP-43 in svPPA (80%) and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and APOE genotype should be taken into account when interpreting Aβ biomarkers in PPA patients. This article is protected by copyright. All rights reserved.

The Canadian Dementia Imaging Protocol: Harmonizing National Cohorts

Abstract: BACKGROUND Harmonized protocols to collect imaging data must be devised, employed, and maintained in multicentric studies to reduce interscanner variability in subsequent analyses. PURPOSE To present a standardized protocol for multicentric research on dementia linked to neurodegeneration in aging, harmonized on all three major vendor platforms. The protocol includes a common procedure for qualification, quality control, and quality assurance and feasibility in large-scale studies. STUDY TYPE Prospective. SUBJECTS The study involved a geometric phantom, a single individual volunteer, and 143 cognitively healthy, mild cognitively impaired, and Alzheimer's disease participants in a large-scale, multicentric study. FIELD STRENGTH/SEQUENCES MRI was perform with 3T scanners (GE, Philips, Siemens) and included 3D T1 w, PD/T2 w, T2* , T2 w-FLAIR, diffusion, and BOLD resting state acquisitions. ASSESSMENT Measures included signal- and contrast-to-noise ratios (SNR and CNR, respectively), total brain volumes, and total scan time. STATISTICAL TESTS SNR, CNR, and scan time were compared between scanner vendors using analysis of variance (ANOVA) and Tukey tests, while brain volumes were tested using linear mixed models. RESULTS Geometric phantom T1 w SNR was significantly (P < 0.001) higher in Philips (mean: 71.4) than Siemens (29.5), while no significant difference was observed between vendors for T2 w (32.0 and 37.2, respectively, P = 0.243). Single individual volunteer T1 w CNR was higher in subcortical regions for Siemens (P < 0.001), while Philips had higher cortical CNR (P = 0.044). No significant difference in brain volumes was observed between vendors (P = 0.310/0.582/0.055). The average scan time was 41.0 minutes (SD: 2.8) and was not significantly different between sites (P = 0.071) and cognitive groups (P = 0.853). DATA CONCLUSION The harmonized Canadian Dementia Imaging Protocol suits the needs of studies that need to ensure quality MRI data acquisition for the measurement of brain changes across adulthood, due to aging, neurodegeneration, and other etiologies. A detailed description, exam cards, and operators' manual are freely available at the following site: www.cdip-pcid.ca. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:456-465.

Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease.

Abstract: Objective To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD). Design This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases. Setting Patients were recruited from a long-term care facility and geriatric psychiatry clinics. Participants Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3). Intervention Nabilone (target 1–2 mg) versus placebo. Measurements The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events. Results Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = −4.0 [−6.5 to −1.5], t(30.2) = −3.3, p = 0.003), NPI-NH total (b = −4.6 [−7.5 to −1.6], t(32.9) = −3.1, p = 0.004), NPI-NH caregiver distress (b = −1.7 [−3.4 to −0.07, t(33.7) = −2.1, p = 0.041), and sMMSE (b = 1.1 [0.1–2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = −4.6 [−7.3 to −1.8], t(20.7) = −4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22). Conclusions Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored.

Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria

Abstract: This article presents the revised consensus criteria for the diagnosis of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS) based on an international research workshop on frontotemporal dementia (FTD) and ALS held in London, Canada in June 2015. Since the publication of the Strong criteria, there have been considerable advances in the understanding of the neuropsychological profile of patients with ALS. Not only is the breadth and depth of neuropsychological findings broader than previously recognised –– including deficits in social cognition and language – but mixed deficits may also occur. Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neu...

Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia

Abstract: Objective: To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease. Methods: Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau ( MAPT ; 11), or progranulin ( GRN ; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume. Results: Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL [SD 51.3 pg/mL]) than controls (19.6 pg/mL [SD 8.2 pg/mL]; p C9orf72 and MAPT subgroups (79.2 and 40.5 pg/mL [SD 48.2 and 20.9 pg/mL], respectively) with a trend to a higher level in the GRN subgroup (138.5 pg/mL [SD 103.3 pg/mL). However, there was variability within all groups. Serum concentrations correlated particularly with frontal lobe atrophy rate ( r = 0.53, p = 0.003). Conclusions: Increased serum NfL concentrations are seen in FTD but show wide variability within each clinical and genetic group. Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes.

Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group.

Abstract: In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

Abstract: The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10-4) or temporal stage (p = 3.96 × 10-5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.