Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

Introduction: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.

Methods: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies.

Results: Among the sporadic patients, 16 (5.

Nonlinear Z-score modeling for improved detection of cognitive abnormality.

Introduction: Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these "adjusted" Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.

β-Amyloid PET and neuropathology in dementia with Lewy bodies.

Objective: β-Amyloid (Aβ) pathology is common in patients with probable dementia with Lewy bodies (DLB). However, the pathologic basis and the differential diagnostic performance of Aβ PET are not established in DLB. Our objective was to investigate the pathologic correlates of C-Pittsburgh compound B(PiB) uptake on PET in cases with antemortem diagnosis of probable DLB or Lewy body disease (LBD) at autopsy.

REM sleep atonia loss distinguishes synucleinopathy in older adults with cognitive impairment.

Objective: To determine whether quantitative polysomnographic REM sleep without atonia (RSWA) distinguishes between cognitive impairment phenotypes.

Background: Neurodegenerative cognitive impairment in older adults predominantly correlates with tauopathy or synucleinopathy. Accurate antemortem phenotypic diagnosis has important prognostic and treatment implications; additional clinical tools might distinguish between dementia syndromes.

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.

Association of Longitudinal β-Amyloid Accumulation Determined by Positron Emission Tomography With Clinical and Cognitive Decline in Adults With Probable Lewy Body Dementia.

Importance: In patients with probable dementia with Lewy bodies (DLB), overlapping Alzheimer disease pathology is frequent and is associated with faster decline and shorter survival. More than half of patients with DLB have elevated β-amyloid levels on carbon-11 labeled Pittsburgh compound B (PiB) positron emission tomography, but the trajectory of longitudinal β-amyloid accumulation and its associations with clinical and cognitive decline in DLB are not known.

Objectives: To determine the trajectory of β-amyloid accumulation in patients with probable DLB and to investigate the associations of β-amyloid accumulation with measures of clinical and cognitive decline over time in DLB.

Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration.

Introduction: The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations.

Methods: We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.

Results: Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes.

Tau-positron emission tomography correlates with neuropathology findings.

Introduction: Comparison of tau (flortaucipir) positron emission tomography (FTP-PET) to autopsy is important to demonstrate the relationship of FTP-PET to neuropathologic findings.

Methods: Autopsies were performed on 26 participants who had antemortem FTP-PET. FTP-PET standardized uptake value ratios (SUVRs) were compared to autopsy diagnoses and Braak tangle stage.

Incidence of frontotemporal disorders in Olmsted County: A population-based study.

Introduction: Frontotemporal dementia disorders (FTDs) are heterogeneous phenotypical behavioral and language disorders usually associated with frontal and/or temporal lobe degeneration. We investigated their incidence in a population-based cohort.

Methods: Using a records-linkage system, we identified all patients with a diagnostic code for dementia in Olmsted County, MN, 1995-2010, and confirmed the diagnosis of FTD.

Linear vs volume measures of ventricle size: Relation to present and future gait and cognition.

Objective: To compare the clinical utility of volume-based ratios with the standard linear ratio of Evans index (EI) by examining their associations with gait, cognition, and other patient and imaging variables.

Methods: From MRI scans of 1,774 participants in the Mayo Clinic Study of Aging, we calculated 3 ventricle size measures: Evan index (frontal horn width divided by widest width of skull inner table), total ventricular volume, and frontal horn volume as ratios of total intracranial volume. Gait was measured by a timed 25-foot walk and cognition by a composite of psychometric tests.

New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures.

Introduction: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed.

Methods: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD.

The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology.

Introduction: It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase.

Methods: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes-microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72.

Results: We present the theoretical considerations of f-FTLD and the aims/objectives of this protocol.

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

Submentalis Rapid Eye Movement Sleep Muscle Activity: A Potential Biomarker for Synucleinopathy.

Accurate antemortem diagnosis of parkinsonism is primarily based on clinical evaluation with limited biomarkers. We evaluated the diagnostic utility of quantitative rapid eye movement (REM) sleep without atonia analysis in the submentalis and anterior tibialis muscles in parkinsonian patients (53 synucleinopathy, 24 tauopathy). Receiver operating characteristic curves determined REM sleep without atonia cutoffs distinguishing synucleinopathies from tauopathies.

Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers.

The majority of the clinico-pathological variability observed in patients harboring a repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) remains unexplained. This expansion, which represents the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), results in a loss of C9orf72 expression and the generation of RNA foci and dipeptide repeat (DPR) proteins. The C9orf72 protein itself plays a role in vesicular transport, serving as a guanine nucleotide exchange factor that regulates GTPases.

Incidence and Trends of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Population-Based Study.

Background: Few studies have investigated the incidence of PSP and CBS in the population.

Objective: To examine the incidence of and trends in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in a population-based cohort of residents of Olmsted County, MN.

Methods: We used the 1991-2005 population-based, Olmsted County Parkinsonism-cohort study, defined via the Rochester Epidemiology Project.

Normative and isolated rapid eye movement sleep without atonia in adults without REM sleep behavior disorder.

Study Objectives: Values for normative REM sleep without atonia (RSWA) remain unclear. Older age and male sex are associated with greater RSWA, and isolated elevated RSWA has been reported. We aimed to describe normative RSWA and characterize isolated RSWA frequency in adults without REM sleep behavior disorder (RBD).

Tracking white matter degeneration in asymptomatic and symptomatic MAPT mutation carriers.

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed.

Physician and patient determinants of prognostic counseling in idiopathic REM sleep-behavior disorder.

Objectives/background: Prognostic counseling about the risk for developing overt neurodegenerative disorders for patients with idiopathic REM sleep-behavior disorder (iRBD) and isolated REM sleep without atonia (iRSWA) is difficult, given lack of disease-modifying interventions and uncertainty in accurate prognostication for individuals. We aimed to analyze patient and physician characteristics associated with documented prognostic discussions for patients with iRBD and iRSWA.

Patients/methods: We retrospectively reviewed the medical records for 138 (112 iRBD and 26 iRSWA) patients seen at the Mayo Clinic between 2012 and 2015.

Antemortem volume loss mirrors TDP-43 staging in older adults with non-frontotemporal lobar degeneration.

Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects.

Transient Epileptic Amnesia: A Treatable Cause of Spells Associated With Persistent Cognitive Symptoms.

To characterize the clinical, EEG, and neuroimaging profiles of transient epileptic amnesia (TEA). We performed a retrospective analysis of patients diagnosed with TEA at the Mayo Clinic Minnesota from January 1, 1998 to September 21, 2017. Diagnostic criteria included the presence of recurrent episodes of transient amnesia with preservation of other cognitive functions and evidence for epilepsy [epileptiform abnormalities on EEG, clinical features of seizures, or symptomatic response to anti-seizure medications (ASMs)].

New evidence on the management of Lewy body dementia.

Dementia with Lewy bodies and Parkinson's disease dementia, jointly known as Lewy body dementia, are common neurodegenerative conditions. Patients with Lewy body dementia present with a wide range of cognitive, neuropsychiatric, sleep, motor, and autonomic symptoms. Presentation varies between patients and can vary over time within an individual.

The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes.

Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-β and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice.

Use of the CDR® plus NACC FTLD in mild FTLD: Data from the ARTFL/LEFFTDS consortium.

Introduction: Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD).

Methods: We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium.

Results: The CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0.

REM sleep muscle activity in idiopathic REM sleep behavior disorder predicts phenoconversion.

Objective: To determine whether REM sleep without atonia (RSWA) during polysomnography (PSG) predicts phenoconversion in patients with idiopathic REM sleep behavior disorder (iRBD), a prodromal feature of a neurodegenerative disease.

Methods: We analyzed RSWA in 60 patients with iRBD, including manual phasic, tonic, and any muscle activity in the submentalis and anterior tibialis muscles and the automated REM atonia index in the submentals. We identified patients who developed parkinsonism or mild cognitive impairment (MCI) during at least 3 years of follow-up after PSG.