Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes.

OBJECTIVE: To test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of diagnostic group. METHODS: We used a transdiagnostic approach to survival in an epidemiological cohort in the UK, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (bvFTD n=64), non-fluent variant primary progressive aphasia (nfvPPA n=36), semantic variant primary progressive aphasia (svPPA n=25), progressive supranuclear palsy (PSP n=101) and corticobasal syndrome (CBS n=68). A principal components analysis identified six dimensions of clinical features. Using Cox proportional hazards and logistic regression, we identified the association between each of these dimensions and both functionally independent survival (time from clinical assessment to care home admission) and absolute survival (time to death). Analyses adjusted for the covariates of age, gender and diagnostic group. Secondary analysis excluded specific diagnostic groups. RESULTS: Behavioural disturbance, including impulsivity and apathy, was associated with reduced functionally independent survival (OR 2.46, p<0.001), even if patients with bvFTD were removed from the analysis. Motor impairments were associated with reduced absolute survival, even if patients with PSP and CBS were removed from the analysis. CONCLUSION: Our results can assist individualised prognostication and planning of disease-modifying trials, and they support a transdiagnostic approach to symptomatic treatment trials in patients with clinical syndromes associated with frontotemporal lobar degeneration.

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-ß plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

Neurophysiological signatures of Alzheimer's disease and frontotemporal lobar degeneration: pathology versus phenotype.

The disruption of brain networks is characteristic of neurodegenerative dementias. However, it is controversial whether changes in connectivity reflect only the functional anatomy of disease, with selective vulnerability of brain networks, or the specific neurophysiological consequences of different neuropathologies within brain networks. We proposed that the oscillatory dynamics of cortical circuits reflect the tuning of local neural interactions, such that different pathologies are selective in their impact on the frequency spectrum of oscillations, whereas clinical syndromes reflect the anatomical distribution of pathology and physiological change. To test this hypothesis, we used magnetoencephalography from five patient groups, representing dissociated pathological subtypes and distributions across frontal, parietal and temporal lobes: amnestic Alzheimer's disease, posterior cortical atrophy, and three syndromes associated with frontotemporal lobar degeneration. We measured effective connectivity with graph theory-based measures of local efficiency, using partial directed coherence between sensors. As expected, each disease caused large-scale changes of neurophysiological brain networks, with reductions in local efficiency compared to controls. Critically however, the frequency range of altered connectivity was consistent across clinical syndromes that shared a likely underlying pathology, whilst the localization of changes differed between clinical syndromes. Multivariate pattern analysis of the frequency-specific topographies of local efficiency separated the disorders from each other and from controls (accuracy 62% to 100%, according to the groups' differences in likely pathology and clinical syndrome). The data indicate that magnetoencephalography has the potential to reveal specific changes in neurophysiology resulting from neurodegenerative disease. Our findings confirm that while clinical syndromes have characteristic anatomical patterns of abnormal connectivity that may be identified with other methods like structural brain imaging, the different mechanisms of neurodegeneration also cause characteristic spectral signatures of physiological coupling that are not accessible with structural imaging nor confounded by the neurovascular signalling of functional MRI. We suggest that these spectral characteristics of altered connectivity are the result of differential disruption of neuronal microstructure and synaptic physiology by Alzheimer's disease versus frontotemporal lobar degeneration.

Apathy and impulsivity in frontotemporal lobar degeneration syndromes.

Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration. They cause substantial carer distress, but their aetiology remains elusive. There are critical limitations to previous studies in this area including (i) the assessment of either apathy or impulsivity alone, despite their frequent co-existence; (ii) the assessment of behavioural changes within single diagnostic groups; and (iii) the use of limited sets of tasks or questions that relate to just one aspect of these multifactorial constructs. We proposed an alternative, dimensional approach that spans behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. This accommodates the commonalities of apathy and impulsivity across disorders and reveals their cognitive and anatomical bases. The ability to measure the components of apathy and impulsivity and their associated neural correlates across diagnostic groups would provide better novel targets for pharmacological manipulations, and facilitate new treatment strategies and strengthen translational models. We therefore sought to determine the neurocognitive components of apathy and impulsivity in frontotemporal lobar degeneration syndromes. The frequency and characteristics of apathy and impulsivity were determined by neuropsychological and behavioural assessments in 149 patients and 50 controls from the PIck's disease and Progressive supranuclear palsy Prevalence and INcidence study (PiPPIN). We derived dimensions of apathy and impulsivity using principal component analysis and employed these in volumetric analyses of grey and white matter in a subset of 70 patients (progressive supranuclear palsy, n = 22; corticobasal syndrome, n = 13; behavioural variant, n = 14; primary progressive aphasias, n = 21) and 27 control subjects. Apathy and impulsivity were present across diagnostic groups, despite being criteria for behavioural variant frontotemporal dementia alone. Measures of apathy and impulsivity frequently loaded onto the same components reflecting their overlapping relationship. However, measures from objective tasks, patient-rated questionnaires and carer-rated questionnaires loaded onto separate components and revealed distinct neurobiology. Corticospinal tracts correlated with patients' self-ratings. In contrast, carer ratings correlated with atrophy in established networks for goal-directed behaviour, social cognition, motor control and vegetative functions, including frontostriatal circuits, orbital and temporal polar cortex, and the brainstem. Components reflecting response inhibition deficits correlated with focal frontal cortical atrophy. The dimensional approach to complex behavioural changes arising from frontotemporal lobar degeneration provides new insights into apathy and impulsivity, and the need for a joint therapeutic strategy against them. The separation of objective tests from subjective questionnaires, and patient from carer ratings, has important implications for clinical trial design.awx101media15448041163001.

Prognostic importance of apathy in syndromes associated with frontotemporal lobar degeneration.

OBJECTIVE: To determine the influence of apathy, impulsivity, and behavioral change on survival in patients with frontotemporal dementia, progressive supranuclear palsy, and corticobasal syndrome. METHODS: We assessed 124 patients from the epidemiologic PiPPIN (Pick's Disease and Progressive Supranuclear Palsy, Prevalence and Incidence) study. Patients underwent detailed baseline cognitive and behavioral assessment focusing on apathy, impulsivity, and behavioral change. Logistic regression identified predictors of death within 2.5 years from assessment, including age, sex, diagnosis, cognition, and 8 neurobehavioral profiles derived from a principal component analysis of neuropsychological and behavioral measures. RESULTS: An apathetic neurobehavioral profile predicted death (Wald statistic = 8.119, p = 0.004, Exp(B) = 2.912, confidence interval = >1 [1.396-6.075]) and was elevated in all patient groups. This profile represented apathy, weighted strongly to carer reports from the Apathy Evaluation Scale, Neuropsychiatric Inventory, and Cambridge Behavioral Inventory. Age at assessment, sex, and global cognitive impairment were not significant predictors. Differences in mortality risk across diagnostic groups were accounted for by their neuropsychiatric and behavioral features. CONCLUSIONS: The relationship between apathy and survival highlights the need to develop more effective and targeted measurement tools to improve its recognition and facilitate treatment. The prognostic importance of apathy suggests that neurobehavioral features might be useful to predict survival and stratify patients for interventional trials. Effective symptomatic interventions targeting the neurobiology of apathy might ultimately also improve prognosis.

White matter change with apathy and impulsivity in frontotemporal lobar degeneration syndromes.

OBJECTIVE: To identify the white matter correlates of apathy and impulsivity in the major syndromes associated with frontotemporal lobar degeneration, using diffusion-weighted imaging and data from the PiPPIN (Pick's Disease and Progressive Supranuclear Palsy: Prevalence and Incidence) study. We included behavioral and language variants of frontotemporal dementia, corticobasal syndrome, and progressive supranuclear palsy. METHODS: Seventy patients and 30 controls underwent diffusion tensor imaging at 3-tesla after detailed assessment of apathy and impulsivity. We used tract-based spatial statistics of fractional anisotropy and mean diffusivity, correlating with 8 orthogonal dimensions of apathy and impulsivity derived from a principal component analysis of neuropsychological, behavioral, and questionnaire measures. RESULTS: Three components were associated with significant white matter tract abnormalities. Carer-rated change in everyday skills, self-care, and motivation correlated with widespread changes in dorsal frontoparietal and corticospinal tracts, while carer observations of impulsive-apathetic and challenging behaviors revealed disruption in ventral frontotemporal tracts. Objective neuropsychological tests of cognitive control, reflection impulsivity, and reward responsiveness were associated with focal changes in the right frontal lobe and presupplementary motor area. These changes were observed across clinical diagnostic groups, and were not restricted to the disorders for which diagnostic criteria include apathy and impulsivity. CONCLUSION: The current study provides evidence of distinct structural network changes in white matter associated with different neurobehavioral components of apathy and impulsivity across the diverse spectrum of syndromes and pathologies associated with frontotemporal lobar degeneration.

Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes.

OBJECTIVES: To estimate the lifetime risk, prevalence, incidence, and mortality of the principal clinical syndromes associated with frontotemporal lobar degeneration (FTLD) using revised diagnostic criteria and including intermediate clinical phenotypes. METHODS: Multisource referral over 2 years to identify all diagnosed or suspected cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) in 2 UK counties (population 1.69 million). Diagnostic confirmation used current consensus diagnostic criteria after interview and reexamination. Results were adjusted to the 2013 European standard population. RESULTS: The prevalence of FTD, PSP, and CBS was 10.8/100,000. The incidence and mortality were very similar, at 1.61/100,000 and 1.56/100,000 person-years, respectively. The estimated lifetime risk is 1 in 742. Survival following diagnosis varied widely: from PSP 2.9 years to semantic variant FTD 9.1 years. Age-adjusted prevalence peaked between 65 and 69 years at 42.6/100,000: the age-adjusted prevalence for persons older than 65 years is double the prevalence for those between 40 and 64 years. Fifteen percent of those screened had a relevant genetic mutation. CONCLUSIONS: Key features of this study include the revised diagnostic criteria with improved specificity and sensitivity, an unrestricted age range, and simultaneous assessment of multiple FTLD syndromes. The prevalence of FTD, PSP, and CBS increases beyond 65 years, with frequent genetic causes. The time from onset to diagnosis and from diagnosis to death varies widely among syndromes, emphasizing the challenge and importance of accurate and timely diagnosis. A high index of suspicion for FTLD syndromes is required by clinicians, even for older patients.