Showing papers by "Katherine P. Rankin published in 2019"
TL;DR: An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic T DP-43 inclusion, and showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that the loss of nuclear TD-43 function promotes neurodegeneration, even when TDP's aggregation is inconspicuous or absent.
Abstract: TAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in the FI across a clinical spectrum including 17 patients with sporadic bvFTD, MND, or both. In an exploratory analysis based on our initial observations, we further assessed ten patients with C9orf72-associated bvFTD/MND. VENs and fork cells showed early, disproportionate TDP-43 aggregation that correlated with anatomical and clinical severity, including loss of emotional empathy. The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy. An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic TDP-43 inclusion. These cells showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that the loss of nuclear TDP-43 function promotes neurodegeneration, even when TDP-43 aggregation is inconspicuous or absent.
74 citations
TL;DR: This study demonstrates how PCPs approach diagnosis and management of patients with NCDs, and identified areas for improvement in regards to cognitive testing and neuroimaging and all providers’ lack of familiarity with published diagnostic criteria for NCD syndromes.
Abstract: Primary care providers (PCPs) are typically the first to screen and evaluate patients for neurocognitive disorders (NCDs), including mild cognitive impairment and dementia. However, data on PCP attitudes and evaluation and management practices are sparse. Our objective was to quantify perspectives and behaviors of PCPs and neurologists with respect to NCD evaluation and management. A cross-sectional survey with 150 PCPs and 50 neurologists in the United States who evaluated more than 10 patients over age 55 per month. The 51-item survey assessed clinical practice characteristics, and confidence, perceived barriers, and typical practices when diagnosing and managing patients with NCDs. PCPs and neurologists reported similar confidence and approaches to general medical care and laboratory testing. Though over half of PCPs performed cognitive screening or referred patients for cognitive testing in over 50% of their patients, only 20% reported high confidence in interpreting results of cognitive tests. PCPs were more likely to order CT scans than MRIs, and only 14% of PCPs reported high confidence interpreting brain imaging findings, compared to 70% of specialists. Only 21% of PCPs were highly confident that they correctly recognized when a patient had an NCD, and only 13% were highly confident in making a specific NCD diagnosis (compared to 72 and 44% for neurologists, both p < 0.001). A quarter of all providers identified lack of familiarity with diagnostic criteria for NCD syndromes as a barrier to clinical practice. This study demonstrates how PCPs approach diagnosis and management of patients with NCDs, and identified areas for improvement in regards to cognitive testing and neuroimaging. This study also identified all providers’ lack of familiarity with published diagnostic criteria for NCD syndromes. These findings may inform the development of new policies and interventions to help providers improve the efficacy of their decision processes and deliver better quality care to patients with NCDs.
29 citations
Helen Wills Neuroscience Institute1, Mayo Clinic2, Rush University3, University of Gothenburg4, Biogen Idec5, Washington University in St. Louis6, University of Cologne7, University of Pennsylvania8, Stanford University9, National Institutes of Health10, University of California, San Francisco11, University of Melbourne12, VU University Medical Center13, Eli Lilly and Company14, Brigham and Women's Hospital15
TL;DR: The authors misunderstand a central issue addressed in the framework: the fundamental definition of Alzheimer's disease (AD) and its distinction from the terms “Alzheimer’s clinical syndrome” and dementia, and propose these terms to distinguish between the pathological features of the disease and its clinical consequences.
Abstract: In this issue of Alzheimer’s & Dementia, Sweeney et al. [1] propose to extend the recently published NIA-AA Research Framework [2] by incorporating measures of vascular dysfunction as putative AD biomarkers. Although we strongly agree with the importance of a wide range of vascular factors in the development of cognitive decline, the authors misunderstand a central issue addressed in the framework: the fundamental definition of Alzheimer’s disease (AD) and its distinction from the terms “Alzheimer’s clinical syndrome” and dementia. We propose these terms to distinguish between the pathological features of the disease and its clinical consequences. Although there is extensive evidence that vascular factors contribute to the Alzheimer’s clinical syndrome and dementia, the evidence that they contribute to AD pathological changes is limited. For decades, AD has been defined as a clinical dementia syndrome confirmed at autopsy by the neuropathological observation of neuritic plaques and neurofibrillary tangles, which are now known to be composed of b-amyloid and paired helical filament tau. This has most recently been codified in the 2012 NIA-Alzheimer’s Association guidelines for the neuropathologic evaluation of AD that define an approach to characterizing the plaque and tangle hallmark lesions [3]. These guidelines note the likely importance of other pathological findings to the clinical presentation and specifically suggest the measurement of a number of them including vascular brain injury, Lewy body disease, and TDP-43 inclusions. However, none of these pathologies is, or have ever been, required for the neuropathological diagnosis of AD, which for decades has been and remains entirely based on the density and distribution of neuritic plaques and neurofibrillary tangles. The neuropathologic guidelines accomplished two important goals: (1) they provided a clear measure for neuropathologists to define AD neuropathologic change and (2) they divorced the pathological diagnosis of AD from the clinical diagnosis. This latter point is crucial because the clinical features associated with the pathologic changes are highly variable, including multiple cognitive and behavioral syndromes along with the complete absence of symptoms. The NIA-AA research framework built on these neuropathologic advances now that we can detect amyloid and
22 citations
TL;DR: The spatial similarity of medial and lateral pulvinar connectivity changes to those seen in the SN and DMN suggests a role for the pulvinars in intrinsic connectivity network changes in PCA.
21 citations
TL;DR: It is suggested that measures of interpersonal warmth can provide important clinical information about changes in underlying brain networks, and help clinicians and clinical researchers better identify which bvFTD and svPPA patients are at greater risk for interpersonal disruption.
16 citations
TL;DR: bv FTD displays more diverse diagnostic change than other neurodegenerative syndromes, and first-visit bvFTD diagnoses may waver if based on meeting possible criteria only.
Abstract: To determine the frequency and characteristics of clinical diagnostic change in frontotemporal dementia (FTD)-spectrum syndromes and Alzheimer’s disease (AD)-type dementia. We reviewed records and categorized diagnostic changes in patients seen ≥ 2 times with behavioral variant FTD (bvFTD, n = 99), nonfluent and semantic variant primary progressive aphasia (nfvPPA, n = 32; svPPA, n = 59), corticobasal syndrome (CBS, n = 40), progressive supranuclear palsy-Richardson syndrome (PSP-RS, n = 34), and AD-type dementia (n = 49). For bvFTD, we compared patients with and without diagnostic change, and assessed predictors of diagnostic change by logistic regression. Initial diagnoses changed infrequently at subsequent visits in svPPA (6.8%), PSP-RS (8.8%), and nfvPPA (12.5%), with rare changes largely involving clinicopathological overlap or diagnostic ambiguity. Changes in AD-type dementia (30.6%) and CBS (37.5%) were more common, but reflected greater specificity, predicted co-pathology, or overlapping syndromes. Diagnostic change in bvFTD was also common (32.3%), but more diverse, including motor neuron disease development, alternative neurodegenerative syndromes, and non-neurodegenerative diseases. Diagnostic change occurred more often in those who met possible rather than probable bvFTD criteria (70.6% vs 15.3%, p < 0.001). Patients with stable diagnoses showed greater overall impairment, bvFTD behavioral severity, and atrophy in core right-hemisphere bvFTD regions. Patients with diagnostic change had more severe depression (p < 0.05) and more frequent contributing, secondary diagnoses (p = 0.01), such as cerebrovascular disease. By logistic regression, the accuracy of predicting stable bvFTD diagnoses using first-visit data was 80%. bvFTD displays more diverse diagnostic change than other neurodegenerative syndromes. First-visit bvFTD diagnoses may waver if based on meeting possible criteria only.
15 citations
TL;DR: Intranasal oxytocin enhanced eye gaze in men with schizophrenia, consistent with findings that Oxytocin optimizes processing of social stimuli, and whether changes in eye gaze impact social cognition and functional outcomes is investigated.
14 citations
University of California, San Francisco1, Mayo Clinic2, Oregon Health & Science University3, University of Michigan4, Northwestern University5, Florida Atlantic University6, Case Western Reserve University7, University of California, Los Angeles8, University of Pennsylvania9, University of Washington10, Harvard University11, Indiana University – Purdue University Indianapolis12, University of North Carolina at Chapel Hill13, Johns Hopkins University14, University of Toronto15, Washington University in St. Louis16, Columbia University17, National Institutes of Health18, University of British Columbia19, University of California, San Diego20, University of Alabama at Birmingham21
TL;DR: Conventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation, but 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.
13 citations
Mayo Clinic1, University of Pennsylvania2, University of California, Los Angeles3, Harvard University4, Indiana University – Purdue University Indianapolis5, University of California, San Francisco6, Washington University in St. Louis7, Columbia University8, University of British Columbia9, University of Washington10, Northwestern University11
TL;DR: A potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials was showed and cross-sectional and longitudinal data showed.
12 citations
TL;DR: In the bvFTD group, patients who experienced relationship dissolution or infidelity had significantly lower empathy than those who did not, and changes in relationship status differed across dementia groups and were associated with empathy decline.
Abstract: Author(s): Takeda, Akitoshi; Sturm, Virginia E; Rankin, Katherine P; Ketelle, Robin; Miller, Bruce L; Perry, David C | Abstract: BackgroundBehavioral variant frontotemporal dementia (bvFTD) is characterized by marked deficits in empathy and social behavior; however, the effect of these symptoms on partner relationships has not been quantitatively measured.ObjectiveWe aimed to determine the effect of empathy loss and behavioral symptoms on partner and familial relationship status in bvFTD. We ascertained whether patients were currently in marriage/partner relationships or were separated/divorced, the timing and duration of these relationships, and whether the patients had relationship infidelity. We investigated the relationship status of 483 patients (156 with bvFTD, 38 with nonfluent variant primary progressive aphasia, 72 with semantic variant primary progressive aphasia, 49 with corticobasal syndrome, 45 with progressive supranuclear palsy syndrome, and 123 with Alzheimer disease) over the course of follow-up, and correlated relationship status with patients' first visit Interpersonal Reactivity Index and Neuropsychiatric Inventory.ResultsRelationship dissolution and infidelity were significantly more frequent among patients with bvFTD than in the other groups. Across all patients, empathy loss was associated with relationship dissolution. In the bvFTD group, patients who experienced relationship dissolution or infidelity had significantly lower empathy than those who did not.ConclusionsChanges in relationship status differed across dementia groups and were associated with empathy decline.
11 citations
TL;DR: Memory and executive functions are associated with different patterns of WM diffusivity, adding insight into WM alterations underlying age- and disease-related cognitive decline.
Abstract: Objective: White matter (WM) microstructural changes are increasingly recognized as a mechanism of age-related cognitive differences. This study examined the associations between patterns of WM microstructure and cognitive performance on the University of California, San Francisco (UCSF) Brain Health Assessment (BHA) subtests of memory (Favorites), executive functions and speed (Match), and visuospatial skills (Line Orientation) within a sample of older adults. Method: Fractional anisotropy (FA) in WM tracts and BHA performance were examined in 84 older adults diagnosed as neurologically healthy (47), with mild cognitive impairment (19), or with dementia (18). The relationships between FA and subtest performances were evaluated using regression analyses. We then explored whether regional WM predicted performance after accounting for variance explained by global FA. Results: Memory performance was associated with FA of the fornix and the superior cerebellar peduncle; and executive functions and speed, with the body of the corpus callosum. The fornix–memory association and the corpus callosum–executive association remained significant after accounting for global FA. Neither tract-based nor global FA was associated with visuospatial performance. Conclusions: Memory and executive functions are associated with different patterns of WM diffusivity. Findings add insight into WM alterations underlying age- and disease-related cognitive decline.
TL;DR: The results suggest that patients with dementia present decreased ability of self-monitoring, probably due to impaired insula and orbitofrontal cortex and their disconnection from structures of the salience network.
Abstract: Objective:Self-monitoring is a crucial component of human empathy and necessary for the formation and repair of social relations. Several studies have brought to light possible neuronal substrates ...
TL;DR: Four robust aINS time-varying functional connectivity modes that displayed both “state” and “trait” characteristics were identified: while modes featuring connectivity to sensory regions were modulated by eye closure, modes featuring connections to higher cognitive and emotional processing regions were stable over time and related to empathy measures.
Abstract: The human anterior insula (aINS) is a topographically organized brain region, in which ventral portions contribute to socio-emotional function through limbic and autonomic connections, whereas the dorsal aINS contributes to cognitive processes through frontal and parietal connections. Open questions remain, however, regarding how aINS connectivity varies over time. We implemented a novel approach combining seed-to-whole-brain sliding-window functional connectivity MRI and k-means clustering to assess time-varying functional connectivity of aINS subregions. We studied three independent large samples of healthy participants and longitudinal datasets to assess inter- and intra-subject stability, and related aINS time-varying functional connectivity profiles to dispositional empathy. We identified four robust aINS time-varying functional connectivity modes that displayed both "state" and "trait" characteristics: while modes featuring connectivity to sensory regions were modulated by eye closure, modes featuring connectivity to higher cognitive and emotional processing regions were stable over time and related to empathy measures.
TL;DR: This research highlights the need to understand more fully the role of emotion in the development of memory impairment and how these emotions are influenced by age, disease and disability.
Abstract: Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, San Francisco, CA, USA; Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA; Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco,CA, USA; University ofWashington School ofMedicine, Seattle,WA, USA; Division ofGeriatrics, Department ofMedicine, University of California, San Francisco, San Francisco, CA, USA.
TL;DR: Overall, the findings suggest that VENs and fork cells facilitate specialized human social-emotional capacities by contributing to salience network function.
Abstract: Each neurodegenerative syndrome presents with characteristic symptoms that reflect the specific pattern of cellular, regional, and large-scale network vulnerability. In behavioral variant frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs) and fork cells are among the initial cellular targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function via roles in autonomic processing and homeostatic behavioral guidance. Here, we combined questionnaire-based empathy assessments, in vivo structural neuroimaging, and quantitative histopathological data from 16 patients across the FTD-amyotrophic lateral sclerosis clinicopathological spectrum linked to TAR DNA-binding protein 43 pathobiology. We sought to examine how neuron type-specific degeneration is linked to regional gray and white matter atrophy and, in turn, to loss of emotional empathy. We show that disease protein aggregation within right FI VENs and fork cells is associated with atrophy in insular, medial frontal, and subcortical regions including the dorsomedial thalamus that represent key nodes within the salience network. Gray and white matter degeneration within these structures, in turn, mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing the signature bvFTD clinical features. Overall, the findings suggest that VENs and fork cells facilitate specialized human social- emotional capacities by contributing to salience network function.
Mayo Clinic1, University of California, San Francisco2, Case Western Reserve University3, University of California, Los Angeles4, Harvard University5, University of Washington Medical Center6, Indiana University7, Washington University in St. Louis8, Columbia University9, University of Pennsylvania10, University of British Columbia11, University of North Carolina at Chapel Hill12, University of Texas Southwestern Medical Center13, University of Washington14, University of California, San Diego15, National Institutes of Health16, Johns Hopkins University17, Johns Hopkins University School of Medicine18, University of Alabama at Birmingham19, Northwestern University20, University Health Network21, University of Southern California22
TL;DR: Forsberg, Leah K; Boeve, Bradley F; Boxer, Adam L; Rosen, Howard J; Kornak, John; Heuer, Hilary W; Fields, Julie A; Brushaber, Danielle; Machulda, Mary M; Sturm, Virginia; Staffaroni, Adam M; Ljubenkov, Peter A; Denver, Reilly; Ong, Elise; Appleby, Brian; Bordelon, Yvette M; Brannelly, Patrick; Coppola, Giovanni; Dickerson, Brad C; Dickinson, Susan;
Abstract: Author(s): Forsberg, Leah K; Boeve, Bradley F; Boxer, Adam L; Rosen, Howard J; Kornak, John; Heuer, Hilary W; Fields, Julie A; Brushaber, Danielle; Machulda, Mary M; Sturm, Virginia; Staffaroni, Adam M; Ljubenkov, Peter A; Denver, Reilly; Ong, Elise; Appleby, Brian; Bordelon, Yvette M; Brannelly, Patrick; Coppola, Giovanni; Dickerson, Brad C; Dickinson, Susan; Kimiko, Domoto-Reilly; Faber, Kelley; Fong, Jamie; Foroud, Tatiana M; Gavrilova, Ralitza H; Gearhart, Debra; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathan; Graff-Radford, Neil R; Grossman, Murray; Robin Hsiung, Ging-Yuek; Huey, Edward D; Irwin, David; Jones, David T; Kantarci, Kejal; Karydas, Anna M; Kaufer, Daniel; Kerwin, Diana R; Knopman, David S; Kraft, Ruth A; Kramer, Joel H; Kremers, Walter K; Kukull, Walter A; Litvan, Irene; Lucente, Diane E; Lungu, Codrin; Mackenzie, Ian R; McGinnis, Scott M; Mendez, Mario F; Miller, Bruce L; Onyike, Chiadi U; Pantelyat, Alex; Pearlman, Rodney; Petrucelli, Leonard; Potter, Madeline; Rademakers, Rosa; Ramos, Eliana Marisa; Rankin, Katherine; Rascovsky, Katya; Roberson, Erik D; Rogalski, Emily J; Shaw, Leslie M; Sutherland, Marg; Syrjanen, Jeremy; Tartaglia, Carmela; Tatton, Nadine; Taylor, Joanne; Toga, Arthur W; Trojanowski, John Q; Weintraub, Sandra; Wong, Bonnie; Wszolek, Zbigniew
TL;DR: Patients with PCA have relatively preserved FE recognition compared to FI recognition, as seen in affective blindsight.
Abstract: Objective To compare recognition of facial expression (FE) vs recognition of facial identity (FI) in posterior cortical atrophy (PCA), with the hypothesis that FE recognition would be relatively preserved in PCA. Methods In this observational study, FI and expression recognition tasks were performed by 194 participants in 4 groups, including 39 with Alzheimer disease (AD) (non-PCA), 49 with behavioral variant frontotemporal dementia (bvFTD), 15 with PCA, and 91 healthy controls. Between-group differences in test scores were compared. Results Patients with PCA performed worse than healthy controls in FI and emotion recognition tasks ( p Conclusions Patients with PCA have relatively preserved FE recognition compared to FI recognition, as seen in affective blindsight.
DOI•
16 May 2019
TL;DR: Interpersonal Reactivity Index scale (IRI) is a cross-cultural useful tool for immediate neuropsychological examination regarding the evaluation of empathy in patients with different types of dementia and different patterns of anatomical lesions show a reduction in distinct aspects of empathy.
Abstract: Background: Empathy, which refers to a cognitive and emotional process of continuously detecting the changing intentions of others, differs in the behavioral variant frontotemporal degeneration (bvFTD) compared with other dementia types. Interpersonal Reactivity Index scale (IRI) could help in understanding their differential patterns of empathy. We suggested that both emotional and cognitive aspects of empathy would be significantly decreased in bvFTD patients compared to other dementia groups in the Greek population.
Methods: We examined 162 subjects with dementia of various types and normal control. (normal control: 61; Alzheimer’s disease (AD): 61; bvFTD 19; semantic variant of Primary Progressive Aphasia: 14; nonfluent variant of Primary Progressive Aphasia: 7).Two subscales of IRI, Empathic Concern and Perspective-Taking, used to measure the cognitive and emotional components of empathy.
Results: Patients with bvFTD showed extreme deficits in both empathic concern and perspective taking compared to the other patient groups. AD patients showed greater impairment in empathic concern but not in perspective taking than has previously been seen.
Conclusions: In the Greek population, patients with different types of dementia and different patterns of anatomical lesions show a reduction in distinct aspects of empathy. Thus, IRI is a cross-cultural useful tool for immediate neuropsychological examination regarding the evaluation of empathy.