Clinical recognition of frontotemporal dementia with right anterior temporal predominance: A multicenter retrospective cohort study.

INTRODUCTION: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. HIGHLIGHTS: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

Symptomatic progression of frontotemporal dementia with the TARDBP I383V variant.

We present a longitudinal description of a man with the TARDBP I383V variant of frontotemporal dementia (FTD). His progressive changes in behavior and language resulted in a diagnosis of the right temporal variant of FTD, also called the semantic behavioral variant (sbvFTD). We also present data from a small series of patients with the TARDBP I383V variant who were enrolled in a nationwide FTD research collaboration (ALLFTD). These data support slowly progressive loss of semantic function. While semantic dementia is infrequently considered genetic, the TARDBP I383V variant seems to be an exception. Longitudinal analyses in larger samples are warranted.

Psychiatric Screening Measures in Behavioral Variant Frontotemporal Dementia.

OBJECTIVE: Behavioral variant frontotemporal dementia (bvFTD) is sometimes misdiagnosed as a primary psychiatric disorder, such as major depressive disorder, bipolar disorder, an anxiety disorder, autism spectrum disorder (ASD), or attention-deficit hyperactivity disorder (ADHD). Nonspecialists often use screening measures for primary psychiatric disorders in early assessments of persons with bvFTD. The investigators aimed to evaluate the manifestations of bvFTD in surveys intended to screen for primary psychiatric disorders. METHODS: Patients with bvFTD (N=27) presenting to an academic neurobehavior specialty clinic and their caregivers were provided questionnaire packets including the Mood Disorder Questionnaire (MDQ), the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 scale (GAD-7), the Adult ADHD Self-Report Scale, version 1.1, the Ritvo Autism and Asperger Diagnostic Scale, and the Neuropsychiatric Inventory Questionnaire. Established cutoff scores suggesting the presence of a primary psychiatric disorder were used to define a "positive" response. Individual questions from each screening questionnaire were examined for a more granular characterization of bvFTD. RESULTS: Overall, 15% of bvFTD patients screened positive for bipolar disorder, 54% screened positive for ADHD, and 89% screened positive for ASD. Hyperactivity or hypersensitivity symptoms were infrequently endorsed. In addition, 57% of respondents screened positive for depressive symptoms on the PHQ-9, and 43% screened positive for anxiety symptoms on the GAD-7. CONCLUSIONS: The use of cutoff scores on screening measures for primary psychiatric disorders resulted in potentially problematic positive screens of primary psychiatric disorders among persons with bvFTD. Identifying specific questions that distinguish between bvFTD and primary psychiatric disorders requires further study.

Astrogliosis, neuritic microstructure, and sex effects: GFAP is an indicator of neuritic orientation in women.

BACKGROUND: Data from human studies suggest that immune dysregulation is associated with Alzheimer's disease (AD) pathology and cognitive decline and that neurites may be affected early in the disease trajectory. Data from animal studies further indicate that dysfunction in astrocytes and inflammation may have a pivotal role in facilitating dendritic damage, which has been linked with negative cognitive outcomes. To elucidate these relationships further, we have examined the relationship between astrocyte and immune dysregulation, AD-related pathology, and neuritic microstructure in AD-vulnerable regions in late life. METHODS: We evaluated panels of immune, vascular, and AD-related protein markers in blood and conducted in vivo multi-shell neuroimaging using Neurite Orientation Dispersion and Density Imaging (NODDI) to assess indices of neuritic density (NDI) and dispersion (ODI) in brain regions vulnerable to AD in a cohort of older adults (n = 109). RESULTS: When examining all markers in tandem, higher plasma GFAP levels were strongly related to lower neurite dispersion (ODI) in grey matter. No biomarker associations were found with higher neuritic density. Associations between GFAP and neuritic microstructure were not significantly impacted by symptom status, APOE status, or plasma Aß42/40 ratio; however, there was a large sex effect observed for neurite dispersion, wherein negative associations between GFAP and ODI were only observed in females. DISCUSSION: This study provides a comprehensive, concurrent appraisal of immune, vascular, and AD-related biomarkers in the context of advanced grey matter neurite orientation and dispersion methodology. Sex may be an important modifier of the complex associations between astrogliosis, immune dysregulation, and brain microstructure in older adults.

Expressive Prosody in Patients With Focal Anterior Temporal Neurodegeneration.

BACKGROUND AND OBJECTIVES: Progressive focal anterior temporal lobe (ATL) neurodegeneration has been historically called semantic dementia. More recently, semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) have been linked with predominant left and right ATL neurodegeneration, respectively. Nonetheless, clinical tools for an accurate diagnosis of sbvFTD are still lacking. Expressive prosody refers to the modulation of pitch, loudness, tempo, and quality of voice used to convey emotional and linguistic information and has been linked to bilateral but right-predominant frontotemporal functioning. Changes in expressive prosody can be detected with semiautomated methods and could represent a useful diagnostic marker of socioemotional functioning in sbvFTD. METHODS: Participants underwent a comprehensive neuropsychological and language evaluation and a 3T MRI at the University of California San Francisco. Each participant provided a verbal description of the picnic scene from the Western Aphasia Battery. The fundamental frequency (f0) range, an acoustic measure of pitch variability, was extracted for each participant. We compared the f0 range between groups and investigated associations with an informant-rated measure of empathy, a facial emotion labeling task, and gray matter (GM) volumes using voxel-based morphometry. RESULTS: Twenty-eight patients with svPPA, 18 with sbvFTD, and 18 healthy controls (HCs) were included. f0 range was significantly different across groups: patients with sbvFTD showed reduced f0 range in comparison with both patients with svPPA (mean difference of -1.4 ± 2.4 semitones; 95% CI -2.4 to -0.4]; p < 0.005) and HCs (mean difference of -1.9 ± 3.0 semitones; 95% CI -3.0 to -0.7]; p < 0.001). A higher f0 range was correlated with a greater informant-rated empathy (r = 0.355; p ≤ 0.05), but not facial emotion labeling. Finally, the lower f0 range was correlated with lower GM volume in the right superior temporal gyrus, encompassing anterior and posterior portions (p < 0.05 FWE cluster corrected). DISCUSSION: Expressive prosody may be a useful clinical marker of sbvFTD. Reduced empathy is a core symptom in sbvFTD; the present results extend this to prosody, a core component of social interaction, at the intersection of speech and emotion. They also inform the long-standing debate on the lateralization of expressive prosody in the brain, highlighting the critical role of the right superior temporal lobe.

Delirium Following Anticholinergic Use in Hospitalized Patients With Dementia.

We sought to explore rates of delirium amongst hospitalized patients with dementia following orders for anticholinergic medications. We hypothesized that patients receiving anticholinergic medications would have higher rates of delirium than similar, unexposed patients. We performed a retrospective chart review of 23 031 hospitalized individuals with Alzheimer's disease, vascular dementia, or unspecified dementia from 2011-2018. Rates of delirium diagnosis and haloperidol orders following anticholinergic administration were compared to patients with dementia without anticholinergic orders. Significant differences in rates of delirium and orders for haloperidol were observed between exposed and unexposed groups, with delirium having a relative risk of 2.3 and orders for haloperidol having a relative risk of 10.4. The number needed to harm for anticholinergic exposure was 5.45 for delirium and 7.09 for haloperidol. The identified difference suggests that inpatient use of anticholinergic medications may increase the risk of delirium in hospitalized patients with dementia. Despite this risk, our review suggests that anticholinergic administration is common during hospital stays among patients with dementia. Anticholinergic use may be a modifiable risk factor for delirium prevention, which could improve inpatient management of patients with dementia.

Incongruences Between Facial Expression and Self-Reported Emotional Reactivity in Frontotemporal Dementia and Related Disorders.

OBJECTIVE: Emotional reactivity normally involves a synchronized coordination of subjective experience and facial expression. These aspects of emotional reactivity can be uncoupled by neurological illness and produce adverse consequences for patient and caregiver quality of life because of misunderstandings regarding the patient's presumed internal state. Frontotemporal dementia (FTD) is often associated with altered social and emotional functioning. FTD is a heterogeneous disease, and socioemotional changes in patients could result from altered internal experience, altered facial expressive ability, altered language skills, or other factors. The authors investigated how individuals with FTD subtypes differ from a healthy control group regarding the extent to which their facial expressivity aligns with their self-reported emotional experience. METHODS: Using a compound measure of emotional reactivity to assess reactions to three emotionally provocative videos, the authors explored potential explanations for differences in alignment of facial expressivity with emotional experience, including parkinsonism, physiological reactivity, and nontarget verbal responses. RESULTS: Participants with the three main subtypes of FTD all tended to express less emotion on their faces than they did through self-report. CONCLUSIONS: Exploratory analyses suggest that reasons for this incongruence likely differ not only between but also within diagnostic subgroups.

Development of the Colorado posterior cortical questionnaire within an Alzheimer's disease study cohort.

INTRODUCTION: Non-amnestic presentations of neurodegenerative dementias, including posterior- and visual-predominant cognitive forms, are under-recognized. Specific screening measures for posterior cortical symptoms could allow for earlier, more accurate diagnosis and directed treatment. METHODS: Based on clinical experience with posterior cortical atrophy evaluations, high-yield screening questions were collected and organized into a 15-item self-report questionnaire, titled the Colorado Posterior Cortical Questionnaire (CPC-Q). The CPC-Q was then piloted within a longitudinal cohort of cognitive aging, including 63 older adults, including healthy older adults (n = 33) and adults with either amnestic Alzheimer's disease (n = 21) or posterior cortical atrophy (PCA, n = 9). RESULTS: The CPC-Q demonstrated acceptable psychometric properties (internal consistency, α = 0.89; mean item-total correlation = 0.62), correlated strongly with visuospatial measures on cognitive testing (p < 0.001), and could distinguish PCA from non-PCA groups (p < 0.001; AUC 0.95 (95% CI 0.88, 1.0)). CONCLUSIONS: The CPC-Q captured posterior cortical symptoms in older adults, using a gold standard of expert consensus PCA diagnosis. Future studies will validate the CPC-Q in a larger cohort, with recruitment of additional PCA participants, to evaluate its convergent and discriminant validity more thoroughly. As a short, self-report tool, the CPC-Q demonstrates potential to improve detection of non-amnestic neurodegenerative dementias in the clinical setting.

Use of coffee grounds to test olfaction for predicting cognitive dysfunction and decline.

INTRODUCTION: Our objective was to determine whether non-standardized testing of olfaction may provide useful information for predicting cognitive dysfunction and decline in patients with neurobehavioral disorders. METHODS: We conducted cross-sectional and longitudinal analyses of 82 patients who presented to a Memory Clinic with a chief complaint of cognitive deficits using non-standardized odor identification testing (nSOIT). Each patient was classified as having intact or impaired olfaction based on the ability to identify and name the odor of coffee grounds. The cross-sectional study used Student's t-test to examine whether nSOIT results were related to cognitive dysfunction as approximated by Montreal Cognitive Assessment (MoCA) scores. The longitudinal study used mixed effects multiple regression with an interaction term to investigate whether nSOIT results were predictive of cognitive decline over a period of follow-up testing (0.4 to 4.0 years [mean 1.4, SD 0.8]) to compare patients who exhibited cognitive decline over the evaluation period (decliners) and those who did not (non-decliners). RESULTS: Analysis of the initial use of nSOIT in the cross-sectional study demonstrated no association between nSOIT performance and objective cognitive dysfunction. In the longitudinal study, impairment in follow-up nSOIT testing was found to be a sensitive but nonspecific predictor of cognitive decline. CONCLUSION: These results suggest that routine olfactory testing may serve as a convenient and readily available method that can be used by clinicians to better predict cognitive dysfunction and decline in patients with a variety of neurobehavioral disorders.

Distinguishing Behavioral Variant Frontotemporal Dementia From Primary Psychiatric Disorders: A Review of Recently Published Consensus Recommendations From the Neuropsychiatric International Consortium for Frontotemporal Dementia.

The behavioral variant of frontotemporal dementia (bvFTD) is the second most common cause of dementia for individuals <65 years old, but accurate diagnosis is often delayed for several years. While previous criteria have increased the ability of diagnosticians to distinguish between bvFTD and other neurocognitive disorders such as Alzheimer's disease, distinguishing bvFTD from a primary psychiatric disorder (PPD) has been more challenging. In early 2020, the Neuropsychiatric International Consortium for Frontotemporal Dementia published the first consensus recommendations to help clinicians distinguish between bvFTD and PPD. These recommendations were produced by a consortium of 45 scientists and clinicians from more than 15 different countries, who explored aspects of history taking, neuropsychological assessments, clinical scales, neuroimaging, CSF and serum biomarkers, and genetics. A multidisciplinary approach is encouraged throughout. In this article, the authors also review those consensus recommendations and highlight use of novel tests and techniques. Additionally, they indicate where further research is needed, including methods to assess the dissemination and implementation of these recommendations. In this way, future efforts by clinicians and researchers alike to improve accurate recognition of bvFTD are encouraged, thereby expanding opportunities for improved guidance and management.

P-Hacking Lexical Richness Through Definitions of "Type" and "Token".

"P-hacking" is the repeated analysis of data until a statistically significant result is achieved. We show that p-hacking can also occur during data generation, sometimes unintentionally. We use the type-token ratio to demonstrate that differences in the definitions of "type" and "token" can produce significantly different results. Since these terms are rarely defined in the biomedical literature, the result is an inability to meaningfully interpret the body of literature that makes use of this measure.

Interpersonal prosodic correlation in frontotemporal dementia.

Communication accommodation describes how individuals adjust their communicative style to that of their conversational partner. We predicted that interpersonal prosodic correlation related to pitch and timing would be decreased in behavioral variant frontotemporal dementia (bvFTD). We predicted that the interpersonal correlation in a timing measure and a pitch measure would be increased in right temporal FTD (rtFTD) due to sparing of the neural substrate for speech timing and pitch modulation but loss of social semantics. We found no significant effects in bvFTD, but conversations including rtFTD demonstrated higher interpersonal correlations in speech rate than healthy controls.

Aprosodia and prosoplegia with right frontal neurodegeneration.

Affective prosody and facial expression are essential components of human communication. Aprosodic syndromes are associated with focal right cerebral lesions that impair the affective-prosodic aspects of language, but are rarely identified because affective prosody is not routinely assessed by clinicians. Inability to produce emotional faces (affective prosoplegia) is a related and important aspect of affective communication has overlapping neuroanatomic substrates with affective prosody. We describe a patient with progressive aprosodia and prosoplegia who had right greater than left perisylvian and temporal atrophy with an anterior predominance. We discuss the importance of assessing affective prosody and facial expression to arrive at an accurate clinical diagnosis.

Relative preservation of facial expression recognition in posterior cortical atrophy.

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 < 0.001 for all). Patients with PCA also performed worse than AD and bvFTD groups in FI recognition, with no difference in FE recognition. CONCLUSIONS: Patients with PCA have relatively preserved FE recognition compared to FI recognition, as seen in affective blindsight.

Neuroanatomy of Shared Conversational Laughter in Neurodegenerative Disease.

Perceiving another person's emotional expression often sparks a corresponding signal in the observer. Shared conversational laughter is a familiar example. Prior studies of shared laughter have made use of task-based functional neuroimaging. While these methods offer insight in a controlled setting, the ecological validity of such controlled tasks has limitations. Here, we investigate the neural correlates of shared laughter in patients with one of a variety of neurodegenerative disease syndromes (N = 75), including Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), right and left temporal variants of semantic dementia (rtvFTD, svPPA), nonfluent/agrammatic primary progressive aphasia (nfvPPA), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). Patients were recorded in a brief unrehearsed conversation with a partner (e.g., a friend or family member). Laughter was manually labeled, and an automated system was used to assess the timing of that laughter relative to the partner's laughter. The probability of each participant with neurodegenerative disease laughing during or shortly after his or her partners' laughter was compared to differences in brain morphology using voxel-based morphometry, thresholded based on cluster size and a permutation method and including age, sex, magnet strength, disease-specific atrophy and total intracranial volumes as covariates. While no significant correlations were found at the critical T value, at a corrected voxelwise threshold of p < 0.005, a cluster in the left posterior cingulate gyrus demonstrated a trend at p = 0.08 (T = 4.54). Exploratory analysis with a voxelwise threshold of p = 0.001 also suggests involvement of the left precuneus (T = 3.91) and right fusiform gyrus (T = 3.86). The precuneus has been previously implicated in the detection of socially complex laughter, and the fusiform gyrus has a well-described role in the recognition and processing of others' emotional cues. This study is limited by a relatively small sample size given the number of covariates. While further investigation is needed, these results support our understanding of the neural underpinnings of shared conversational laughter.

Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia.

Importance: The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. Objective: To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). Design, Setting, and Participants: This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11-labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA. Main Outcomes and Measures: Clinical, cognitive, neuroimaging, and pathology results. Results: Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET-positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy. Conclusions and Relevance: Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11-labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease.

Observing conversational laughter in frontotemporal dementia.

BACKGROUND: We performed an observational study of laughter during seminaturalistic conversations between patients with dementia and familial caregivers. Patients were diagnosed with (1) behavioural variant frontotemporal dementia (bvFTD), (2) right temporal variant frontotemporal dementia (rtFTD), (3) semantic variant of primary progressive aphasia (svPPA), (4) non-fluent variant primary progressive aphasia (nfvPPA) or (5) early onset Alzheimer's disease (eoAD). We hypothesised that those with bvFTD would laugh less in response to their own speech than other dementia groups or controls, while those with rtFTD would laugh less regardless of who was speaking. METHODS: Patients with bvFTD (n=39), svPPA (n=19), rtFTD (n=14), nfvPPA (n=16), eoAD (n=17) and healthy controls (n=156) were recorded (video and audio) while discussing a problem in their relationship with a healthy control companion. Using the audio track only, laughs were identified by trained coders and then further classed by an automated algorithm as occurring during or shortly after the participant's own vocalisation ('self' context) or during or shortly after the partner's vocalisation ('partner' context). RESULTS: Individuals with bvFTD, eoAD or rtFTD laughed less across both contexts of self and partner than the other groups. Those with bvFTD laughed less relative to their own speech comparedwith healthy controls. Those with nfvPPA laughed more in the partner context compared with healthy controls. CONCLUSIONS: Laughter in response to one's own vocalisations or those of a conversational partner may be a clinically useful measure in dementia diagnosis.

Comparing Volume Loss in Neuroanatomical Regions of Emotion versus Regions of Cognition in Healthy Aging.

Many emotional functions are relatively preserved in aging despite declines in several cognitive domains and physical health. High levels of happiness exist even among centenarians. To address the hypothesis of whether preservation of emotional function in healthy aging may relate to different rates of age-related volume loss across brain structures, we performed two volumetric analyses on structural magnetic resonance neuroimaging of a group of healthy aging research participants using Freesurfer version 5.1. Volumes selected as supporting cognition included bilateral midfrontal and lateral frontal gyri, lateral parietal and temporal cortex, and medial temporal lobes. Volumes supporting emotion included bilateral amygdala, rostral anterior cingulate, insula, orbitofrontal cortex, and nucleus accumbens. A cross-sectional analysis was performed using structural MRI scans from 258 subjects. We found no difference in proportional change between groups. A longitudinal mixed effects model was used to compare regional changes over time in a subset of 84 subjects. Again, there was no difference in proportional change over time. While our results suggest that aging does not collectively target cognitive brain regions more than emotional regions, subgroup analysis suggests relative preservation of the anterior cingulate cortex, with greater volume loss in the nucleus accumbens. Implications of these relative rates of age-related volume loss in healthy aging are discussed and merit further research.