Publications by authors named "Bruce L Miller"

696 Publications

Resting functional connectivity in the semantic appraisal network predicts accuracy of emotion identification.

Neuroimage Clin 2021 Jul 7;31:102755. Epub 2021 Jul 7.

Memory and Aging Center, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158, United States. Electronic address:

Objective: Structural and task-based functional studies associate emotion reading with frontotemporal brain networks, though it remains unclear whether functional connectivity (FC) alone predicts emotion reading ability. The predominantly frontotemporal salience and semantic appraisal (SAN) networks are selectively impacted in neurodegenerative disease syndromes like behavioral-variant frontotemporal dementia (bvFTD) and semantic-variant primary progressive aphasia (svPPA). Accurate emotion identification diminishes in some of these patients, but studies investigating the source of this symptom in patients have predominantly examined structural rather than functional brain changes. Thus, we investigated the impact of altered connectivity on their emotion reading.

Methods: One-hundred-eighty-five participants (26 bvFTD, 21 svPPA, 24 non-fluent variant PPA, 24 progressive supranuclear palsy, 49 Alzheimer's disease, 41 neurologically healthy older controls) underwent task-free fMRI, and completed the Emotion Evaluation subtest of The Awareness of Social Inference Test (TASIT-EET), watching videos and selecting labels for actors' emotions.

Results: As expected, patients averaged significantly worse on emotion reading, but with wide inter-individual variability. Across all groups, lower mean FC in the SAN, but not other ICNs, predicted worse TASIT-EET performance. Node-pair analysis revealed that emotion identification was predicted by FC between 1) right anterior temporal lobe (RaTL) and right anterior orbitofrontal (OFC), 2) RaTL and right posterior OFC, and 3) left basolateral amygdala and left posterior OFC.

Conclusion: Emotion reading test performance predicts FC in specific SAN regions mediating socioemotional semantics, personalized evaluations, and salience-driven attention, highlighting the value of emotion testing in clinical and research settings to index neural circuit dysfunction in patients with neurodegeneration and other neurologic disorders.
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http://dx.doi.org/10.1016/j.nicl.2021.102755DOI Listing
July 2021

Computationally derived anatomic subtypes of behavioral variant frontotemporal dementia show temporal stability and divergent patterns of longitudinal atrophy.

Alzheimers Dement (Amst) 2021 12;13(1):e12183. Epub 2021 Jul 12.

Department of Neurology Memory and Aging Center University of California San Francisco San Francisco California USA.

Introduction: Behavioral variant frontotemporal dementia (bvFTD) can be computationally divided into four distinct anatomic subtypes based on patterns of frontotemporal and subcortical atrophy. To more precisely predict disease trajectories of individual patients, the temporal stability of each subtype must be characterized.

Methods: We investigated the longitudinal stability of the four previously identified anatomic subtypes in 72 bvFTD patients. We also applied a voxel-wise mixed effects model to examine subtype differences in atrophy patterns across multiple timepoints.

Results: Our results demonstrate the stability of the anatomic subtypes at baseline and over time. While they had common salience network atrophy, each subtype showed distinctive baseline and longitudinal atrophy patterns.

Discussion: Recognizing these anatomically heterogeneous subtypes and their different patterns of atrophy progression in early bvFTD will improve disease course prediction in individual patients. Longitudinal volumetric predictions based on these anatomic subtypes may be used as a more accurate endpoint in treatment trials.
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http://dx.doi.org/10.1002/dad2.12183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274310PMC
July 2021

Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.

Alzheimers Dement (Amst) 2021 5;13(1):e12197. Epub 2021 Jul 5.

The Florey Institute University of Melbourne Parkville Victoria Australia.

Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.

Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.

Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.

Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.
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http://dx.doi.org/10.1002/dad2.12197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256623PMC
July 2021

Dissociating nouns and verbs in temporal and perisylvian networks: Evidence from neurodegenerative diseases.

Cortex 2021 Jun 2;142:47-61. Epub 2021 Jun 2.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Naming of nouns and verbs can be selectively impaired in neurological disorders, but the specificity of the neural and cognitive correlates of such dissociation remains unclear. Functional imaging and stroke research sought to identify cortical regions selectively recruited for nouns versus verbs, yet findings are inconsistent. The present study investigated this issue in neurodegenerative diseases known to selectively affect different brain networks, thus providing new critical evidence of network specificity. We examined naming performances on nouns and verbs in 146 patients with different neurodegenerative syndromes (Primary Progressive Aphasia - PPA, Alzheimer's disease - AD, and behavioral variant Frontotemporal Dementia - FTD) and 30 healthy adults. We then correlated naming scores with MRI-derived cortical thickness values as well as with performances in semantic and syntactic tasks, across all subjects. Results indicated that patients with the semantic variant PPA named significantly fewer nouns than verbs. Instead, nonfluent/agrammatic PPA patients named fewer verbs than nouns. Across all subjects, performance on nouns (adjusted for verbs) specifically correlated with cortical atrophy in left anterior temporal regions, and performance on verbs (adjusted for nouns) with atrophy in left inferior and middle frontal, inferior parietal and posterior temporal regions. Furthermore, lower lexical-semantic abilities correlated with deficits in naming both nouns and verbs, while lower syntactic abilities only correlated with naming verbs. Our results show that different neural and cognitive mechanisms underlie naming of specific grammatical categories in neurodegenerative diseases. Importantly, our findings showed that verb processing depends on a widespread perisylvian networks, suggesting that some regions might be involved in processing different types of action knowledge. These findings have important implications for early differential diagnosis of neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.cortex.2021.05.006DOI Listing
June 2021

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease: A Head-to-Head Comparison Against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging.

JAMA Neurol 2021 Jun 28. Epub 2021 Jun 28.

Clinical Memory Research Unit, Lund University, Malmö, Sweden.

Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear.

Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers.

Design, Setting, And Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ).

Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation.

Main Outcomes And Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations.

Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels.

Conclusions And Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
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http://dx.doi.org/10.1001/jamaneurol.2021.1858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240013PMC
June 2021

Lower White Matter Volume and Worse Executive Functioning Reflected in Higher Levels of Plasma GFAP among Older Adults with and Without Cognitive Impairment.

J Int Neuropsychol Soc 2021 Jun 22:1-12. Epub 2021 Jun 22.

Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.

Objective: There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer's dementia.

Methods: We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates.

Results: Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: β = -0.33, p = .002; Cohort 2: β = -0.36, p = .03) and parietal ROIs (Cohort 1: β = -0.31, p = .01; Cohort 2: β = -0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: β = -0.38, p = .01; Cohort 2: β = -0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP.

Conclusions: Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.
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http://dx.doi.org/10.1017/S1355617721000813DOI Listing
June 2021

Reduction of Time on the Ground Related to Real-Time Video Detection of Falls in Memory Care Facilities: Observational Study.

J Med Internet Res 2021 Jun 17;23(6):e17551. Epub 2021 Jun 17.

SafelyYou, Inc, San Francisco, CA, United States.

Background: Lying on the floor for a long period of time has been described as a critical determinant of prognosis following a fall. In addition to fall-related injuries due to the trauma itself, prolonged immobilization on the floor results in a wide range of comorbidities and may double the risk of death in elderly. Thus, reducing the length of Time On the Ground (TOG) in fallers seems crucial in vulnerable individuals with cognitive disorders who cannot get up independently.

Objective: This study aimed to examine the effect of a new technology called SafelyYou Guardian (SYG) on early post-fall care including reduction of Time Until staff Assistance (TUA) and TOG.

Methods: SYG uses continuous video monitoring, artificial intelligence, secure networks, and customized computer applications to detect and notify caregivers about falls in real time while providing immediate access to video footage of falls. The present observational study was conducted in 6 California memory care facilities where SYG was installed in bedrooms of consenting residents and families. Fall events were video recorded over 10 months. During the baseline installation period (November 2017 to December 2017), SYG video captures of falls were not provided on a regular basis to facility staff review. During a second period (January 2018 to April 2018), video captures were delivered to facility staff on a regular weekly basis. During the third period (May 2018 to August 2018), real-time notification (RTN) of any fall was provided to facility staff. Two digital markers (TUA, TOG) were automatically measured and compared between the baseline period (first 2 months) and the RTN period (last 4 months). The total number of falls including those happening outside of the bedroom (such as common areas and bathrooms) was separately reported by facility staff.

Results: A total of 436 falls were recorded in 66 participants suffering from Alzheimer disease or related dementias (mean age 87 years; minimum 65, maximum 104 years). Over 80% of the falls happened in bedrooms, with two-thirds occurring overnight (8 PM to 8 AM). While only 8.1% (22/272) of falls were scored as moderate or severe, fallers were not able to stand up alone in 97.6% (247/253) of the cases. Reductions of 28.3 (CI 19.6-37.1) minutes in TUA and 29.6 (CI 20.3-38.9) minutes in TOG were observed between the baseline and RTN periods. The proportion of fallers with TOG >1 hour fell from 31% (8/26; baseline) to zero events (RTN period). During the RTN period, 76.6% (108/141) of fallers received human staff assistance in less than 10 minutes, and 55.3% (78/141) of them spent less than 10 minutes on the ground.

Conclusions: SYG technology is capable of reducing TOG and TUA while efficiently covering the area (bedroom) and time zone (nighttime) that are at highest risk. After 6 months of SYG monitoring, TOG was reduced by a factor of 3. The drastic reduction of TOG is likely to decrease secondary comorbid complications, improve post-fall prognosis, and reduce health care costs.
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http://dx.doi.org/10.2196/17551DOI Listing
June 2021

Global Perspectives on Brief Cognitive Assessments for Dementia Diagnosis.

J Alzheimers Dis 2021 Jun 9. Epub 2021 Jun 9.

Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.

Background: Timely diagnosis of dementia is a global healthcare priority, particularly in low to middle income countries where rapid increases in older adult populations are expected.

Objective: To investigate global perspectives on the role of brief cognitive assessments (BCAs) in dementia diagnosis, strengths and limitations of existing measures, and future directions and needs.

Methods: This is a qualitative study of 18 dementia experts from different areas of the world. Participants were selected using purposeful sampling based on the following criteria: 1) practicing in countries with projected growth of older adult population of over 100%by 2050; 2) expertise in dementia diagnosis and treatment; 3) involvement in clinical practice and training; and 4) recognition as a national dementia expert based on leadership positions within healthcare system, research, and/or policy work. Participants were individually interviewed in their language of choice over secure videoconference sessions. Interviews were analyzed by a multidisciplinary team using theme identification approach.

Results: Four domains with subthemes emerged illustrating participants' perspectives: 1) strengths of BCAs; 2) limitations of BCAs; 3) needs related to the use of BCAs; and 4) characteristics of an ideal BCA. While most experts agreed that BCAs were important and useful for dementia diagnosis, the themes emphasized the need for development and validation of novel measures that are sensitive, psychometrically sound, and culturally appropriate.

Conclusion: BCAs are important for guiding diagnosis and care for dementia patients. Findings provide a roadmap for novel BCA development to assist in diagnostic decision making for clinicians serving a rapidly growing and diverse dementia population.
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http://dx.doi.org/10.3233/JAD-201403DOI Listing
June 2021

Multimodal neuroimaging of sex differences in cognitively impaired patients on the Alzheimer's continuum: greater tau-PET retention in females.

Neurobiol Aging 2021 Apr 22;105:86-98. Epub 2021 Apr 22.

Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA; Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.

We assessed sex differences in amyloid- and tau-PET retention in 119 amyloid positive patients with mild cognitive impairment or Alzheimer's disease (AD) dementia. Patients underwent 3T-MRI, C-PIB amyloid-PET and F-Flortaucipir tau-PET. Linear ordinary least squares regression models tested sex differences in Flortaucipir-PET SUVR in a summary temporal region of interest as well as global PIB-PET. No sex differences were observed in demographics, Clinical Dementia Rating Sum of Boxes (CDR-SoB), Mini-Mental State Exam (MMSE), raw episodic memory scores, or cortical thickness. Females had higher global PIB SUVR (η²=.043, p=.025) and temporal Flortaucipir SUVR (η²=.070, p=.004), adjusting for age and CDR-SoB. Sex differences in temporal Flortaucipir-PET remained significant when controlling additionally for PIB SUVR and APOE4 status (η²=.055, p=.013), or when using partial volume-corrected data. No sex differences were present in areas of known Flortaucipir off-target binding. Overall, females demonstrated greater AD regional tau-PET burden than males despite clinical comparability. Further characterization of sex differences will provide insight into AD pathogenesis and support development of personalized therapeutic strategies.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.003DOI Listing
April 2021

Retinal imaging demonstrates reduced capillary density in clinically unimpaired ε4 gene carriers.

Alzheimers Dement (Amst) 2021 11;13(1):e12181. Epub 2021 May 11.

Department of Ophthalmology USC Roski Eye Institute Keck School of Medicine of the University of Southern California Los Angeles California USA.

Introduction: Apolipoprotein E () ε4, the strongest non-Mendelian genetic risk factor for Alzheimer's disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test ε4 effects on human central nervous system capillaries.

Methods: We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations.

Results: Our analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal ε4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature.

Discussion: These results suggest that ε4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.
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http://dx.doi.org/10.1002/dad2.12181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111703PMC
May 2021

Selective vulnerability to atrophy in sporadic Creutzfeldt-Jakob disease.

Ann Clin Transl Neurol 2021 06 5;8(6):1183-1199. Epub 2021 May 5.

Department of Neurology, Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco (UCSF), San Francisco, California.

Objective: Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD.

Methods: 3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions.

Results: sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast- and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy.

Interpretation: Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast- and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.
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http://dx.doi.org/10.1002/acn3.51290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164858PMC
June 2021

Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study.

Neurology 2021 May 4. Epub 2021 May 4.

Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA.

Objective: To test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults and postmortem.

Methods: Two independent observational, cross-sectional cohorts: 1) community-dwelling, clinically normal adults from the UCSF Memory and Aging Center completed lumbar puncture and MRI (exclusion criteria, CDR>0), and 2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). measures included cerebrospinal fluid (CSF) synaptic proteins (synaptotagmin-1, SNAP-25, neurogranin, and GAP-43), Aβ, ptau and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, VAMP, and SNARE complex), and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins*amyloid on tau, and synaptic proteins*tau on GMV).

Results: 68 in-vivo older adults (age=71y, 43%F) and 633 decedents (age=90y, 68%F, 34% clinically normal) were included. Each CSF synaptic protein moderated the relationship between Aβ and ptau (-0.23<𝛽s<-0.12, ps<0.05) and the relationship between ptau and GMV (-0.49<𝛽s<-0.32, ps<0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aβ-ptau and ptau-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10<𝛽s<-0.08, ps<0.05).

Conclusions: Pathogenic relationships of Aβ and tau may depend on synaptic state. Synaptic markers may help identify risk and/or resilience to AD proteinopathy.
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http://dx.doi.org/10.1212/WNL.0000000000012145DOI Listing
May 2021

Cannabidiol in the management of bruxism in behavioral variant of frontotemporal degeneration.

Neurocase 2021 Apr 2;27(2):209-211. Epub 2021 May 2.

Memory and Aging Center, University of California, San Francisco, USA.

Awake bruxism is an understudied feature of behavioral variant of frontotemporal dementia (bvFTD). We present the case of aman who presented with psychiatric, behavioral, cognitive changes, and teeth clenching that resulted in significant changes in his teeth alignment including an underbite. He received multiple treatments with partial response. He then started using acannabidiol (CBD) capsule, and the grinding was almost completely relieved after this intervention. There is still no standardized pharmacology treatment for bruxism in patients with bvFTD. As aconsequence, acase-by-case approach is suggested. CBD can be helpful as an adjunct therapeutic agent for awake bruxism.Not StartedCompletedRejected.
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http://dx.doi.org/10.1080/13554794.2021.1917620DOI Listing
April 2021

Reduced synchrony in alpha oscillations during life predicts post mortem neurofibrillary tangle density in early-onset and atypical Alzheimer's disease.

Alzheimers Dement 2021 Apr 21. Epub 2021 Apr 21.

Department Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.

Introduction: Neurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neurofibrillary tangle (NFT) density in autopsy examination, in patients with AD.

Methods: In a well-characterized clinicopathological cohort of AD patients (n = 13), we quantified neuronal synchrony within alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillations, using magnetoencephalography during the disease course, within six selected neocortical and hippocampal regions, including angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1, and subiculum, and correlated these with regional NFT density quantified at histopathological examination.

Results: Abnormal synchrony in alpha, but not in delta-theta, significantly predicted the NFT density at post mortem neuropathological examination.

Discussion: Reduced alpha synchrony is a sensitive neurophysiological index associated with pathological tau, and a potential network biomarker for clinical trials, to gauge the extent of network dysfunction and the degree of rescue in treatments targeting tau pathways in AD.
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http://dx.doi.org/10.1002/alz.12349DOI Listing
April 2021

Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer's disease.

J Neurol Neurosurg Psychiatry 2021 Apr 13. Epub 2021 Apr 13.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

Objective: The clinical phenotype of the rare behavioural variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.

Methods: For the tau PET study, seven amyloid-β positive bvAD patients underwent [F]flortaucipir or [F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a 'typical' memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).

Results: Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05).

Conclusions: Both in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.
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http://dx.doi.org/10.1136/jnnp-2020-325497DOI Listing
April 2021

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

Neurology 2021 05 7;96(18):e2296-e2312. Epub 2021 Apr 7.

From the University of California, San Francisco (J.C.R., P.W., A.M.S., Y.C., A.W., S.-Y.M.G., P.A.L., H.W.H., J.C.F., J.B.T., A.M.K., L.L.M., J.K., J.H.K., B.L.M., H.J.S., A.L.B.); UK Dementia Research Centre (C.H., D.M.C., R.S.C., M.B., M.F., C.V.G., G.P., L.R., I.S., E.T., J.D.R.), UCL Institute of Neurology, Queen Square, London; Quanterix Corp (E.V., L.S., A.J., D.H.), Lexington; Novartis Institutes for Biomedical Research Inc (L.Y., A. Khinikar, R.S.), Cambridge, MA; Novartis Pharma AG (A. Kieloch, M.-A.V.), Basel, Switzerland; Bluefield Project to Cure Frontotemporal Dementia (L.L.M., R.P.), San Francisco, CA; Mayo Clinic (K.K., D.S.K., B.F.B.), Rochester, MN; Mayo Clinic (N.G.-R., L.P., R.R.), Jacksonville, FL; University of Pennsylvania (D.J.I., M.G.), Philadelphia; University of California, Los Angeles (E.M.R., G.C., M.F.M., Y.B.); Harvard University/Massachusetts General Hospital (B.D.C.), Boston, MA; Washington University (N.G.), St. Louis, MO; Columbia University (E.D.H.), New York, NY; University of British Columbia (I.R.M., G.-Y.R.H.), Vancouver, Canada; Case Western Reserve University (B.S.A.), Cleveland, OH; University of Washington (K.D.-R.), Seattle; Laboratory of Neuroimaging (A.W.T.), University of Southern California, Los Angeles; Northwestern University (S.W.), Chicago, IL; University of North Carolina (D.I.K.), Chapel Hill; Texas Health Presbyterian Hospital Dallas (D.K.); University of California, San Diego (I.L.); Johns Hopkins Hospital (C.U.O., A.P.), Baltimore, MD; University of Alabama at Birmingham (E.D.R.); University of Toronto (M.C.T., M.M.), Ontario, Canada; Indiana University School of Medicine (T.F.), Indianapolis; Biogen Inc (W.C., J.C., D.L.G.), Cambridge, MA; Erasmus Medical Centre (J.C.v.S.), Rotterdam, the Netherlands; University of Brescia (B.B.), Italy; University of Barcelona (R.S.-V.); Donostia University Hospital (F.M.), San Sebastian, Gipuzkoa, Spain; Clinique Interdisciplinaire de Mémoire (R.L.), Département des Sciences Neurologiques, CHU de Québec; Faculté de Médecine (R.L.), Université Laval, Quebec, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; University of Tübingen (M.S.); Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Fondazione IRCCS Ospedale Policlinico (D.G.); University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospital (J.B.R.), University of Cambridge, UK; University of Western Ontario (E.F.), London, Canada; KU Leuven (R.V.), Belgium; Neurology Service (R.V.), University Hospitals Leuven, Belgium; University of Lisbon (A.d.M.), Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University of Coimbra (I.S.), Portugal; McGill University (S.D.), Montreal, Québec, Canada; University of Oxford (C.R.B.); Wolfson Molecular Imaging Centre (A.G.), University of Manchester, UK; University of Duisburg-Essen (A.G.), Duisberg; Ludwig-Maximilians-Universität München (J.L., A.D.); German Center for Neurodegenerative Diseases (J.L.), Munich Cluster for Systems Neurology (SyNergy); University of Ulm (M.O.), Germany; and Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence, and IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. , , and mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.

Classification Of Evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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http://dx.doi.org/10.1212/WNL.0000000000011848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166434PMC
May 2021

Assessment of Racial/Ethnic Disparities in Timeliness and Comprehensiveness of Dementia Diagnosis in California.

JAMA Neurol 2021 Jun;78(6):657-665

Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco.

Importance: The US aging population is rapidly becoming more racially and ethnically diverse. Early diagnosis of dementia is a health care priority.

Objective: To examine the associations between race/ethnicity and timeliness of dementia diagnosis and comprehensiveness of diagnostic evaluation.

Design, Setting, And Participants: This retrospective cross-sectional study used 2013-2015 California Medicare fee-for-service data to examine the associations of race/ethnicity, individual factors, and contextual factors with the timeliness and comprehensiveness of dementia diagnosis. Data from 10 472 unique beneficiaries were analyzed. The sample was selected on the basis of the following criteria: presence of 1 or more claims; no diagnoses of dementia or mild cognitive impairment in 2013 to 2014; continuous enrollment in Medicare Parts A and B; Asian, Black, Hispanic, or White race/ethnicity; and incident diagnoses of dementia or mild cognitive impairment in January through June 2015. Data analyses were conducted from November 1, 2019, through November 10, 2020.

Main Outcomes And Measures: Timeliness of diagnosis, defined as incident diagnosis of mild cognitive impairment vs dementia, and comprehensiveness of diagnostic evaluation, defined as presence of the following services in claims within 6 months before or after the incident diagnosis date: specialist evaluation, laboratory testing, and neuroimaging studies.

Results: The sample comprised 10 472 unique Medicare beneficiaries with incident diagnoses of dementia or mild cognitive impairment (6504 women [62.1%]; mean [SD] age, 82.9 [8.0] years) and included 993 individuals who identified as Asian (9.5%), 407 as Black (3.9%), 1255 as Hispanic (12.0%), and 7817 as White (74.6%). Compared with White beneficiaries, those who identified as Asian (odds ratio, 0.46; 95% CI, 0.38-0.56), Black (odds ratio, 0.73; 95% CI, 0.56-0.94), or Hispanic (odds ratio, 0.62; 95% CI, 0.52-0.72) were less likely to receive a timely diagnosis. Asian beneficiaries (incidence rate ratio, 0.81; 95% CI, 0.74-0.87) also received fewer diagnostic evaluation elements. These associations remained significant after adjusting for age, sex, comorbidity burden, neighborhood disadvantage, and rurality.

Conclusions And Relevance: These findings highlight substantial disparities in the timeliness and comprehensiveness of dementia diagnosis. Public health interventions are needed to achieve equitable care for people living with dementia across all racial/ethnic groups.
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http://dx.doi.org/10.1001/jamaneurol.2021.0399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008426PMC
June 2021

The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat): Driving Multicentric Research and Implementation Science.

Front Neurol 2021 11;12:631722. Epub 2021 Mar 11.

Cognitive Neuroscience Center, Universidad de San Andrés, Buenos Aires, Argentina.

Dementia is becoming increasingly prevalent in Latin America, contrasting with stable or declining rates in North America and Europe. This scenario places unprecedented clinical, social, and economic burden upon patients, families, and health systems. The challenges prove particularly pressing for conditions with highly specific diagnostic and management demands, such as frontotemporal dementia. Here we introduce a research and networking initiative designed to tackle these ensuing hurdles, the Multi-partner consortium to expand dementia research in Latin America (ReDLat). First, we present ReDLat's regional research framework, aimed at identifying the unique genetic, social, and economic factors driving the presentation of frontotemporal dementia and Alzheimer's disease in Latin America relative to the US. We describe ongoing ReDLat studies in various fields and ongoing research extensions. Then, we introduce actions coordinated by ReDLat and the Latin America and Caribbean Consortium on Dementia (LAC-CD) to develop culturally appropriate diagnostic tools, regional visibility and capacity building, diplomatic coordination in local priority areas, and a knowledge-to-action framework toward a regional action plan. Together, these research and networking initiatives will help to establish strong cross-national bonds, support the implementation of regional dementia plans, enhance health systems' infrastructure, and increase translational research collaborations across the continent.
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http://dx.doi.org/10.3389/fneur.2021.631722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992978PMC
March 2021

Diagnostic Utility of Measuring Cerebral Atrophy in the Behavioral Variant of Frontotemporal Dementia and Association With Clinical Deterioration.

JAMA Netw Open 2021 03 1;4(3):e211290. Epub 2021 Mar 1.

Memory and Aging Center, Department of Neurology, University of California, San Francisco.

Importance: The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking.

Objective: To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI).

Design, Setting, And Participants: In this diagnostic/prognostic study, data from 235 patients with bvFTD and 225 age- and magnetic resonance imaging-matched control individuals from 3 centers were collected from December 1, 1998, to September 30, 2019. One hundred twenty-one participants with bvFTD had high confidence of frontotemporal lobar degeneration (FTLD) (bvFTD-HC), and 19 had low confidence of FTLD (bvFTD-LC). Blinded clinicians applied 6 previously validated VAS, and the MRPI was calculated with a fully automated approach. Cortical thickness and subcortical volumes were also measured for comparison. Data were analyzed from February 1 to June 30, 2020.

Main Outcomes And Measures: The main outcomes of this study were bvFTD-HC or a neuropathological diagnosis of 4-repeat (4R) tauopathy and the clinical deterioration rate (assessed by longitudinal measurements of Clinical Dementia Rating Sum of Boxes). Measures of cerebral atrophy included VAS scores, the bvFTD atrophy score (sum of VAS scores in orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe, and frontal insula regions), the MRPI, and other computerized quantifications of cortical and subcortical volumes. The areas under the receiver operating characteristic curve (AUROC) were calculated for the differentiation of participants with bvFTD-HC and bvFTD-LC and controls. Linear mixed models were used to evaluate the ability of atrophy measures to estimate longitudinal clinical deterioration.

Results: Of the 460 included participants, 296 (64.3%) were men, and the mean (SD) age was 62.6 (11.4) years. The accuracy of the bvFTD atrophy score for the differentiation of bvFTD-HC from controls (AUROC, 0.930; 95% CI, 0.903-0.957) and bvFTD-HC from bvFTD-LC (AUROC, 0.880; 95% CI, 0.787-0.972) was comparable to computerized measures (AUROC, 0.973 [95% CI, 0.954-0.993] and 0.898 [95% CI, 0.834-0.962], respectively). The MRPI was increased in patients with bvFTD and underlying 4R tauopathies compared with other FTLD subtypes (14.1 [2.0] vs 11.2 [2.6] points; P < .001). Higher bvFTD atrophy scores were associated with faster clinical deterioration in bvFTD (1.86-point change in Clinical Dementia Rating Sum of Boxes score per bvFTD atrophy score increase per year; 95% CI, 0.99-2.73; P < .001).

Conclusions And Relevance: Based on these study findings, in bvFTD, VAS increased the diagnostic certainty of underlying FTLD, and the MRPI showed potential for the detection of participants with underlying 4R tauopathies. These widely available measures of atrophy can also be useful to estimate longitudinal clinical deterioration.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.1290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953307PMC
March 2021

Comorbid neuropathological diagnoses in early versus late-onset Alzheimer's disease.

Brain 2021 Mar 9. Epub 2021 Mar 9.

Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

Copathologies play an important role in the expression of the AD clinical phenotype and may influence treatment efficacy. Early-onset AD (EOAD), defined as manifesting before age 65, is viewed as a relatively pure form of AD with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with EOAD (median age of onset = 55 years, 44 females) and 48 with late-onset AD (LOAD) (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of AD. Prevalence and stage of Lewy body disease (LBD), limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease (AGD), hippocampal sclerosis (HS), cerebral amyloid angiopathy (CAA), and vascular brain injury (VBI) were compared between the two cohorts. We found at least one non-AD pathological diagnosis in 98% of patients with EOAD (versus 100% of LOAD), and the number of comorbid diagnoses per patient was lower in EOAD than in LOAD (median=2 versus 3, Mann-Whitney Z = 3.00, p = 0.002). LBD and CAA were common in both EOAD and LOAD (CAA: 86% versus 79%, Fisher exact p = 0.33; LBD: 49% versus 42%, p = 0.48, respectively), although amygdala-predominant LBD was more commonly found in EOAD than LOAD (22% versus 6%, p = 0.02). In contrast, LATE (35% versus 8%, p < 0.001), HS (15% versus 3%, p = 0.02), AGD (58% versus 41%, p = 0.052), and VBI (65% versus 39%, p = 0.004) were more common in LOAD than EOAD, respectively. The number of copathologies predicted worse cognitive performance at the time of death on MMSE (1.4 points/pathology (95%CI [-2.5, -0.2]) and Clinical Dementia Rating - Sum of Boxes (1.15 point/pathology, 95%CI [0.45, 1.84]), across the EOAD and the LOAD cohorts. The effect of sex on the number of copathologies was not significant (p = 0.17). Prevalence of at least one APOE ε4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of copathologies (+0.40, 95%CI [0.01, 0.79], p = 0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to men, controlling for age of onset, APOE ε4, and disease duration. Our findings suggest that non-AD pathological diagnoses play an important role in the clinical phenotype of EOAD with potentially significant implications for clinical practice and clinical trials design.
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http://dx.doi.org/10.1093/brain/awab099DOI Listing
March 2021

Crossed cerebellar diaschisis on F-FDG PET: Frequency across neurodegenerative syndromes and association with C-PIB and F-Flortaucipir.

J Cereb Blood Flow Metab 2021 Mar 10:271678X211001216. Epub 2021 Mar 10.

Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

We used F-FDG-PET to investigate the frequency of crossed cerebellar diaschisis (CCD) in 197 patients with various syndromes associated with neurodegenerative diseases. In a subset of 117 patients, we studied relationships between CCD and cortical asymmetry of Alzheimer's pathology (β-amyloid (C-PIB) and tau (F-Flortaucipir)). PET images were processed using MRIs to derive parametric SUVR images and define regions of interest. Indices of asymmetry were calculated in the cerebral cortex, basal ganglia and cerebellar cortex. Across all patients, cerebellar F-FDG asymmetry was associated with reverse asymmetry of F-FDG in the cerebral cortex (especially frontal and parietal areas) and basal ganglia. Based on our operational definition (cerebellar asymmetry >3% with contralateral supratentorial hypometabolism), significant CCD was present in 47/197 (24%) patients and was most frequent in corticobasal syndrome and semantic and logopenic variants of primary progressive aphasia. In β-amyloid-positive patients, mediation analyses showed that F-Flortaucipir cortical asymmetry was associated with cerebellar F-FDG asymmetry, but that cortical F-FDG asymmetry mediated this relationship. Analysis of F-FDG-SUVR values suggested that CCD might also occur in the absence of frank cerebellar F-FDG asymmetry due to symmetrical supratentorial degeneration resulting in a bilateral diaschisis process.
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http://dx.doi.org/10.1177/0271678X211001216DOI Listing
March 2021

Uniform data set language measures for bvFTD and PPA diagnosis and monitoring.

Alzheimers Dement (Amst) 2021 20;13(1):e12148. Epub 2021 Feb 20.

Department of Neurology Memory and Aging Center Weill Institute for Neurosciences University of California at San Francisco (UCSF) San Francisco California USA.

Introduction: The Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring.

Methods: Linear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 168), non-fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data.

Results: Among PPAs, the FTLD-MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change.

Discussion: The FTLD-MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.
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http://dx.doi.org/10.1002/dad2.12148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896637PMC
February 2021

Race, genetic admixture and cognitive performance in the Cuban population.

J Gerontol A Biol Sci Med Sci 2021 Feb 27. Epub 2021 Feb 27.

Alzheimer Research Center, Havana School of Medicine.

Background: Population aging will lead to a dramatic increase in dementia prevalence, which will disproportionally affect racial minorities. The presence of racial differences in dementia prevalence has been widely reported in United States, but there are no relevant studies on this topic in low-middle income countries (LMIC).

Methods: In a cross-sectional survey, 2,944 older Cubans were recruited at a community-based level aimed to identify the effects of self-identified race and genetic admixture on cognitive performance. Dementia diagnosis was established using 10/66 Dementia and DSM-IV criteria. APOE-ε4 genotype was determined in 2,511 (85%) and genetic admixture was completed for all dementia cases and in a randomly selected sample of cognitive healthy participants (218 dementia cases and 367 participants without dementia).

Results: The overall prevalence of dementia was 8.7%, without large or statistically significant differences on dementia prevalence (p=0.12) by self-identified race. Mean cognitive scores were similar across racial groups (p=0.46). After controlling for age, sex and education, greater proportion of African ancestry was not associated with cognitive performance (p=0.17).

Conclusions: We found no evidence of an independent effect of self-identified race and/or population ancestry on dementia prevalence or cognitive performance. This suggests that observed differences in dementia prevalence among diverse populations may be driven primarily by social determinants of health.
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http://dx.doi.org/10.1093/gerona/glab063DOI Listing
February 2021

Mild Motor Signs Matter in Typical Brain Aging: The Value of the UPDRS Score Within a Functionally Intact Cohort of Older Adults.

Front Aging Neurosci 2021 11;13:594637. Epub 2021 Feb 11.

Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States.

To characterize the clinical correlates of subclinical Parkinsonian signs, including longitudinal cognitive and neural (via functional connectivity) outcomes, among functionally normal older adults. Participants included 737 functionally intact community-dwelling older adults who performed prospective comprehensive evaluations at ~15-months intervals for an average of 4.8 years (standard deviation 3.2 years). As part of these evaluations, participants completed the Unified Parkinson's Disease Rating Scale (UPDRS) longitudinally and measures of processing speed, executive functioning and verbal episodic memory. T1-weighted structural scans and task-free functional MRI scans were acquired on 330 participants. We conducted linear mixed-effects models to determine the relationship between changes in UPDRS with cognitive and neural changes, using age, sex, and education as covariates. Cognitive outcomes were processing speed, executive functioning, and episodic memory. Greater within-person increases in UPDRS were associated with more cognitive slowing over time. Although higher average UPDRS scores were significantly associated with overall poorer executive functions, there was no association between UPDRS and executive functioning longitudinally. UPDRS scores did not significantly relate to longitudinal memory performances. Regarding neural correlates, greater increases in UPDRS scores were associated with reduced intra-subcortical network connectivity over time. There were no relationships with intra-frontoparietal or inter-subcortical-frontoparietal connectivity. Our findings add to the aging literature by indicating that mild motor changes are negatively associated with cognition and network connectivity in functionally intact adults.
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http://dx.doi.org/10.3389/fnagi.2021.594637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904682PMC
February 2021

Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve.

Alzheimers Dement 2021 Feb 16. Epub 2021 Feb 16.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.

Introduction: Biological sex is an increasingly recognized factor driving clinical and structural heterogeneity in Alzheimer's disease, but its role in the behavioral variant of frontotemporal dementia (bvFTD) is unknown.

Methods: We included 216 patients with bvFTD and 235 controls with magnetic resonance imaging (MRI) from a large multicenter cohort. We compared the clinical characteristics and cortical thickness between men and women with bvFTD and controls. We followed the residuals approach to study behavioral and cognitive reserve.

Results: At diagnosis, women with bvFTD showed greater atrophy burden in the frontotemporal regions compared to men despite similar clinical characteristics. For a similar amount of atrophy, women demonstrated better-than-expected scores on executive function and fewer changes in apathy, sleep, and appetite than men.

Discussion: Our findings suggest that women might have greater behavioral and executive reserve than men, and neurodegeneration must be more severe in women to produce symptoms similar in severity to those in men.
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http://dx.doi.org/10.1002/alz.12299DOI Listing
February 2021

Detecting Alzheimer's disease biomarkers with a brief tablet-based cognitive battery: sensitivity to Aβ and tau PET.

Alzheimers Res Ther 2021 02 8;13(1):36. Epub 2021 Feb 8.

Department of Neurology, Memory and Aging Center, University of California San Francisco, Box 1207, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.

Background: β-amyloid (Aβ) and tau positron emission tomography (PET) detect the pathological changes that define Alzheimer's disease (AD) in living people. Cognitive measures sensitive to Aβ and tau burden may help streamline identification of cases for confirmatory AD biomarker testing.

Methods: We examined the association of Brain Health Assessment (BHA) tablet-based cognitive measures with dichotomized Aβ -PET status using logistic regression models in individuals with mild cognitive impairment (MCI) or dementia (N = 140; 43 Aβ-, 97 Aβ+). We also investigated the relationship between the BHA tests and regional patterns of tau-PET signal using voxel-wise regression analyses in a subsample of 60 Aβ+ individuals with MCI or dementia.

Results: Favorites (associative memory), Match (executive functions and speed), and Everyday Cognition Scale scores were significantly associated with Aβ positivity (area under the curve [AUC] = 0.75 [95% CI 0.66-0.85]). We found significant associations with tau-PET signal in mesial temporal regions for Favorites, frontoparietal regions for Match, and occipitoparietal regions for Line Orientation (visuospatial skills) in a subsample of individuals with MCI and dementia.

Conclusion: The BHA measures are significantly associated with both Aβ and regional tau in vivo imaging markers and could be used for the identification of patients with suspected AD pathology in clinical practice.
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http://dx.doi.org/10.1186/s13195-021-00776-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871372PMC
February 2021

Persistent COVID-19-associated neurocognitive symptoms in non-hospitalized patients.

J Neurovirol 2021 02 2;27(1):191-195. Epub 2021 Feb 2.

Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, CA, USA.

As cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits. An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39 years (interquartile range: 35-56), and cognitive symptoms were present for at least a median of 98 days (interquartile range: 71-120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production.
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http://dx.doi.org/10.1007/s13365-021-00954-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852463PMC
February 2021

Salience driven attention is pivotal to understanding others' intentions.

Cogn Neuropsychol 2021 02;38(1):88-106

Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Interpreting others' beliefs, desires and intentions is known as "theory of mind" (ToM), and is often evaluated using simplified measurement tools, which may not correctly reflect the brain circuits that are required for real-life ToM functioning. We aimed to identify the brain structures necessary to correctly infer intentions from realistic scenarios by administering The Awareness of Social Inference Test, Enriched subtest to 47 patients with behavioural variant frontotemporal dementia, 24 patients with progressive supranuclear palsy syndrome, 31 patients with Alzheimer's syndrome, and 77 older healthy controls. Neuroimaging data was analyzed using voxel based morphometry, and participants' understanding of intentions was correlated with voxel-wise and region-of interest data. We found that structural integrity of the cinguloinsular cortex in the salience network (SN) was more pivotal for accurate ToM than previously described, emphasizing the importance of the SN for selectively recognizing and attending to social cues during ToM inferences.
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http://dx.doi.org/10.1080/02643294.2020.1868984DOI Listing
February 2021

Psychosis in neurodegenerative disease: differential patterns of hallucination and delusion symptoms.

Brain 2021 Apr;144(3):999-1012

Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, 94158, USA.

Although psychosis is a defining feature of Lewy body disease, psychotic symptoms occur in a subset of patients with every major neurodegenerative disease. Few studies, however, have compared disease-related rates of psychosis prevalence in a large autopsy-based cohort, and it remains unclear how diseases differ with respect to the nature or content of the psychosis. We conducted a retrospective chart review of 372 patients with autopsy-confirmed neurodegenerative pathology: 111 with Alzheimer's disease, 59 with Lewy body disease and concomitant Alzheimer's disease, 133 with frontotemporal lobar degeneration (FTLD) with tau inclusions (including progressive supranuclear palsy, corticobasal degeneration or Pick's disease), and 69 with FTLD and TDP inclusions (FTLD-TDP, including types A-C). Psychosis content was classified by subtype, and the frequency of each subtype was compared among pathological diagnoses using logistic regression. A total of 111 of 372 patients had psychosis. Compared to other groups, patients with Lewy body disease/Alzheimer's disease pathology were significantly more likely to have hallucinations and were more likely to have more than one subtype of hallucination. Patients with Braak Parkinson stage 5-6 Lewy body disease were significantly more likely than those with no Lewy body disease to have visual hallucinations of misperception, peripheral hallucinations, hallucinations that moved, hallucinations of people/animals/objects, as well as delusions regarding a place and delusions of misidentification. The feeling of a presence occurred significantly more frequently in patients with Lewy body disease/Alzheimer's disease than all other pathologies. Patients with FTLD-TDP were significantly more likely to have delusions, and for the delusions to occur in the first 3 years of the disease, when compared to patients with Alzheimer's disease and FTLD-tau, though rates were not significantly greater than patients with Lewy body disease/Alzheimer's disease. Paranoia occurred more frequently in the FTLD-TDP and Lewy body disease/Alzheimer's disease categories compared to patients with Alzheimer's disease or FTLD-tau. Patients with FTLD-TDP pathology had delusions of misidentification as frequently as patients with Lewy body disease/Alzheimer's disease, and were significantly more likely to have self-elevating delusions such as grandiosity and erotomania compared to patients with other pathologies including FTLD-tau. These data show that the nature and content of psychosis can provide meaningful information about the underlying neurodegenerative pathology, emphasizing the importance of characterizing patients' psychoses for prediction of the neuropathological diagnosis, regardless of a patient's clinical syndrome.
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http://dx.doi.org/10.1093/brain/awaa413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041322PMC
April 2021
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