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1. Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration.

Author

Vandebergh, Marijne, Ramos, Eliana, Corriveau-Lecavalier, Nick, Ramanan, Vijay, Kornak, John, Mester, Carly, Kolander, Tyler, Brushaber, Danielle, Staffaroni, Adam, Geschwind, Daniel, Wolf, Amy, Kantarci, Kejal, Gendron, Tania, Petrucelli, Leonard, Van den Broeck, Marleen, Wynants, Sarah, Baker, Matthew, Borrego-Écija, Sergi, Appleby, Brian, Barmada, Sami, Bozoki, Andrea, Clark, David, Darby, R, Dickerson, Bradford, Domoto-Reilly, Kimiko, Fields, Julie, Galasko, Douglas, Ghoshal, Nupur, Graff-Radford, Neill, Grant, Ian, Honig, Lawrence, Hsiung, Ging-Yuek, Huey, Edward, Irwin, David, Knopman, David, Kwan, Justin, Léger, Gabriel, Litvan, Irene, Masdeu, Joseph, Mendez, Mario, Onyike, Chiadi, Pascual, Belen, Pressman, Peter, Ritter, Aaron, Roberson, Erik, Snyder, Allison, Sullivan, Anna, Tartaglia, Maria, Wint, Dylan, Heuer, Hilary, Forsberg, Leah, Boxer, Adam, Rosen, Howard, Boeve, Bradley, and Rademakers, Rosa

Subjects
Humans, Female, Male, Membrane Proteins, Middle Aged, Frontotemporal Lobar Degeneration, Aged, Nerve Tissue Proteins, Brain, Polymorphism, Single Nucleotide, Gray Matter, Cognition, Organ Size, Cross-Sectional Studies, Longitudinal Studies, Magnetic Resonance Imaging
Abstract

BACKGROUND AND OBJECTIVES: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106Bs effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

Published
2024

2. Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration.

Author

Tipton, Philip Wade, Deutschlaender, Angela B, Savica, Rodolfo, Heckman, Michael G, Brushaber, Danielle E, Dickerson, Bradford C, Gavrilova, Ralitza H, Geschwind, Daniel H, Ghoshal, Nupur, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grossman, Murray, Hsiung, Ging-Yuek R, Huey, Edward D, Irwin, David John, Jones, David T, Knopman, David S, McGinnis, Scott M, Rademakers, Rosa, Ramos, Eliana Marisa, Forsberg, Leah K, Heuer, Hilary W, Onyike, Chiadi, Tartaglia, Carmela, Domoto-Reilly, Kimiko, Roberson, Erik D, Mendez, Mario F, Litvan, Irene, Appleby, Brian S, Grant, Ian, Kaufer, Daniel, Boxer, Adam L, Rosen, Howard J, Boeve, Brad F, and Wszolek, Zbigniew K

Subjects
C9orf72 Protein: genetics, Frontotemporal Dementia: diagnosis, genetics, Frontotemporal Lobar Degeneration: genetics, Granulins: genetics, Humans, Mutation: genetics, Progranulins: genetics, Quality of Life, Supranuclear Palsy, Progressive, tau Proteins: genetics
Abstract

Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes.We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test.We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants.We present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders.NCT02365922, NCT02372773, and NCT04363684.

Published
2022

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

Author

Rojas, Julio C, Wang, Ping, Staffaroni, Adam M, Heller, Carolin, Cobigo, Yann, Wolf, Amy, Goh, Sheng-Yang M, Ljubenkov, Peter A, Heuer, Hilary W, Fong, Jamie C, Taylor, Joanne B, Veras, Eliseo, Song, Linan, Jeromin, Andreas, Hanlon, David, Yu, Lili, Khinikar, Arvind, Sivasankaran, Rajeev, Kieloch, Agnieszka, Valentin, Marie-Anne, Karydas, Anna M, Mitic, Laura L, Pearlman, Rodney, Kornak, John, Kramer, Joel H, Miller, Bruce L, Kantarci, Kejal, Knopman, David S, Graff-Radford, Neill, Petrucelli, Leonard, Rademakers, Rosa, Irwin, David J, Grossman, Murray, Ramos, Eliana Marisa, Coppola, Giovanni, Mendez, Mario F, Bordelon, Yvette, Dickerson, Bradford C, Ghoshal, Nupur, Huey, Edward D, Mackenzie, Ian R, Appleby, Brian S, Domoto-Reilly, Kimiko, Hsiung, Ging-Yuek R, Toga, Arthur W, Weintraub, Sandra, Kaufer, Daniel I, Kerwin, Diana, Litvan, Irene, Onyike, Chiadikaobi U, Pantelyat, Alexander, Roberson, Erik D, Tartaglia, Maria C, Foroud, Tatiana, Chen, Weiping, Czerkowicz, Julie, Graham, Danielle L, van Swieten, John C, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B, Masellis, Mario, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris R, Gerhard, Alexander, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Cash, David M, Convery, Rhian S, Bocchetta, Martina, Foiani, Martha, Greaves, Caroline V, Peakman, Georgia, Russell, Lucy, Swift, Imogen, Todd, Emily, Rohrer, Jonathan D, Boeve, Bradley F, Rosen, Howard J, Boxer, Adam L, and consortia, on behalf of the ALLFTD and GENFI

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Clinical Trials and Supportive Activities, Genetics, Prevention, Genetic Testing, Neurodegenerative, Clinical Research, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Aging, Brain Disorders, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Neurological, Adult, Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Disease Progression, Female, Frontotemporal Lobar Degeneration, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neurofilament Proteins, Predictive Value of Tests, Young Adult, ALLFTD and GENFI consortia, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe 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.MethodsBaseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT 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.ResultsIn 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, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 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.ConclusionsPlasma 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 informationClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.Classification of evidenceThis study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

Published
2021

4. Clinical and pathologic features of cognitive-predominant corticobasal degeneration

Author

Sakae, Nobutaka, Santos, Octavio A, Pedraza, Otto, Litvan, Irene, Murray, Melissa E, Duara, Ranjan, Uitti, Ryan J, Wszolek, Zbigniew K, Graff-Radford, Neill R, Josephs, Keith A, and Dickson, Dennis W

Subjects
Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Brain Disorders, Neurosciences, Alzheimer's Disease, Dementia, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Rare Diseases, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Cognition Disorders, Diagnosis, Differential, Female, Frontotemporal Dementia, Humans, Male, Middle Aged, Tauopathies, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo describe clinical and pathologic characteristics of corticobasal degeneration (CBD) with cognitive predominant problems during the disease course.MethodsIn a series of autopsy-confirmed cases of CBD, we identified patients with cognitive rather than motor predominant features (CBD-Cog), including 5 patients thought to have Alzheimer disease (AD) and 10 patients thought to have behavioral variant frontotemporal dementia (FTD). We compared clinical and pathologic features of CBD-Cog with those from a series of 31 patients with corticobasal syndrome (CBD-CBS). For pathologic comparisons between CBD-Cog and CBD-CBS, we used semiquantitative scoring of neuronal and glial lesion types in multiple brain regions and quantitative assessments of tau burden from image analysis.ResultsFive of 15 patients with CBD-Cog never had significant motor problems during their disease course. The most common cognitive abnormalities in CBD-Cog were executive and visuospatial dysfunction. The frequency of language problems did not differ between CBD-Cog and CBD-CBS. Argyrophilic grain disease, which is a medial temporal tauopathy associated with mild cognitive impairment, was more frequent in CBD-Cog. Apathy was also more frequent in CBD-Cog. Tau pathology in CBD-Cog was greater in the temporal and less in perirolandic cortices than in CBD-CBS.ConclusionA subset of patients with CBD has a cognitive predominant syndrome than can be mistaken for AD or FTD. Our findings suggest that distribution of tau cortical pathology (greater in temporal and less in perirolandic cortices) may be the basis of this uncommon clinical variant of CBD.

Published
2020

5. Revised Self-Monitoring Scale: A potential endpoint for frontotemporal dementia clinical trials.

Author

Toller, Gianina, Ranasinghe, Kamalini, Cobigo, Yann, Staffaroni, Adam, Appleby, Brian, Brushaber, Danielle, Coppola, Giovanni, Dickerson, Bradford, Domoto-Reilly, Kimiko, Fields, Julie, Fong, Jamie, Forsberg, Leah, Ghoshal, Nupur, Graff-Radford, Neill, Grossman, Murray, Heuer, Hilary, Hsiung, Gink-Yuek, Huey, Edward, Irwin, David, Kantarci, Kejal, Kaufer, Daniel, Kerwin, Diana, Knopman, David, Kornak, John, Kramer, Joel, Litvan, Irene, Mackenzie, Ian, Mendez, Mario, Miller, Bruce, Rademakers, Rosa, Ramos, Eliana, Rascovsky, Katya, Roberson, Erik, Syrjanen, Jeremy, Tartaglia, Carmela, Weintraub, Sandra, Boeve, Brad, Boxer, Adam, Rosen, Howard, and Rankin, Katherine

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Frontotemporal Dementia (FTD), Clinical Research, Acquired Cognitive Impairment, Behavioral and Social Science, Rare Diseases, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Dementia, Aging, Neurodegenerative, Brain Disorders, Alzheimer's Disease, Adult, Aged, Caregivers, Clinical Trials as Topic, Expressed Emotion, Facial Expression, Female, Frontotemporal Dementia, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Reproducibility of Results, Self-Management, Surveys and Questionnaires, ARTFL/LEFFTDS Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD).MethodsWe investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation-, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation-). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation-, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy.ResultsRSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F 4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] -1.90 to -0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI -0.30 to -0.11).ConclusionsThe RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

Published
2020

6. Frontal lobe 1H MR spectroscopy in asymptomatic and symptomatic MAPT mutation carriers.

Author

Chen, Qin, Boeve, Bradley F, Tosakulwong, Nirubol, Lesnick, Timothy, Brushaber, Danielle, Dheel, Christina, Fields, Julie, Forsberg, Leah, Gavrilova, Ralitza, Gearhart, Debra, Haley, Dana, Gunter, Jeffrey L, Graff-Radford, Jonathan, Jones, David, Knopman, David, Graff-Radford, Neill, Kraft, Ruth, Lapid, Maria, Rademakers, Rosa, Syrjanen, Jeremy, Wszolek, Zbigniew K, Rosen, Howie, Boxer, Adam L, and Kantarci, Kejal

Subjects
Neurodegenerative, Prevention, Neurosciences, Dementia, Brain Disorders, Clinical Research, Acquired Cognitive Impairment, Biomedical Imaging, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Aspartic Acid, Asymptomatic Diseases, Biomarkers, Case-Control Studies, Creatine, Female, Frontal Lobe, Frontotemporal Lobar Degeneration, Heterozygote, Humans, Inositol, Male, Middle Aged, Mutation, Proton Magnetic Resonance Spectroscopy, Young Adult, tau Proteins, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations.MethodsWe recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons.ResultsAsymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset.ConclusionFrontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

Published
2019

7. Cross-sectional Associations of β-Amyloid, Tau, and Cerebrovascular Biomarkers With Neurodegeneration in Probable Dementia With Lewy Bodies

Author

Ferreira, Daniel, Przybelski, Scott A, Lesnick, Timothy G, Schwarz, Christopher G, Diaz-Galvan, Patricia, Graff-Radford, Jonathan, Senjem, Matthew L, Fields, Julie A, Knopman, David S, Jones, David T., Savica, Rodolfo, Ferman, Tanis J., Graff-Radford, Neill, Lowe, Val J., Jack, Clifford R., Petersen, Ronald C, Westman, Eric, Boeve, Brad F, and Kantarci, Kejal

Published
2022
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8. Diagnosis and management of dementia with Lewy bodies

Author

McKeith, Ian G, Boeve, Bradley F, Dickson, Dennis W, Halliday, Glenda, Taylor, John-Paul, Weintraub, Daniel, Aarsland, Dag, Galvin, James, Attems, Johannes, Ballard, Clive G, Bayston, Ashley, Beach, Thomas G, Blanc, Frédéric, Bohnen, Nicolaas, Bonanni, Laura, Bras, Jose, Brundin, Patrik, Burn, David, Chen-Plotkin, Alice, Duda, John E, El-Agnaf, Omar, Feldman, Howard, Ferman, Tanis J, Ffytche, Dominic, Fujishiro, Hiroshige, Galasko, Douglas, Goldman, Jennifer G, Gomperts, Stephen N, Graff-Radford, Neill R, Honig, Lawrence S, Iranzo, Alex, Kantarci, Kejal, Kaufer, Daniel, Kukull, Walter, Lee, Virginia MY, Leverenz, James B, Lewis, Simon, Lippa, Carol, Lunde, Angela, Masellis, Mario, Masliah, Eliezer, McLean, Pamela, Mollenhauer, Brit, Montine, Thomas J, Moreno, Emilio, Mori, Etsuro, Murray, Melissa, O'Brien, John T, Orimo, Sotoshi, Postuma, Ronald B, Ramaswamy, Shankar, Ross, Owen A, Salmon, David P, Singleton, Andrew, Taylor, Angela, Thomas, Alan, Tiraboschi, Pietro, Toledo, Jon B, Trojanowski, John Q, Tsuang, Debby, Walker, Zuzana, Yamada, Masahito, and Kosaka, Kenji

Subjects
Brain Disorders, Clinical Research, Acquired Cognitive Impairment, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Lewy Body Dementia, Alzheimer's Disease, Prevention, Aging, Dementia, Neurodegenerative, Neurological, Biomarkers, Humans, Lewy Body Disease, Practice Guidelines as Topic, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Published
2017

12. Mild Cognitive Impairment at Risk for Lewy Body Dementia

Author

Chen, Qin, Lowe, Val J., Boeve, Bradley F., Przybelski, Scott A., Miyagawa, Toji, Senjem, Matthew L., Jack, Clifford R., Jr, Lesnick, Timothy G., Kremers, Walter K., Fields, Julie A., Min, Hoon-Ki, Schwarz, Christopher G., Gunter, Jeffrey L., Graff-Radford, Jonathan, Savica, Rodolfo, Knopman, David S., Jones, David, Ferman, Tanis J., Graff-Radford, Neill R., Petersen, Ronald C., and Kantarci, Kejal

Published
2021
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13. MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies

Author

Murray, Melissa E, Ferman, Tanis J, Boeve, Bradley F, Przybelski, Scott A, Lesnick, Timothy G, Liesinger, Amanda M, Senjem, Matthew L, Gunter, Jeffrey L, Preboske, Gregory M, Lowe, Val J, Vemuri, Prashanthi, Dugger, Brittany N, Knopman, David S, Smith, Glenn E, Parisi, Joseph E, Silber, Michael H, Graff-Radford, Neill R, Petersen, Ronald C, Jack, Clifford R, Dickson, Dennis W, and Kantarci, Kejal

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Dementia, Lewy Body Dementia, Acquired Cognitive Impairment, Neurodegenerative, Neurosciences, Sleep Research, Brain Disorders, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Amyloid beta-Peptides, Autopsy, Brain, Cohort Studies, Female, Humans, Image Processing, Computer-Assisted, Lewy Body Disease, Likelihood Functions, Magnetic Resonance Imaging, Male, REM Sleep Behavior Disorder, Retrospective Studies, Severity of Illness Index, alpha-Synuclein, tau Proteins, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.MethodsPatients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.ResultspRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.ConclusionPresence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.

Published
2013

14. C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Author

van Blitterswijk, Marka, Baker, Matthew C, DeJesus-Hernandez, Mariely, Ghidoni, Roberta, Benussi, Luisa, Finger, Elizabeth, Hsiung, Ging-Yuek R, Kelley, Brendan J, Murray, Melissa E, Rutherford, Nicola J, Brown, Patricia E, Ravenscroft, Thomas, Mullen, Bianca, Ash, Peter EA, Bieniek, Kevin F, Hatanpaa, Kimmo J, Karydas, Anna, Wood, Elisabeth McCarty, Coppola, Giovanni, Bigio, Eileen H, Lippa, Carol, Strong, Michael J, Beach, Thomas G, Knopman, David S, Huey, Edward D, Mesulam, Marsel, Bird, Thomas, White, Charles L, Kertesz, Andrew, Geschwind, Dan H, Van Deerlin, Vivianna M, Petersen, Ronald C, Binetti, Giuliano, Miller, Bruce L, Petrucelli, Leonard, Wszolek, Zbigniew K, Boylan, Kevin B, Graff-Radford, Neill R, Mackenzie, Ian R, Boeve, Bradley F, Dickson, Dennis W, and Rademakers, Rosa

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Dementia, Aging, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Rare Diseases, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Acquired Cognitive Impairment, Genetics, Frontotemporal Dementia (FTD), 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Autopsy, C9orf72 Protein, Cohort Studies, DNA Repeat Expansion, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Intercellular Signaling Peptides and Proteins, Male, Microtubule-Associated Proteins, Middle Aged, Neurodegenerative Diseases, Phenotype, Progranulins, Proteins, tau Proteins, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.MethodsA 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.ResultsWe detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.ConclusionsOur findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

Published
2013

15. Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

Author

Allen, Mariet, Zou, Fanggeng, Chai, High Seng, Younkin, Curtis S, Crook, Julia, Pankratz, V Shane, Carrasquillo, Minerva M, Rowley, Christopher N, Nair, Asha A, Middha, Sumit, Maharjan, Sooraj, Nguyen, Thuy, Ma, Li, Malphrus, Kimberly G, Palusak, Ryan, Lincoln, Sarah, Bisceglio, Gina, Georgescu, Constantin, Schultz, Debra, Rakhshan, Fariborz, Kolbert, Christopher P, Jen, Jin, Haines, Jonathan L, Mayeux, Richard, Pericak-Vance, Margaret A, Farrer, Lindsay A, Schellenberg, Gerard D, Petersen, Ronald C, Graff-Radford, Neill R, Dickson, Dennis W, Younkin, Steven G, Ertekin-Taner, Nilüfer, Alzheimer's Disease Genetics Consortium (ADGC), Apostolova, Liana G, Arnold, Steven E, Baldwin, Clinton T, Barber, Robert, Barmada, Michael M, Beach, Thomas, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Buros, Jacqueline, Buxbaum, Joseph D, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cotman, Carl W, Crane, Paul K, Cruchaga, Carlos, Cummings, Jeffrey L, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Diaz-Arrastia, Ramon, Dick, Malcolm, Dombroski, Beth A, Duara, Ranjan, Ellis, William D, Evans, Denis, Faber, Kelley M, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew, Galasko, Douglas R, Gallins, Paul J, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Gilman, Sid, Giordani, Bruno, Glass, Jonathan D, Goate, Alison M, Green, Robert C, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Hardy, John, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, and Huentelman, Matthew J

Subjects
Alzheimer's Disease Genetics Consortium, Temporal Lobe, Humans, Alzheimer Disease, Genetic Predisposition to Disease, RNA, Autopsy, Linear Models, Risk Factors, Gene Expression, Brain Chemistry, Genotype, Gene Dosage, Polymorphism, Single Nucleotide, Alleles, Aged, Female, Male, Apolipoprotein E4, Clinical Research, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, Human Genome, Neurosciences, Dementia, Neurodegenerative, Genetics, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveRecent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.MethodsWe measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.ResultsCLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).ConclusionsCLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

Published
2012

16. β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies

Author

Ferreira, Daniel, Przybelski, Scott A., Lesnick, Timothy G., Lemstra, Afina W., Londos, Elisabet, Blanc, Frederic, Nedelska, Zuzana, Schwarz, Christopher G., Graff-Radford, Jonathan, Senjem, Matthew L., Fields, Julie A., Knopman, David S., Savica, Rodolfo, Ferman, Tanis J., Graff-Radford, Neill R., Lowe, Val J., Jack, Clifford R., Jr, Petersen, Ronald C., Mollenhauer, Brit, Garcia-Ptacek, Sara, Abdelnour, Carla, Hort, Jakub, Bonanni, Laura, Oppedal, Ketil, Kramberger, Milica G., Boeve, Bradley F., Aarsland, Dag, Westman, Eric, and Kantarci, Kejal

Published
2020
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17. Sequence of Alzheimer disease biomarker changes in cognitively normal adults: A cross-sectional study

Author

Luo, Jingqin, Agboola, Folasade, Grant, Elizabeth, Masters, Colin L., Albert, Marilyn S., Johnson, Sterling C., McDade, Eric M., Vöglein, Jonathan, Fagan, Anne M., Benzinger, Tammie, Massoumzadeh, Parinaz, Hassenstab, Jason, Bateman, Randall J., Morris, John C., Perrin, Richard J., Chhatwal, Jasmeer, Jucker, Mathias, Ghetti, Bernardino, Cruchaga, Carlos, Graff-Radford, Neill R., Schofield, Peter R., Mori, Hiroshi, and Xiong, Chengjie

Published
2020
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18. Subtypes of dementia with Lewy bodies are associated with α-synuclein and tau distribution

Author

Ferman, Tanis J., Aoki, Naoya, Boeve, Bradley F., Aakre, Jeremiah A., Kantarci, Kejal, Graff-Radford, Jonathan, Parisi, Joseph E., Van Gerpen, Jay A., Graff-Radford, Neill R., Uitti, Ryan J., Pedraza, Otto, Murray, Melissa E., Wszolek, Zbigniew K., Reichard, R. Ross, Fields, Julie A., Ross, Owen A., Knopman, David S., Petersen, Ronald C., and Dickson, Dennis W.

Published
2020
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19. Association of Plasma Biomarkers of Alzheimer Disease With Cognition and Medical Comorbidities in a Biracial Cohort

Author

Ramanan, Vijay K., primary, Graff-Radford, Jonathan, additional, Syrjanen, Jeremy, additional, Shir, Dror, additional, Algeciras-Schimnich, Alicia, additional, Lucas, John, additional, Martens, Yuka A., additional, Carrasquillo, Minerva M., additional, Day, Gregory S., additional, Ertekin-Taner, Nilüfer, additional, Lachner, Christian, additional, Willis, Floyd B., additional, Knopman, David S., additional, Jack, Clifford R., additional, Petersen, Ronald C., additional, Vemuri, Prashanthi, additional, Graff-Radford, Neill, additional, and Mielke, Michelle M., additional

Published
2023
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20. Retrospective Evaluation of Neuropathologic Proxies of the Minimal Atrophy Subtype Compared With Corticolimbic Alzheimer Disease Subtypes

Author

Boon, Baayla D.C., primary, Labuzan, Sydney A., additional, Peng, Zhongwei, additional, Matchett, Billie J., additional, Kouri, Naomi, additional, Hinkle, Kelly M., additional, Lachner, Christian, additional, Ross, Owen A., additional, Ertekin-Taner, Nilufer, additional, Carter, Rickey E., additional, Ferman, Tanis J., additional, Duara, Ranjan, additional, Dickson, Dennis W., additional, Graff-Radford, Neill R., additional, and Murray, Melissa E., additional

Published
2023
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21. Clinicoradiologic and Neuropathologic Evaluation of Corticobasal Syndrome

Author

Shir, Dror, primary, Pham, Nha Trang Thu, additional, Botha, Hugo, additional, Koga, Shunsuke, additional, Kouri, Naomi, additional, Ali, Farwa, additional, Knopman, David S., additional, Petersen, Ronald C., additional, Boeve, Brad F., additional, Kremers, Walter K., additional, Nguyen, Aivi T., additional, Murray, Melissa E., additional, Reichard, R. Ross, additional, Dickson, Dennis W., additional, Graff-Radford, Neill, additional, Josephs, Keith Anthony, additional, Whitwell, Jennifer, additional, and Graff-Radford, Jonathan, additional

Published
2023
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23. β-Amyloid PET and neuropathology in dementia with Lewy bodies

Author

Kantarci, Kejal, Lowe, Val J., Chen, Qin, Przybelski, Scott A., Lesnick, Timothy G., Schwarz, Christopher G., Senjem, Matthew L., Gunter, Jeffrey L., Jack, Clifford R., Jr, Graff-Radford, Jonathan, Jones, David T., Knopman, David S., Graff-Radford, Neill, Ferman, Tanis J., Parisi, Joseph E., Dickson, Dennis W., Petersen, Ronald C., Boeve, Bradley F., and Murray, Melissa E.

Published
2020
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26. β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies

Author

Diaz-Galvan, Patricia, primary, Przybelski, Scott A, additional, Lesnick, Timothy G, additional, Schwarz, Christopher G, additional, Senjem, Matthew L, additional, Gunter, Jeffrey L, additional, Jack, Clifford R., additional, Paul Min, Hoon-Ki, additional, Jain, Manoj, additional, Miyagawa, Toji, additional, Forsberg, Leah K, additional, Fields, Julie A, additional, Savica, Rodolfo, additional, Graff-Radford, Jonathan, additional, Jones, David T., additional, Botha, Hugo, additional, St Louis, Erik K., additional, Knopman, David S, additional, Ramanan, Vijay K, additional, Ross, Owen, additional, Graff-Radford, Neill, additional, Day, Gregory S, additional, Dickson, Dennis W., additional, Ferman, Tanis J., additional, Petersen, Ronald C, additional, Lowe, Val J., additional, Boeve, Brad F, additional, and Kantarci, Kejal, additional

Published
2023
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27. β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies

Author

Patricia Diaz-Galvan, Scott A Przybelski, Timothy G Lesnick, Christopher G Schwarz, Matthew L Senjem, Jeffrey L Gunter, Clifford R. Jack, Hoon-Ki Paul Min, Manoj Jain, Toji Miyagawa, Leah K Forsberg, Julie A Fields, Rodolfo Savica, Jonathan Graff-Radford, David T. Jones, Hugo Botha, Erik K. St Louis, David S Knopman, Vijay K Ramanan, Owen Ross, Neill Graff-Radford, Gregory S Day, Dennis W. Dickson, Tanis J. Ferman, Ronald C Petersen, Val J. Lowe, Brad F Boeve, and Kejal Kantarci

Subjects
Neurology (clinical)
Abstract

Background:Amyloid-β plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but amyloid-β load at prodromal stages of DLB still needs to be elucidated. We investigated amyloid-β load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB.Methods:We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer’s Disease Research Center. Amyloid-β levels were measured by Pittsburgh compound B (PiB) PET and global cortical standard uptake value ratio (SUVr) was calculated. Global cortical PiB SUVr values from each clinical group were compared to each other and to cognitively unimpaired individuals (CU; n=100) balanced on age and sex using ANCOVA. We used multiple linear regression testing for interaction to study the influences of sex andAPOEε4 status on PiB SUVr along the DLB continuum.Results:Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared to CU, global cortical PiB SUVr was higher in DLB (p <0.001) and MCI-LB (p=0.012). The DLB group included the highest proportion of amyloid-β positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVr was higher inAPOEε4 carriers compared toAPOEε4 non-carriers in MCI-LB (pp=0.049). Women had higher PiB SUVr with older age compared to men across the DLB continuum (βeta estimate=0.014,p=0.02).Conclusion:In this cross-sectional study, levels of amyloid-β load was higher further along the DLB continuum. Whereas amyloid-β levels were comparable to cognitively unimpaired individuals in iRBD, a significant elevation in amyloid-β levels was observed in the pre-dementia stage of MCI-LB and in DLB. Specifically,APOEε4 carriers had higher amyloid-β levels thanAPOEε4 non-carriers and women tended to have higher amyloid-β levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.

Published
2023
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28. Clinical Reasoning: A 55-Year-Old Woman With Recurrent Episodes of Aphasia and Vision Changes

Author

Valerie Jeanneret, Stewart Neill, James G. Greene, Olivia Groover, and Carlos S. Kase

Subjects
Cerebral Amyloid Angiopathy, Amyloid beta-Peptides, mental disorders, Aphasia, Humans, Female, Neurology (clinical), Middle Aged, Clinical Reasoning, Magnetic Resonance Imaging, Cerebral Hemorrhage
Abstract

A 55-year-old woman presented with recurrent episodes of headache, vision changes, and language disturbances. Brain MRI showed multifocal white matter lesions, microhemorrhages, and enlarged perivascular spaces. After an extensive and unrevealing workup, she underwent a biopsy of brain and meninges that revealed thick and hyalinized leptomeningeal and cortical vessel walls that were strongly positive for β-amyloid by immunohistochemical staining, suggestive of cerebral amyloid angiopathy (CAA). CAA can present as a spectrum of inflammatory responses to the deposition of amyloid-β in the vessel walls. Her clinical presentation, radiologic, and histopathologic findings supported a diagnosis of probable CAA-related inflammation (CAA-ri). Although an uncommon entity, it is important to recognize it because most patients respond to immunosuppressive therapy.

Published
2021
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29. Type 2 diabetes mellitus, brain atrophy, and cognitive decline

Author

Moran, Chris, Beare, Richard, Wang, Wei, Callisaya, Michele, Srikanth, Velandai, Weiner, Michael, Aisen, Paul, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R., Jr., Jagust, William, Trojanowki, John Q., Toga, Arthur W., Beckett, Laurel, Green, Robert C., Saykin, Andrew J., Morris, John, Liu, Enchi, Green, Robert C., Montine, Tom, Petersen, Ronald, Aisen, Paul, Gamst, Anthony, Thomas, Ronald G., Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Beckett, Laurel, Harvey, Danielle, Gamst, Anthony, Donohue, Michael, Kornak, John, Jack, Clifford R., Jr., Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Jagust, William, Bandy, Dan, Koeppe, Robert A., Foster, Norm, Reiman, Eric M., Chen, Kewei, Mathis, Chet, Morris, John, Cairns, Nigel J., Taylor-Reinwald, Lisa, Trojanowki, J.Q., Shaw, Les, Lee, Virginia M.Y., Korecka, Magdalena, Toga, Arthur W., Crawford, Karen, Neu, Scott, Saykin, Andrew J., Foroud, Tatiana M., Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J., Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S., Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Petersen, Ronald, Johnson, Kris, Doody, Rachelle S., Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Morris, John C., Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A., Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P. Murali, Petrella, Jeffrey R., Coleman, R. Edward, Arnold, Steven E., Karlawish, Jason H., Wolk, David, Smith, Charles D., Jicha, Greg, Hardy, Peter, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Porsteinsson, Anton P., Goldstein, Bonnie S., Martin, Kim, Makino, Kelly M., Ismail, M. Saleem, Brand, Connie, Mulnard, Ruth A., Thai, Gaby, McAdams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Burns, Jeffrey M., Anderson, Heather S., Swerdlow, Russell H., Apostolova, Liana, Lu, Po H., Bartzokis, George, Silverman, Daniel H.S., Graff-Radford, Neill R, Parfitt, Francine, Johnson, Heather, Farlow, Martin R., Hake, Ann Marie, Matthews, Brandy R., Herring, Scott, van Dyck, Christopher H., Carson, Richard E., MacAvoy, Martha G., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Robin Hsiung, Ging-Yuek, Feldman, Howard, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A., Johnson, Keith A., Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L., Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Killiany, Ronald, Budson, Andrew E., Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O., Wolday, Saba, Bwayo, Salome K., Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Dr Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Brown, Alice D., Pearlson, Godfrey D., Blank, Karen, Anderson, Karen, Saykin, Andrew J., Santulli, Robert B., Schwartz, Eben S., Sink, Kaycee M., Williamson, Jeff D., Garg, Pradeep, Watkins, Franklin, Ott, Brian R., Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabether, Rachinsky, Irina, Rogers, John, Kertesz, Andrew, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K., Boles Ponto, Laura L., Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, and Raj, Balebail Ashok

Published
2019
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30. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, Ganesh, Adams, Hieab H.H., Satizabal, Claudia L., Bis, Joshua C., Teumer, Alexander, Sargurupremraj, Muralidharan, Hofer, Edith, Trompet, Stella, Hilal, Saima, Smith, Albert Vernon, Jian, Xueqiu, Malik, Rainer, Traylor, Matthew, Pulit, Sara L., Amouyel, Philippe, Mazoyer, Bernard, Zhu, Yi-Cheng, Kaffashian, Sara, Schilling, Sabrina, Beecham, Gary W., Montine, Thomas J., Schellenberg, Gerard D., Kjartansson, Olafur, Guðnason, Vilmundur, Knopman, David S., Griswold, Michael E., Windham, B. Gwen, Gottesman, Rebecca F., Mosley, Thomas H., Schmidt, Reinhold, Saba, Yasaman, Schmidt, Helena, Takeuchi, Fumihiko, Yamaguchi, Shuhei, Nabika, Toru, Kato, Norihiro, Rajan, Kumar B., Aggarwal, Neelum T., De Jager, Philip L., Evans, Denis A., Psaty, Bruce M., Rotter, Jerome I., Rice, Kenneth, Lopez, Oscar L., Liao, Jiemin, Chen, Christopher, Cheng, Ching-Yu, Wong, Tien Y., Ikram, Mohammad K., van der Lee, Sven J., Amin, Najaf, Chouraki, Vincent, DeStefano, Anita L., Aparicio, Hugo J., Romero, Jose R., Maillard, Pauline, DeCarli, Charles, Wardlaw, Joanna M., Hernández, Maria del C. Valdés, Luciano, Michelle, Liewald, David, Deary, Ian J., Starr, John M., Bastin, Mark E., Muñoz Maniega, Susana, Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, Uh, Hae-Won, Lemmens, Robin, Brodaty, Henry, Wright, Margaret J., Ames, David, Boncoraglio, Giorgio B., Hopewell, Jemma C., Beecham, Ashley H., Blanton, Susan H., Wright, Clinton B., Sacco, Ralph L., Wen, Wei, Thalamuthu, Anbupalam, Armstrong, Nicola J., Chong, Elizabeth, Schofield, Peter R., Kwok, John B., van der Grond, Jeroen, Stott, David J., Ford, Ian, Jukema, J. Wouter, Vernooij, Meike W., Hofman, Albert, Uitterlinden, André G., van der Lugt, Aad, Wittfeld, Katharina, Grabe, Hans J., Hosten, Norbert, von Sarnowski, Bettina, Völker, Uwe, Levi, Christopher, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie L.M., Rosand, Jonathan, Woo, Daniel, Cole, John W., Meschia, James F., Slowik, Agnieszka, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Grewal, Raji P., Rundek, Tatjana, Rexrode, Kathy, Rothwell, Peter M., Arnett, Donna K., Jern, Christina, Johnson, Julie A., Benavente, Oscar R., Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Wong, Quenna, Mitchell, Braxton D., Rich, Stephen S., McArdle, Patrick F., Geerlings, Mirjam I., van der Graaf, Yolanda, de Bakker, Paul I.W., Asselbergs, Folkert W., Srikanth, Velandai, Thomson, Russell, McWhirter, Rebekah, Moran, Chris, Callisaya, Michele, Phan, Thanh, Rutten-Jacobs, Loes C.A., Bevan, Steve, Tzourio, Christophe, Mather, Karen A., Sachdev, Perminder S., van Duijn, Cornelia M., Worrall, Bradford B., Dichgans, Martin, Kittner, Steven J., Markus, Hugh S., Ikram, Mohammad A., Fornage, Myriam, Launer, Lenore J., Seshadri, Sudha, Longstreth, W.T., Jr, Debette, Stéphanie, Almgren, Peter, Anderson, Christopher D., Arnett, Donna K., Attia, John, Ay, Hakan, Benavente, Oscar R., Bevan, Steve, Brown, Robert D., Bustamante, Mariana, Cheng, Yu-Ching, Cole, John W., Cotlarciuc, Ioana, Cruchaga, Carlos, de Bakker, Paul IW., Delavaran, Hossein, Dichgans, Martin, Engström, Gunnar, Fornage, Myriam, Grewal, Raji P., Heitsch, Laura, Holliday, Elizabeth, Ibanez, Laure, Ilinca, Andreea, Irvin, Marguerite R., Jackson, Rebecca D., Jern, Christina, Jimenez-Conde, Jordi, Johnson, Julie A., Jood, Katarina, Kissela, Brett M., Kittner, Steven J., Kleindorfer, Dawn O., Labovitz, Daniel, Laurie, Cathy C., Lee, Jin-Moo, Lemmens, Robin, Levi, Christopher, Li, Linxin, Lindgren, Arne G., Maguire, Jane, Markus, Hugh S., McArdle, Patrick F., Melander, Olle, Meschia, James F., Mitchell, Braxton D., Müller-Nurasyid, Martina, Norrving, Bo, Peddareddygari, Leema Reddy, Pera, Joanna, Pulit, Sara L., Rexrode, Kathryn, Ribasés, Marta, Roquer, Jaume, Rost, Natalia S., Rothwell, Peter M., Rundek, Tatjana, Sacco, Ralph L., Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Soriano-Tárraga, Carolina, Stanne, Tara, Stauch, Konstantin, Stine, O C., Sudlow, Cathie LM., Thijs, Vincent N.S., Wasssertheil-Smoller, Sylvia, Weir, David, Williams, Stephen R., Wong, Quenna, Woo, Daniel, Worrall, Bradford B., Xu, Huichun, Seshadri, Sudha, Hyacinth, Hyacinth I, Marini, Sandro, Nyquist, Paul, Lewis, Cathryn, Hansen, Bjorn, Norrving, Bo, Rosand, Jonathan, Biffi, Alessandro, Kourkoulis, Christina, Anderson, Chris, Giese, Anne-Katrin, Sacco, Ralph, Sharma, Pankaj, Chung, Jong-Won, Kim, Gyeong-Moon, Lubitz, Steven, Bourcier, Romain, Howson, Joanna, Granata, Alessandra, Drazyk, Anna, Markus, Hugh, Wardlaw, Joanna, Mitchell, Braxton, Cole, John, Hopewell, Jemma, Walters, Robin, Turnbull, Iain, Worrall, Bradford, Bis, Josh, Reiner, Alex, Dhar, Raj, Heitsch, Laura, Lee, Jin-Moo, Prasad, Kameshwar, Sarnowski, Chloé, Aparicio, Hugo Javier, Yang, Qiong, Chasman, Daniel, Rexrode, Kathryn, Phuah, Chia-Ling, Liu, Guiyou, Elkind, Mitchell, Lange, Leslie, Rost, Natalia, James, Michael, Stewart, Jill, Vojinovic, Dina, Thijs, Vincent, Parati, Eugenio, Boncoraglio, Giorgio, Zand, Ramin, Bijlenga, Philippe, Selim, Magdy, Grond-Ginsbach, Caspar, Strbian, Daniel, Tomppo, Liisa, Sallinen, Hanne, Pfeiffer, Dorothea, Torres, Nuria, Barboza, Miguel, Laarman, Melanie, Carriero, Roberta, Holliday, Elizabeth, Jimenez-Conde, Jordi, Soriano, Carolina, Gill, Dipender, Debette, Stephanie, Mishra, Aniket, Wu, Jer-Yuarn, Ko, Tai-Ming, Bione, Silvia, Jood, Katarina, Tatlisumak, Turgut, Holmegaard, Lukas, Yue, Suo, bersano, Anna, Pera, Joanna, Slowik, Agnieszka, Levi, Christopher, Schlicht, Kristina, Lemmens, Robin, Ninomiya, Toshiharu, Oberstein, Saskia Lesnik, Lee, Tsong-Hai, Malik, Rainer, Dichgans, Martin, Lindgren, Arne, Wasselius, Johan, Drake, Mattias, Melander, Olle, Stenman, Martin, Ilinca, Andreea, Crawford, Katherine, Lena, Umme, Mateen, Farrah, Ay, Hakan, Wu, Ona, Schirmer, Markus, Cramer, Steve, Golland, Polina, Brown, Robert, Meschia, James, Ross, Owen A., Pare, Guillaume, Chong, Mike, Rundek, Tatjana, Gwinn, Katrina, Chen, Christopher, Koenig, Jim, Giralt, Eva, Saleheen, Danish, de Leeuw, Frank-Erik, Klijn, Karin, Kamatani, Yoichiro, Kubo, Michiaki, Okada, Yukinori, Pedersen, Annie, Olsson, Maja, Martín, Juan José, Xu, Huichun, Tan, Eng King, Frid, Petrea, Lee, Chaeyoung, Tregouet, David, Leung, Thomas, Choy, Richard, Jern, Christina, Loo, Keat Wei, Rinkel, Gabriel, Franca, Paulo, Cendes, Iscia, Carrera, Caty, Fernandez-Cadenas, Israel, Montaner, Joan, Kim, Helen, Owolabi, Mayowa, Sofat, Reecha, Bakker, Mark, Ruigrok, Ynte, Hauer, Allard, Pulit, Sara L., van der Laan, Sander W., Irvin, Ryan, Sargurupremraj, Murali, Pezzini, Alessandro, Abd-Allah, Foad, Liebeskind, David, Traylor, Matthew, Tan, Rhea, Danesh, John, Rutten-Jacobs, Loes, Donatti, Amanda, Avelar, Wagner, Broderick, Joseph, Woo, Daniel, Sudlow, Cathie, Rannikmae, Kristiina, McDonough, Caitrin Wheeler, van Agtmael, Tom, Walters, Matthew, Söderholm, Martin, Lorentzen, Erik, Olsson, Sandra, Stanne, Tara, Olsson, Martina, Akinyemi, Rufus, Cotlatciuc, Ioana, McArdle, Patrick, Dave, Tushar, Kittner, Steven, Attia, John, Faber, James E, Millwood, Iona, Márquez, Elsa Valdés, Mancuso, Michelangelo, Vibo, Riina, Korv, Janika, Maguire, Jane, Fornage, Myriam, Majersik, Jennifer, DeHavenon, Adam, Alexander, Matthew, Sale, Michele, Southerland, Andrew, Owens, Debra, Psaty, Bruce, Longstreth, W. T., Jr, Wolfe, Stacey Quintero, Langefeld, Carl, Cruchaga, Carlos, Konrad, Jan, Sheth, Kevin, Falcone, Guido, Donahue, Kathleen, Simpkins, Alexis N, Liang Byorn, Tan Wei, Chan, Bernard, Clatworthy, Phil, Florez, Jose, Harshfield, Eric, Hozawa, Atsushi, Hsu, Chung, Hu, Chaur-Jong, Ibanez, Laure, Ihara, Masafumi, Lange, Marcos, Lee, Soo Ji, Lee, I-Hui, Musolino, Patricia, Nakatomi, Hirofumi, Park, Kwang-Yeol, Rich, Stephen S, Riley, Chris, Sung, Joohon, Suzuki, Hideaki, Vo, Katie, Washida, Kazuo, Ibenez, Laura Garcia, Slowik, Agnieszka, Hofman, Albert, Algra, Ale, Reiner, Alex P, Doney, Alexander S F, Gschwendtner, Andreas, Ilinca, Andreea, Giese, Anne-Katrin, Lindgren, Arne, Vicente, Astrid M, Norrving, Bo, Nordestgaard, Børge G, Mitchell, Braxton D, Worrall, Bradford B, Psaty, Bruce M, Carty, Cara L, Sudlow, Cathie, Anderson, Christopher D, Levi, Christopher, Satizabal, Claudia L, Palmer, Colin N A, Gamble, Dale M, Woo, Daniel, Saleheen, Danish, Ringelstein, E Bernd, Valdimarsson, Einar, Holliday, Elizabeth, Davies, Gail, Chauhan, Ganesh, Pasterkamp, Gerard, Boncoraglio, Giorgio, Kuhlenbäumer, Gregor, Thorleifsson, Gudmar, Falcone, Guido J, Pare, Guillame, Schmidt, Helena, Delavaran, Hossein, Markus, Hugh S, Aparicio, Hugo J, Deary, Ian, Cotlarciuc, Ioana, Fernandez-Cadenas, Israel, Meschia, James, Hopewell, Jemma C, Liu, Jingmin, Montaner, Joan, Pera, Joanna, Cole, John, Attia, John R, Rosand, Jonathan, Ferro, Jose M, Bis, Joshua, Furie, Karen, Stefansson, Kari, Berger, Klaus, Kostulas, Konstantinos, Rannikmae, Kristina, Ikram, M Arfan, Benn, Marianne, Dichgans, Martin, Farrall, Martin, Pandolfo, Massimo, Traylor, Matthew, Walters, Matthew, Sale, Michele, Nalls, Mike, Fornage, Myriam, van Zuydam, Natalie R, Sharma, Pankaj, Abrantes, Patricia, de Bakker, Paul IW, Higgins, Peter, Lichtner, Peter, Rothwell, Peter M, Amouyel, Philippe, Yang, Qiong, Malik, Rainer, Schmidt, Reinhold, Clarke, Robert, Lemmens, Robin, van der Laan, Sander W, Pulit, Sara L, Abboud, Sherine, Oliveira, Sofia A, Gretarsdottir, Solveig, Debette, Stephanie, Williams, Stephen R, Bevan, Steve, Kittner, Steven J, Seshadri, Sudha, Mosley, Thomas, Battey, Thomas WK, Tatlisumak, Turgut, Thorsteinsdottir, Unnur, Thijs, Vincent NS, Longstreth, W T, Zhao, Wei, Chen, Wei-Min, Cheng, Yu-Ching, Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barmada, M. Michael, Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Beecham, Gary W., Beekly, Duane, Bennett, David A., Bigio, Eileen H., Bird, Thomas D., Blacker, Deborah, Boeve, Bradley F., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Byrd, Goldie S., Cai, Guiqing, Cairns, Nigel J., Cantwell, Laura B., Cao, Chuanhai, Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., Cruchaga, Carlos, De Jager, Philip L., DeCarli, Charles, Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W., Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A., Faber, Kelley M., Fallin, M. Daniele, Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Farrer, Lindsay A., Ferris, Steven, Foroud, Tatiana M., Frosch, Matthew P., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Go, Rodney C.P., Goate, Alison M., Graff-Radford, Neill R., Green, Robert C., Griffith, Patrick, Growdon, John H., Haines, Jonathan L., Hakonarson, Hakon, Hamilton, Ronald L., Hamilton-Nelson, Kara L., Haroutunian, Vahram, Harrell, Lindy E., Honig, Lawrence S., Huebinger, Ryan M., Hulette, Christine M., Hyman, Bradley T., Jicha, Gregory A., Jin, Lee-Way, Jun, Gyungah, Kamboh, M. Ilyas, Karydas, Anna, Kauwe, John S.K., Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., Kukull, Walter A., Kunkle, Brian W., LaFerla, Frank M., Lah, James J., Lang-Walker, Rosalyn, Larson, Eric B., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Logue, Mark W., Lopez, Oscar L., Lunetta, Kathryn L., Lyketsos, Constantine G., Mack, Wendy J., Manly, Jennifer J., Marson, Daniel C., Martin, Eden R., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, Mayeux, Richard, McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Montine, Thomas J., Morris, John C., Murrell, Jill R., Naj, Adam C., Obisesan, Thomas O., Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Partch, Amanda, Paulson, Henry L., Pericak-Vance, Margaret A., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raj, Towfique, Raskind, Murray, Reiman, Eric M., Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Sano, Mary, Saykin, Andrew J., Schellenberg, Gerard D., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Tsuang, Debby W., Valladares, Otto, Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Wang, Li-San, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wingo, Thomas S., Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Younkin, Steven G., Yu, Chang-En, Yu, Lei, Chauhan, Ganesh, Chu, Audrey Y., Fornage, Myriam, Bis, Joshua C., Havulinna, Aki S., Sargurupremraj, Muralidharan, Smith, Albert Vernon, Adams, Hieab H.H., Choi, Seung Hoan, Trompet, Stella, Garcia, Melissa E., Manichaikul, Ani, Teumer, Alexander, Gustafsson, Stefan, Bartz, Traci M., Bellenguez, Céline, Vidal, Jean Sebastien, Jian, Xueqiu, Kjartansson, Olafur, Wiggins, Kerri L., Satizabal, Claudia L., Xue, Flora, Ripatti, Samuli, Liu, Yongmei, Deelen, Joris, Hoed, Marcel den, Heckbert, Susan R., Rice, Kenneth, Smith, Nicholas L., Wong, Quenna, Aparicio, Hugo J., Buring, Julie E., Ridker, Paul M, Berr, Claudine, Dartigues, Jean-François, Hamsten, Anders, Magnusson, Patrik K., Pedersen, Nancy L., Lannfelt, Lars, Lind, Lars, Lindgren, Cecilia M., Morris, Andrew P., Hofman, Albert, Koudstaal, Peter J., Portegies, Marileen LP., Uitterlinden, André G., de Craen, Anton JM, Ford, Ian, Jukema, J. Wouter, Stott, David J, Allen, Norrina B., Sale, Michele M., Johnson, Andrew D, Bennett, David A., De Jager, Philip L., White, Charles C., Grabe, Hans Jörgen, Paulista Markus, Marcello Ricardo, Lopez, Oscar L, Rotter, Jerome I., Nalls, Michael A., Gottesman, Rebecca F., Griswold, Michael E., Knopman, David S., Windham, B. Gwen, Beiser, Alexa, Vartiainen, Erkki, French, Curtis R., Kurth, Tobias, Psaty, Bruce M., Harris, Tamara B., Rich, Stephen S, deStefano, Anita L., Schmidt, Carsten Oliver, Salomaa, Veikko, Mosley, Thomas H., Ingelsson, Erik, van Duijn, Cornelia M., Tzourio, Christophe, Launer, Lenore J, Ikram, M. Arfan, Chasman, Daniel I., Longstreth, W. T., Jr, Seshadri, Sudha, Debette, Stéphanie, Verhaaren, Benjamin F.J., Debette, Stéphanie, Bis, Joshua C., Smith, Jennifer A., Ikram, M. Kamran, Adams, Hieab H., Beecham, Ashley H., Rajan, Kumar B., Lopez, Lorna M., Barral, Sandra, van Buchem, Mark A., van der Grond, Jeroen, Smith, Albert V., Hegenscheid, Katrin, Aggarwal, Neelum T., de Andrade, Mariza, Atkinson, Elizabeth J., Beekman, Marian, Beiser, Alexa S., Blanton, Susan H., Boerwinkle, Eric, Brickman, Adam M., Bryan, R. Nick, Chauhan, Ganesh, Chen, Christopher P.L.H., Chouraki, Vincent, de Craen, Anton J.M., Crivello, Fabrice, Deary, Ian J., Deelen, Joris, De Jager, Philip L., Dufouil, Carole, Elkind, Mitchell S.V., Evans, Denis A., Freudenberger, Paul, Gottesman, Rebecca F., Guðnason, Vilmundur, Habes, Mohamad, Heckbert, Susan R., Heiss, Gerardo, Hilal, Saima, Hofer, Edith, Hofman, Albert, Ibrahim-Verbaas, Carla A., Knopman, David S., Lewis, Cora E., Liao, Jiemin, Liewald, David C.M., Luciano, Michelle, van der Lugt, Aad, Martinez, Oliver O., Mayeux, Richard, Mazoyer, Bernard, Nalls, Mike, Nauck, Matthias, Niessen, Wiro J., Oostra, Ben A., Psaty, Bruce M., Rice, Kenneth M., Rotter, Jerome I., von Sarnowski, Bettina, Schmidt, Helena, Schreiner, Pamela J., Schuur, Maaike, Sidney, Stephen S., Sigurdsson, Sigurdur, Slagboom, P. Eline, Stott, David J.M., van Swieten, John C., Teumer, Alexander, Töglhofer, Anna Maria, Traylor, Matthew, Trompet, Stella, Turner, Stephen T., Tzourio, Christophe, Uh, Hae-Won, Uitterlinden, André G., Vernooij, Meike W., Wang, Jing J., Wong, Tien Y., Wardlaw, Joanna M., Windham, B. Gwen, Wittfeld, Katharina, Wolf, Christiane, Wright, Clinton B., Yang, Qiong, Zhao, Wei, Zijdenbos, Alex, Jukema, J. Wouter, Sacco, Ralph L., Kardia, Sharon L.R., Amouyel, Philippe, Mosley, Thomas H., Longstreth, W. T., Jr, DeCarli, Charles C., van Duijn, Cornelia M., Schmidt, Reinhold, Launer, Lenore J., Grabe, Hans J., Seshadri, Sudha S., Ikram, M. Arfan, Fornage, Myriam, Bis, Joshua C., Kavousi, Maryam, Franceschini, Nora, Isaacs, Aaron, Abecasis, Gonçalo R, Schminke, Ulf, Post, Wendy, Smith, Albert V., Cupples, L. Adrienne, Markus, Hugh S, Schmidt, Reinhold, Huffman, Jennifer E., Lehtimäki, Terho, Baumert, Jens, Münzel, Thomas, Heckbert, Susan R., Dehghan, Abbas, North, Kari, Oostra, Ben, Bevan, Steve, Stoegerer, Eva-Maria, Hayward, Caroline, Raitakari, Olli, Meisinger, Christa, Schillert, Arne, Sanna, Serena, Völzke, Henry, Cheng, Yu-Ching, Thorsson, Bolli, Fox, Caroline S., Rice, Kenneth, Rivadeneira, Fernando, Nambi, Vijay, Halperin, Eran, Petrovic, Katja E., Peltonen, Leena, Wichmann, H. Erich, Schnabel, Renate B., Dörr, Marcus, Parsa, Afshin, Aspelund, Thor, Demissie, Serkalem, Kathiresan, Sekar, Reilly, Muredach P., Taylor, Kent, Uitterlinden, Andre, Couper, David J., Sitzer, Matthias, Kähönen, Mika, Illig, Thomas, Wild, Philipp S., Orru, Marco, Lüdemann, Jan, Shuldiner, Alan R., Eiriksdottir, Gudny, White, Charles C., Rotter, Jerome I., Hofman, Albert, Seissler, Jochen, Zeller, Tanja, Usala, Gianluca, Ernst, Florian, Launer, Lenore J., DʼAgostino, Ralph B., Sr, OʼLeary, Daniel H., Ballantyne, Christie, Thiery, Joachim, Ziegler, Andreas, Lakatta, Edward G., Chilukoti, Ravi Kumar, Harris, Tamara B., Wolf, Philip A., Psaty, Bruce M., Polak, Joseph F, Li, Xia, Rathmann, Wolfgang, Uda, Manuela, Boerwinkle, Eric, Klopp, Norman, Schmidt, Helena, Wilson, James F, Viikari, Jorma, Koenig, Wolfgang, Blankenberg, Stefan, Newman, Anne B., Witteman, Jacqueline, Heiss, Gerardo, van Duijn, Cornelia, Scuteri, Angelo, Homuth, Georg, Mitchell, Braxton D., Gudnason, Vilmundur, and O’Donnell, Christopher J.

Published
2019
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32. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease

Author

McDade, Eric, Wang, Guoqiao, Gordon, Brian A., Hassenstab, Jason, Benzinger, Tammie L.S., Buckles, Virginia, Fagan, Anne M., Holtzman, David M., Cairns, Nigel J., Goate, Alison M., Marcus, Daniel S., Morris, John C., Paumier, Katrina, Xiong, Chengjie, Allegri, Ricardo, Berman, Sarah B., Klunk, William, Noble, James, Ringman, John, Ghetti, Bernardino, Farlow, Martin, Sperling, Reisa A., Chhatwal, Jasmeer, Salloway, Stephen, Graff-Radford, Neill R., Schofield, Peter R., Masters, Colin, Rossor, Martin N., Fox, Nick C., Levin, Johannes, Jucker, Mathias, and Bateman, Randall J.

Published
2018
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35. Polygenic risk scores in familial Alzheimer disease

Author

Tosto, Giuseppe, Bird, Thomas D., Tsuang, Debby, Bennett, David A., Boeve, Bradley F., Cruchaga, Carlos, Faber, Kelley, Foroud, Tatiana M., Farlow, Martin, Goate, Alison M., Bertlesen, Sarah, Graff-Radford, Neill R., Medrano, Martin, Lantigua, Rafael, Manly, Jennifer, Ottman, Ruth, Rosenberg, Roger, Schaid, Daniel J., Schupf, Nicole, Stern, Yaakov, Sweet, Robert A., and Mayeux, Richard

Published
2017
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36. β-Amyloid PET and 123I-FP-CIT SPECT in Mild Cognitive Impairment at Risk for Lewy Body Dementia

Author

Val J. Lowe, Toji Miyagawa, Walter K. Kremers, Hoon Ki Min, Jeffrey L. Gunter, Julie A. Fields, Clifford R. Jack, Qin Chen, Ronald C. Petersen, Jonathan Graff-Radford, Kejal Kantarci, Christopher G. Schwarz, Rodolfo Savica, Bradley F. Boeve, David S. Knopman, Scott A. Przybelski, Tanis J. Ferman, Neill R. Graff-Radford, David T.W. Jones, Timothy G. Lesnick, and Matthew L. Senjem

Subjects
0301 basic medicine, medicine.medical_specialty, Standardized uptake value, Gastroenterology, REM sleep behavior disorder, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, mental disorders, medicine, Dementia, Dopamine transporter, biology, Lewy body, business.industry, Dementia with Lewy bodies, Putamen, medicine.disease, 030104 developmental biology, chemistry, biology.protein, Neurology (clinical), Pittsburgh compound B, business, 030217 neurology & neurosurgery
Abstract

ObjectiveTo determine the clinical phenotypes associated with the β-amyloid PET and dopamine transporter imaging (123I-FP-CIT SPECT) findings in mild cognitive impairment (MCI) with the core clinical features of dementia with Lewy bodies (DLB; MCI-LB).MethodsPatients with MCI who had at least 1 core clinical feature of DLB (n = 34) were grouped into β-amyloid A+ or A− and 123I-FP-CIT SPECT D+ or D− groups based on previously established abnormality cut points for A+ with Pittsburgh compound B PET standardized uptake value ratio (PiB SUVR) ≥1.48 and D+ with putamen z score with DaTQUANT 123I-FP-CIT SPECT. Individual patients with MCI-LB fell into 1 of 4 groups: A+D+, A+D−, A−D+, or A−D−. Log-transformed PiB SUVR and putamen z score were tested for associations with patient characteristics.ResultsThe A−D+ biomarker profile was most common (38.2%), followed by A+D+ (26.5%) and A−D− (26.5%). The least common was the A+D- biomarker profile (8.8%). The A+ group was older, had a higher frequency of APOE ε4 carriers, and had a lower Mini-Mental State Examination score than the A− group. The D+ group was more likely to have probable REM sleep behavior disorder. Lower putamen DaTQUANT z scores and lower PiB SUVRs were independently associated with higher Unified Parkinson’s Disease Rating Scale-III scores.ConclusionsA majority of patients with MCI-LB are characterized by low β-amyloid deposition and reduced dopaminergic activity. β-Amyloid PET and 123I-FP-CIT SPECT are complementary in characterizing clinical phenotypes of patients with MCI-LB.

Published
2021

37. β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies

Author

Milica G. Kramberger, Timothy G. Lesnick, Clifford R. Jack, Julie A. Fields, Bradley F. Boeve, Zuzana Nedelska, Carla Abdelnour, Brit Mollenhauer, Jonathan Graff-Radford, Val J. Lowe, Scott A. Przybelski, Dag Aarsland, Daniel Ferreira, Neill R. Graff-Radford, Sara Garcia-Ptacek, Matthew L. Senjem, Afina W. Lemstra, Elisabet Londos, Eric Westman, David S. Knopman, Frédéric Blanc, Ketil Oppedal, Christopher G. Schwarz, Rodolfo Savica, Jakub Hort, Kejal Kantarci, Laura Bonanni, Ronald C. Petersen, Tanis J. Ferman, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Lewy Body Disease, Male, 0301 basic medicine, Apolipoprotein E, medicine.medical_specialty, Apolipoprotein E4, tau Proteins, REM sleep behavior disorder, Gastroenterology, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, mental disorders, medicine, Humans, Cognitive Dysfunction, Aged, Aged, 80 and over, Amyloid beta-Peptides, business.industry, Dementia with Lewy bodies, Parkinsonism, Age Factors, Middle Aged, medicine.disease, Peptide Fragments, Phenotype, 030104 developmental biology, chemistry, Positron-Emission Tomography, Cohort, Biomarker (medicine), Female, Neurology (clinical), Alzheimer's disease, business, Pittsburgh compound B, Biomarkers, 030217 neurology & neurosurgery
Abstract

ObjectiveIn a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype.MethodsWe included 417 patients with DLB (age 45–93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid1-42 and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A−T−, A+T−, A−T+, and A+T+.ResultsA−T− was the largest group (39%), followed by A+T− (32%), A+T+ (15%), and A−T+ (13%). The percentage of A−T− decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in APOE ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.ConclusionsAlzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.Classification of evidenceThis study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.

Published
2020
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38. Clinical and pathologic features of cognitive-predominant corticobasal degeneration

Author

Melissa E. Murray, D. Dickson, Irene Litvan, Ryan J. Uitti, Zbigniew K. Wszolek, Octavio A. Santos, K. A. Josephs, Nobutaka Sakae, Otto Pedraza, Ranjan Duara, and Neill R. Graff-Radford

Subjects
Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Clinical Sciences, digestive system, Article, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Diagnosis, mental disorders, Language Problems, medicine, Humans, Corticobasal degeneration, Apathy, Cognitive impairment, Aged, Neurology & Neurosurgery, business.industry, Neurosciences, Cognition, Middle Aged, medicine.disease, digestive system diseases, surgical procedures, operative, 030104 developmental biology, Tauopathies, Frontotemporal Dementia, Differential, Cognitive Sciences, Female, Neurology (clinical), Tauopathy, Alzheimer's disease, medicine.symptom, Cognition Disorders, business, human activities, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

ObjectiveTo describe clinical and pathologic characteristics of corticobasal degeneration (CBD) with cognitive predominant problems during the disease course.MethodsIn a series of autopsy-confirmed cases of CBD, we identified patients with cognitive rather than motor predominant features (CBD-Cog), including 5 patients thought to have Alzheimer disease (AD) and 10 patients thought to have behavioral variant frontotemporal dementia (FTD). We compared clinical and pathologic features of CBD-Cog with those from a series of 31 patients with corticobasal syndrome (CBD-CBS). For pathologic comparisons between CBD-Cog and CBD-CBS, we used semiquantitative scoring of neuronal and glial lesion types in multiple brain regions and quantitative assessments of tau burden from image analysis.ResultsFive of 15 patients with CBD-Cog never had significant motor problems during their disease course. The most common cognitive abnormalities in CBD-Cog were executive and visuospatial dysfunction. The frequency of language problems did not differ between CBD-Cog and CBD-CBS. Argyrophilic grain disease, which is a medial temporal tauopathy associated with mild cognitive impairment, was more frequent in CBD-Cog. Apathy was also more frequent in CBD-Cog. Tau pathology in CBD-Cog was greater in the temporal and less in perirolandic cortices than in CBD-CBS.ConclusionA subset of patients with CBD has a cognitive predominant syndrome than can be mistaken for AD or FTD. Our findings suggest that distribution of tau cortical pathology (greater in temporal and less in perirolandic cortices) may be the basis of this uncommon clinical variant of CBD.

Published
2020
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39. Cross-sectional Associations of β-Amyloid, Tau, and Cerebrovascular Biomarkers With Neurodegeneration in Probable Dementia With Lewy Bodies

Author

Daniel Ferreira, Scott A. Przybelski, Timothy G. Lesnick, Christopher G. Schwarz, Patricia Diaz-Galvan, Jonathan Graff-Radford, Matthew L. Senjem, Julie A. Fields, David S. Knopman, David T. Jones, Rodolfo Savica, Tanis J. Ferman, Neill Graff-Radford, Val J. Lowe, Clifford R. Jack, Ronald C. Petersen, Eric Westman, Brad F. Boeve, and Kejal Kantarci

Subjects
Neurology (clinical), Research Article
Abstract

Background and ObjectivesAlthough alpha-synuclein–related pathology is the hallmark of dementia with Lewy bodies (DLB), cerebrovascular and Alzheimer disease pathologies are common in patients with DLB. Little is known about the contribution of these pathologies to neurodegeneration in DLB. We investigated associations of cerebrovascular, β-amyloid, and tau biomarkers with gray matter (GM) volume in patients with probable DLB.MethodsWe assessed patients with probable DLB and cognitively unimpaired (CU) controls with11C-Pittsburgh compound B (PiB) and18F-flortaucipir PET as markers of β-amyloid and tau, respectively. MRI was used to assess white matter hyperintensity (WMH) volume (a marker of cerebrovascular lesion load) and regional GM volume (a marker of neurodegeneration). We used correlations and analysis of covariance (ANCOVA) in the entire cohort and structural equation models (SEMs) in patients with DLB to investigate associations of WMH volume and regional β-amyloid and tau PET standardized uptake value ratios (SUVrs) with regional GM volume.ResultsWe included 30 patients with DLB (69.3 ± 10.2 years, 87% men) and 100 CU controls balanced on age and sex. Compared with CU controls, patients with DLB showed a lower GM volume across all cortical and subcortical regions except for the cuneus, putamen, and pallidum. A larger WMH volume was associated with a lower volume in the medial and orbital frontal cortices, insula, fusiform cortex, and thalamus in patients with DLB. A higher PiB SUVr was associated with a lower volume in the inferior temporal cortex, while flortaucipir SUVr did not correlate with GM volume. SEMs showed that a higher age and absence of theAPOEε4 allele were significant predictors of higher WMH volume, and WMH volume in turn was a significant predictor of GM volume in medial and orbital frontal cortices, insula, and inferior temporal cortex. By contrast, we observed 2 distinct paths for the fusiform cortex, with age having an effect through PiB and flortaucipir SUVr on one path and through WMH volume on the other path.DiscussionPatients with probable DLB have widespread cortical atrophy, most of which is likely influenced by alpha-synuclein–related pathology. Although cerebrovascular, β-amyloid, and tau pathologies often coexist in probable DLB, their contributions to neurodegeneration seem to be region specific.

Published
2022

40. Patterns of CSF Biomarkers of Alzheimer’s Disease in Specialty Behavioral Neurology Practices (S2.005)

Author

Li, Wentao, primary, Petersen, Ronald, additional, Algeciras-Schimnich, Alicia, additional, Bornhorst, Joshua, additional, Boeve, Bradley, additional, Jones, David, additional, Botha, Hugo, additional, Ramanan, Vijay, additional, Knopman, David, additional, Savica, Rodolfo, additional, Josephs, Keith, additional, Brown, Christine Cliatt, additional, Day, Gregory, additional, Graff-Radford, Neill, additional, Ertekin-Taner, Nilüfer, additional, Woodruff, Bryan, additional, Caselli, Richard, additional, and Graff-Radford, Jonathan, additional

Published
2022
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43. Differences in Motor Features ofiC9orf72/i,iMAPT/i, oriGRN/iVariant Carriers With Familial Frontotemporal Lobar Degeneration

Author

Philip Wade, Tipton, Angela B, Deutschlaender, Rodolfo, Savica, Michael G, Heckman, Danielle E, Brushaber, Bradford C, Dickerson, Ralitza H, Gavrilova, Daniel H, Geschwind, Nupur, Ghoshal, Jonathan, Graff-Radford, Neill R, Graff-Radford, Murray, Grossman, Ging-Yuek R, Hsiung, Edward D, Huey, David John, Irwin, David T, Jones, David S, Knopman, Scott M, McGinnis, Rosa, Rademakers, Eliana Marisa, Ramos, Leah K, Forsberg, Hilary W, Heuer, Chiadi, Onyike, Carmela, Tartaglia, Kimiko, Domoto-Reilly, Erik D, Roberson, Mario F, Mendez, Irene, Litvan, Brian S, Appleby, Ian, Grant, Daniel, Kaufer, Adam L, Boxer, Howard J, Rosen, Brad F, Boeve, and Zbigniew K, Wszolek

Subjects
Progranulins, C9orf72 Protein, Frontotemporal Dementia, Mutation, Quality of Life, Humans, tau Proteins, Neurology (clinical), Supranuclear Palsy, Progressive, Frontotemporal Lobar Degeneration, Research Articles, Granulins
Abstract

Background and ObjectivesFamilial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes.MethodsWe screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy–Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test.ResultsWe identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants.DiscussionWe present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders.Trial Registration InformationNCT02365922, NCT02372773, and NCT04363684.

Published
2021

45. Linear vs volume measures of ventricle size

Author

David S. Knopman, Bradley F. Boeve, David T.W. Jones, Clifford R. Jack, Jeffrey L. Gunter, Colleen T. Ball, Julia E. Crook, Ronald C. Petersen, Neill R. Graff-Radford, and Jonathan Graff-Radford

Subjects
Male, medicine.medical_specialty, Apolipoprotein E4, Article, Cerebral Ventricles, Cognition, Gait (human), Internal medicine, Humans, Medicine, Gait, Aged, Aged, 80 and over, Cerebral Cortex, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Organ Size, medicine.disease, Magnetic Resonance Imaging, White Matter, Hydrocephalus, Normal Pressure, Hydrocephalus, medicine.anatomical_structure, Ventricle, Cardiology, Educational Status, Female, Neurology (clinical), Subarachnoid space, business, Ventriculomegaly
Abstract

ObjectiveTo compare the clinical utility of volume-based ratios with the standard linear ratio of Evans index (EI) by examining their associations with gait, cognition, and other patient and imaging variables.MethodsFrom MRI scans of 1,774 participants in the Mayo Clinic Study of Aging, we calculated 3 ventricle size measures: Evan index (frontal horn width divided by widest width of skull inner table), total ventricular volume, and frontal horn volume as ratios of total intracranial volume. Gait was measured by a timed 25-foot walk and cognition by a composite of psychometric tests. We also evaluated variables associated with the measures of ventricular size. Further, we evaluated gait and cognition associations with MRI of extraventricular findings seen in normal-pressure hydrocephalus: disproportionate enlargement of subarachnoid space (DESH) and focal sulcal dilations (FSD).ResultsVentricular volume measures had stronger association with gait and cognition measures than EI. In decreasing order of strength of association with ventricle size were DESH, FSD, white matter hyperintensity volume ratio, age, male sex, cortical thickness, and education. Modest evidence was observed that FSD was associated with future decline in gait and cognition.ConclusionVentricular volume measures are clinically more useful than EI in indicating current and future gait and cognition. Multiple factors are associated with ventricle volume size, including FSD and DESH, suggesting that changes in CSF dynamics may go beyond simple ventriculomegaly.

Published
2019
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46. Cerebrospinal fluid dynamics disorders

Author

Benjamin D. Elder, Michelle M. Mielke, David S. Knopman, Jeffrey L. Gunter, John Huston, Christopher G. Schwarz, Val J. Lowe, Ronald C. Petersen, Clifford R. Jack, David T.W. Jones, Mary M. Machulda, Scott A. Przybelski, Jonathan Graff-Radford, Neill R. Graff-Radford, Prashanthi Vemuri, Nathaniel B. Gunter, and Kejal Kantarci

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, education.field_of_study, Cerebrospinal fluid dynamics, business.industry, Population, Cognition, Age and sex, Article, Clinical trial, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neuroimaging, Internal medicine, medicine, Biomarker (medicine), Neurology (clinical), business, Cognitive impairment, education, 030217 neurology & neurosurgery
Abstract

ObjectiveTo determine the frequency of high-convexity tight sulci (HCTS) in a population-based sample and whether the presence of HCTS and related features influenced participants' cognitive status and classification within the new Alzheimer-biomarker framework.MethodsWe analyzed 684 participants ≥50 years of age who were enrolled in the prospective population-based Mayo Clinic Study of Aging and underwent structural MRI, amyloid PET imaging, and tau PET imaging. A fully automated machine-learning algorithm that had been developed previously in house was used to detect neuroimaging features of HCTS. On the basis of PET and MRI measures, participants were classified as having normal (A−) or abnormal (A+) amyloid, normal (T−) or abnormal (T+) tau, and normal (N−) or abnormal (N+) neurodegeneration. The neuropsychological battery assessed domain-specific and global cognitive scores. Gait speed also was assessed. Analyses were adjusted for age and sex.ResultsOf 684 participants, 45 (6.6%) were classified with HCTS according to the automated algorithm. Patients with HCTS were older than patients without HCTS (mean [SD] 78.0 [8.3] vs 71.9 [10.8] years; p < 0.001). More were cognitively impaired after age and sex adjustment (27% vs 9%; p = 0.005). Amyloid PET status was similar with and without HCTS, but tau PET standard uptake value ratio (SUVR) was lower for those with HCTS after age and sex adjustment (p < 0.001). Despite a lower tau SUVR, patients with HCTS had lower Alzheimer disease (AD) signature cortical thickness. With the amyloid-tau-neurodegeneration framework, HCTS was overrepresented in the T−(N)+ group, regardless of amyloid status.ConclusionThe HCTS pattern represents a definable subgroup of non-AD pathophysiology (i.e., T−[N]+) that is associated with cognitive impairment. HCTS may confound clinical and biomarker interpretation in AD clinical trials.

Published
2019
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47. Frontal lobe 1H MR spectroscopy in asymptomatic and symptomatic MAPT mutation carriers

Author

Qin Chen, Christina Dheel, Jonathan Graff-Radford, Howie Rosen, Neill R. Graff-Radford, Leah K. Forsberg, Adam L. Boxer, David S. Knopman, Dana Haley, Debra Gearhart, Jeffrey L. Gunter, Zbigniew K. Wszolek, Ruth Kraft, Maria I. Lapid, Jeremy Syrjanen, David R. Jones, Ralitza H. Gavrilova, Timothy G. Lesnick, Kejal Kantarci, Julie A. Fields, Nirubol Tosakulwong, Bradley F. Boeve, Rosa Rademakers, and Danielle Brushaber

Subjects
medicine.medical_specialty, biology, Clinical Dementia Rating, business.industry, Tau protein, Case-control study, Frontotemporal lobar degeneration, medicine.disease, Gastroenterology, Asymptomatic, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Frontal lobe, Internal medicine, medicine, symbols, biology.protein, 030212 general & internal medicine, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Fisher's exact test, Frontotemporal dementia
Abstract

ObjectiveTo determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations.MethodsWe recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons.ResultsAsymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset.ConclusionFrontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

Published
2019
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48. Cross-sectional Associations of β-Amyloid, Tau, and Cerebrovascular Biomarkers With Neurodegeneration in Probable Dementia With Lewy Bodies.

Author

Ferreira, Daniel, Przybelski, Scott A., Lesnick, Timothy G., Schwarz, Christopher G., Diaz-Galvan, Patricia, Graff-Radford, Jonathan, Senjem, Matthew L., Fields, Julie A., Knopman, David S., Jones, David T., Savica, Rodolfo, Ferman, Tanis J., Graff-Radford, Neill, Lowe, Val J., Jack, Clifford R., Petersen, Ronald C., Westman, Eric, Boeve, Brad F., and Kantarci, Kejal

Published
2023
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49. Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis

Author

Claude Steriade, Neill R. Graff-Radford, A. Sebastian Lopez-Chiriboga, Marvin J Fritzler, Warren Mason, Harald Prüss, Gregory S. Day, Robert C. Bucelli, Anne Fagan, Rachel L Henson, Melanie Y Yarbrough, Jack H. Ladenson, John C. Morris, Julien Hébert, David F. Tang-Wai, Elizabeth M Herries, and Peter Md Körtvelyessy

Subjects
0301 basic medicine, Male, Pathology, Corrections, 0302 clinical medicine, Modified Rankin Scale, Neurofilament Proteins, Neurogranin, Child, Aged, 80 and over, Anti-N-Methyl-D-Aspartate Receptor Encephalitis, biology, Intracellular Signaling Peptides and Proteins, Middle Aged, Child, Preschool, NMDA receptor, Encephalitis, Female, Antibody, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Synaptosomal-Associated Protein 25, Inflammation, Nerve Tissue Proteins, tau Proteins, Article, 03 medical and health sciences, Young Adult, Autoimmune Diseases of the Nervous System, medicine, Humans, Chitinase-3-Like Protein 1, Neuroinflammation, Aged, Autoantibodies, Receiver operating characteristic, business.industry, Membrane Proteins, Regret, medicine.disease, 030104 developmental biology, Neurocalcin, Case-Control Studies, Csf biomarkers, Immunology, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract

ObjectiveTo determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.MethodsBiomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or LGI1/CASPR2 (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients.ResultsBiomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = −0.56; p = 0.01), lower VILIP-1 (ρ = −0.60; p < 0.01) and SNAP-25 (ρ = −0.54; p = 0.01), and higher log10(YKL-40/SNAP-25) (ρ = 0.48; p = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; p = 0.02) and neurogranin (ρ = 0.55; p = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge.ConclusionsCSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.

Published
2020

50. Diffuse Lewy body disease manifesting as corticobasal syndrome

Author

Koji Kasanuki, Takuya Konno, Dennis W. Dickson, Nobutaka Sakae, Tanis J. Ferman, Shunsuke Koga, Melissa E. Murray, Neill R. Graff-Radford, Ryan J. Uitti, Keith A. Josephs, Jay A. van Gerpen, Zbigniew K. Wszolek, and Adam Parks

Subjects
Lewy Body Disease, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, Neuropathology, REM sleep behavior disorder, Article, Basal Ganglia, Progressive supranuclear palsy, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Basal Ganglia Diseases, mental disorders, medicine, Humans, Corticobasal degeneration, 030212 general & internal medicine, Prospective Studies, Aged, Retrospective Studies, Final version, Aged, 80 and over, Cerebral Cortex, business.industry, Dementia with Lewy bodies, Parkinsonism, Digital pathology, Correction, Anatomy, Middle Aged, medicine.disease, nervous system diseases, 030104 developmental biology, medicine.anatomical_structure, Female, Neurology (clinical), Alzheimer's disease, Lewy body disease, business, 030217 neurology & neurosurgery, Motor cortex
Abstract

ObjectiveTo describe clinical and pathologic characteristics of diffuse Lewy body disease (DLBD) manifesting as corticobasal syndrome (CBS).MethodsIn 523 autopsy-confirmed cases of DLBD, we identified 11 patients diagnosed with CBS. For comparison, we studied 22 DLBD brains with antemortem presentation of dementia with Lewy bodies (DLB). Given previous studies suggesting the importance of pathology in peri-Rolandic cortices in CBS, we used digital pathology to count Lewy bodies and to quantify intracytoplasmic and neuritic α-synuclein and phospho-tau burden in the motor cortex.ResultsDLBD patients with antemortem features of CBS were significantly younger at disease onset and less likely to have REM sleep behavior disorder than DLBD cases who met clinical criteria for DLB during life. Patients with DLBD manifesting as CBS had more Lewy bodies in the motor cortex than DLBD manifesting as clinically probable DLB. Three cases had concomitant progressive supranuclear palsy and 4 cases had concomitant Alzheimer disease as probable correlates of CBS.ConclusionThe neuropathology underlying CBS is heterogeneous, including corticobasal degeneration, Alzheimer disease, and progressive supranuclear palsy. This study suggests that atypical variants of Lewy body disease with severe peri-Rolandic Lewy-related pathology can present clinically as CBS. Patients with DLBD who present as CBS tend to have an earlier age at onset and are less likely to have clinical features of DLB, such as dream enactment behavior during sleep, visual hallucinations, and levodopa-responsive parkinsonism. Future studies with biofluid or molecular imaging biomarkers for α-synuclein will permit better recognition of this uncommon pathologic substrate of CBS.

Published
2018
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