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Article ; Online: The Free and Cued Selective Reminding Test Predicts Braak Stage.

Grober, Ellen / Qi, Qi / Kuo, Lynn / Hassenstab, Jason / Perrin, Richard J / Lipton, Richard B

2021 Volume 80, Issue 1, Page(s) 175–183

Abstract: Background: The ultimate validation of a clinical marker for Alzheimer's disease (AD) is its association with AD neuropathology.: Objective: To identify clinical measures that predict pathology, we evaluated the relationships of the picture version ... ...

Abstract	Background: The ultimate validation of a clinical marker for Alzheimer's disease (AD) is its association with AD neuropathology. Objective: To identify clinical measures that predict pathology, we evaluated the relationships of the picture version of the Free and Cued Selective Reminding Test (pFCSRT + IR), the Mini-Mental State Exam (MMSE), and the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) to Braak stage. Methods: 315 cases from the clinicopathologic series at the Knight Alzheimer's Disease Research Center were classified according to Braak stage. Boxplots of each predictor were compared to identify the earliest stage at which decline was observed and ordinal logistic regression was used to predict Braak stage. Results: Looking at the assessment closest to death, free recall scores were lower in individuals at Braak stage III versus Braak stages 0 and I (combined) while MMSE and CDR scores for individuals did not differ from Braak stages 0/I until Braak stage IV. The sum of free recall and total recall scores independently predicted Braak stage and had higher predictive validity than MMSE and CDR-SB in models including all three. Conclusion: pFCSRT + IR scores may be more sensitive to early pathological changes than either the CDR-SB or the MMSE.
MeSH term(s)	Aged, 80 and over ; Alzheimer Disease/psychology ; Cues ; Disease Progression ; Female ; Humans ; Male ; Memory ; Mental Recall ; Mental Status and Dementia Tests ; Neuropsychological Tests ; Predictive Value of Tests ; Reproducibility of Results
Language	English
Publishing date	2021-01-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-200980
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Article ; Online: Stages of Objective Memory Impairment Predict Alzheimer's Disease Neuropathology: Comparison with the Clinical Dementia Rating Scale-Sum of Boxes.

Grober, Ellen / Qi, Qi / Kuo, Lynn / Hassenstab, Jason / Perrin, Richard J / Lipton, Richard B

Journal of Alzheimer's disease : JAD

2021 Volume 80, Issue 1, Page(s) 185–195

Abstract: Background: The ultimate validation of a clinical marker for Alzheimer's disease (AD) is its association with AD neuropathology.: Objective: To examine how well the Stages of Objective Memory Impairment (SOMI) system predicts intermediate/high AD ... ...

Abstract	Background: The ultimate validation of a clinical marker for Alzheimer's disease (AD) is its association with AD neuropathology. Objective: To examine how well the Stages of Objective Memory Impairment (SOMI) system predicts intermediate/high AD neuropathologic change and extent of neurofibrillary tangle (NFT) pathology defined by Braak stage, in comparison to the Clinical Dementia Rating (CDR) Scale sum of boxes (CDR-SB). Methods: 251 well-characterized participants from the Knight ADRC clinicopathologic series were classified into SOMI stage at their last assessment prior to death using the free recall and total recall scores from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR). Logistic regression models assessed the predictive validity of SOMI and CDR-SB for intermediate/high AD neuropathologic change. Receiver operating characteristics (ROC) analysis evaluated the discriminative validity of SOMI and CDR-SB for AD pathology. Ordinal logistic regression was used to predict Braak stage using SOMI and CDR-SB in separate and joint models. Results: The diagnostic accuracy of SOMI for AD diagnosis was similar to that of the CDR-SB (AUC: 85%versus 83%). In separate models, both SOMI and CDR-SB predicted Braak stage. In a joint model SOMI remained a significant predictor of Braak stage but CDR-SB did not. Conclusion: SOMI provides a neuropathologically validated staging system for episodic memory impairment in the AD continuum and should be useful in predicting tau positivity based on its association with Braak stage.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/pathology ; Alzheimer Disease/psychology ; Disease Progression ; Educational Status ; Female ; Humans ; Male ; Memory Disorders/psychology ; Memory, Episodic ; Mental Recall ; Mental Status and Dementia Tests ; Neurofibrillary Tangles/pathology ; Neuropsychological Tests ; Predictive Value of Tests ; ROC Curve ; Reproducibility of Results ; Severity of Illness Index ; tau Proteins/genetics
Chemical Substances	MAPT protein, human ; tau Proteins
Language	English
Publishing date	2021-01-25
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-200946
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Article ; Online: A 71-Year-Old Man Presenting with Headache, Blurry Vision and Alexia without Agraphia.

Cimino, Patrick J / Perrin, Richard J

Brain pathology (Zurich, Switzerland)

2017 Volume 26, Issue 6, Page(s) 799–800

MeSH term(s)	Aged ; Alexia, Pure/diagnostic imaging ; Alexia, Pure/etiology ; Amyloidosis/complications ; Amyloidosis/diagnostic imaging ; Antigens, CD/metabolism ; Brain Neoplasms/complications ; Brain Neoplasms/diagnostic imaging ; Headache/diagnostic imaging ; Headache/etiology ; Humans ; Magnetic Resonance Imaging ; Male ; Nerve Tissue Proteins/metabolism ; Vision Disorders/diagnostic imaging ; Vision Disorders/etiology
Chemical Substances	Antigens, CD ; Nerve Tissue Proteins
Language	English
Publishing date	2017-03-02
Publishing country	Switzerland
Document type	Case Reports ; Letter
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
DOI	10.1111/bpa.12448
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Article ; Online: Cerebrospinal fluid biomarkers for clinical trials: why markers for differential diagnosis are important.

Perrin, Richard J

Archives of neurology

2012 Volume 69, Issue 11, Page(s) 1407–1408

MeSH term(s)	Biomarkers/cerebrospinal fluid ; Dementia/cerebrospinal fluid ; Dementia/diagnosis ; Female ; Humans ; Male ; Parkinson Disease/cerebrospinal fluid ; Parkinson Disease/diagnosis
Chemical Substances	Biomarkers
Language	English
Publishing date	2012-08-19
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	80049-1
ISSN	1538-3687 ; 0003-9942
ISSN (online)	1538-3687
ISSN	0003-9942
DOI	10.1001/archneurol.2012.2353
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Article ; Online: Investigating White Matter Neuroinflammation in Alzheimer Disease Using Diffusion-Based Neuroinflammation Imaging.

Wang, Qing / Schindler, Suzanne E / Chen, Gengsheng / Mckay, Nicole S / McCullough, Austin / Flores, Shaney / Liu, Jingxia / Sun, Zhexian / Wang, Sicheng / Wang, Wenshang / Hassenstab, Jason / Cruchaga, Carlos / Perrin, Richard J / Fagan, Anne M / Morris, John C / Wang, Yong / Benzinger, Tammie L S

Neurology

2024 Volume 102, Issue 4, Page(s) e208013

Abstract: Background and objectives: Alzheimer disease (AD) is primarily associated with accumulations of amyloid plaques and tau tangles in gray matter, however, it is now acknowledged that neuroinflammation, particularly in white matter (WM), significantly ... ...

Abstract	Background and objectives: Alzheimer disease (AD) is primarily associated with accumulations of amyloid plaques and tau tangles in gray matter, however, it is now acknowledged that neuroinflammation, particularly in white matter (WM), significantly contributes to the development and progression of AD. This study aims to investigate WM neuroinflammation in the continuum of AD and its association with AD pathologies and cognition using diffusion-based neuroinflammation imaging (NII). Methods: This is a cross-sectional, single-center, retrospective evaluation conducted on an observational study of 310 older research participants who were enrolled in the Knight Alzheimer's Disease Research Center cohort. Hindered water ratio (HR), an index of WM neuroinflammation, was quantified by a noninvasive diffusion MRI method, NII. The alterations of NII-HR were investigated at different AD stages, classified based on CSF concentrations of β-amyloid (Aβ) 42/Aβ40 for amyloid and phosphorylated tau181 (p-tau181) for tau. On the voxel and regional levels, the relationship between NII-HR and CSF markers of amyloid, tau, and neuroinflammation were examined, as well as cognition. Results: This cross-sectional study included 310 participants (mean age 67.1 [±9.1] years), with 52 percent being female. Subgroups included 120 individuals (38.7%) with CSF measures of soluble triggering receptor expressed on myeloid cells 2, 80 participants (25.8%) with CSF measures of chitinase-3-like protein 1, and 110 individuals (35.5%) with longitudinal cognitive measures. The study found that cognitively normal individuals with positive CSF Aβ42/Aβ40 and p-tau181 had higher HR than healthy controls and those with positive CSF Aβ42/Aβ40 but negative p-tau181. WM tracts with elevated NII-HR in individuals with positive CSF Aβ42/Aβ40 and p-tau181 were primarily located in the posterior brain regions while those with elevated NII-HR in individuals with positive CSF Aβ42/Aβ40 and p-tau181 connected the posterior and anterior brain regions. A significant negative correlation between NII-HR and CSF Aβ42/Aβ40 was found in individuals with positive CSF Aβ42/Aβ40. Baseline NII-HR correlated with baseline cognitive composite score and predicted longitudinal cognitive decline. Discussion: Those findings suggest that WM neuroinflammation undergoes alterations before the onset of AD clinical symptoms and that it interacts with amyloidosis. This highlights the potential value of noninvasive monitoring of WM neuroinflammation in AD progression and treatment.
MeSH term(s)	Humans ; Female ; Aged ; Male ; Alzheimer Disease/pathology ; Cross-Sectional Studies ; White Matter/diagnostic imaging ; White Matter/pathology ; Retrospective Studies ; tau Proteins ; Neuroinflammatory Diseases ; Biomarkers ; Amyloid beta-Peptides ; Cognitive Dysfunction ; Peptide Fragments
Chemical Substances	tau Proteins ; Biomarkers ; Amyloid beta-Peptides ; Peptide Fragments
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Observational Study ; Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000208013
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Article ; Online: Identifying individuals with non-Alzheimer's disease co-pathologies: A precision medicine approach to clinical trials in sporadic Alzheimer's disease.

Tosun, Duygu / Yardibi, Ozlem / Benzinger, Tammie L S / Kukull, Walter A / Masters, Colin L / Perrin, Richard J / Weiner, Michael W / Simen, Arthur / Schwarz, Adam J

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 20, Issue 1, Page(s) 421–436

Abstract: Introduction: Biomarkers remain mostly unavailable for non-Alzheimer's disease neuropathological changes (non-ADNC) such as transactive response DNA-binding protein 43 (TDP-43) proteinopathy, Lewy body disease (LBD), and cerebral amyloid angiopathy (CAA) ...

Abstract	Introduction: Biomarkers remain mostly unavailable for non-Alzheimer's disease neuropathological changes (non-ADNC) such as transactive response DNA-binding protein 43 (TDP-43) proteinopathy, Lewy body disease (LBD), and cerebral amyloid angiopathy (CAA). Methods: A multilabel non-ADNC classifier using magnetic resonance imaging (MRI) signatures was developed for TDP-43, LBD, and CAA in an autopsy-confirmed cohort (N = 214). Results: A model using demographic, genetic, clinical, MRI, and ADNC variables (amyloid positive [Aβ+] and tau+) in autopsy-confirmed participants showed accuracies of 84% for TDP-43, 81% for LBD, and 81% to 93% for CAA, outperforming reference models without MRI and ADNC biomarkers. In an ADNI cohort (296 cognitively unimpaired, 401 mild cognitive impairment, 188 dementia), Aβ and tau explained 33% to 43% of variance in cognitive decline; imputed non-ADNC explained an additional 16% to 26%. Accounting for non-ADNC decreased the required sample size to detect a 30% effect on cognitive decline by up to 28%. Discussion: Our results lead to a better understanding of the factors that influence cognitive decline and may lead to improvements in AD clinical trial design.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Precision Medicine ; Cerebral Amyloid Angiopathy ; Lewy Body Disease/pathology ; DNA-Binding Proteins/metabolism ; Biomarkers
Chemical Substances	DNA-Binding Proteins ; Biomarkers
Language	English
Publishing date	2023-09-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13447
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Article ; Online: Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue.

Nature communications

2024 Volume 15, Issue 1, Page(s) 2750

Abstract: The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD ... ...

Abstract	The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn.
MeSH term(s)	Humans ; alpha-Synuclein/chemistry ; Cryoelectron Microscopy ; Lewy Bodies/pathology ; Lewy Body Disease/pathology ; Parkinson Disease/pathology
Chemical Substances	alpha-Synuclein ; SNCA protein, human
Language	English
Publishing date	2024-03-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46832-5
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Article ; Online: Author response: In vivo [

Day, Gregory S / Gordon, Brian A / Perrin, Richard J / Ances, Beau M

Neurology

2018 Volume 92, Issue 3, Page(s) 150

MeSH term(s)	Carbolines ; Creutzfeldt-Jakob Syndrome ; Humans ; Positron-Emission Tomography
Chemical Substances	Carbolines ; 7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole (J09QS3Z3WB)
Language	English
Publishing date	2018-10-31
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000006771
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Article ; Online: Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer's disease.

PLoS biology

2024 Volume 22, Issue 4, Page(s) e3002607

Abstract: Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and ... ...

Abstract	Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD.
Language	English
Publishing date	2024-04-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3002607
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Article ; Online: Flortaucipir (tau) PET in LGI1 antibody encephalitis.

Day, Gregory S / Gordon, Brian A / McCullough, Austin / Bucelli, Robert C / Perrin, Richard J / Benzinger, Tammie L S / Ances, Beau M

Annals of clinical and translational neurology

2021 Volume 8, Issue 2, Page(s) 491–497

Abstract: The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma ...

Abstract	The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with [
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Alzheimer Disease/pathology ; Autoantibodies ; Brain/diagnostic imaging ; Brain/pathology ; Carbolines/metabolism ; Cognitive Dysfunction ; Encephalitis/immunology ; Encephalitis/pathology ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/immunology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neuroimaging/methods ; Positron-Emission Tomography/methods ; tau Proteins/immunology ; tau Proteins/metabolism
Chemical Substances	Autoantibodies ; Carbolines ; Intracellular Signaling Peptides and Proteins ; LGI1 protein, human ; tau Proteins ; 7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole (J09QS3Z3WB)
Language	English
Publishing date	2021-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2740696-9
ISSN	2328-9503 ; 2328-9503
ISSN (online)	2328-9503
ISSN	2328-9503
DOI	10.1002/acn3.51297
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