A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology

Michael L Alosco^{1

2}, Michael A Sugarman^{1

3}, Lilah M Besser⁴, Yorghos Tripodis^{1

5}, Brett Martin^{1

6}, Joseph N Palmisano^{1

6}, Neil W Kowall^{1

2

7

8}, Rhoda Au^{2

9

10

11}, Jesse Mez^{1

2}, Charles DeCarli¹², Thor D Stein^{1

7

13

14}, Ann C McKee^{1

2

7

13

14}, Ronald J Killiany^{1

11

15}, Robert A Stern^{1

2

11

16}

Affiliations

¹ Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA, USA.
² Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
³ Department of Neuropsychology, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA.
⁴ National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, USA.
⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁶ Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA.
⁷ Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
⁸ Neurology Service, VA Boston Healthcare System, Boston, MA, USA.
⁹ Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA, USA.
¹⁰ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
¹¹ Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA.
¹² Department of Neurology, University of California at Davis Health System, Sacramento, CA, USA.
¹³ U.S. Department of Veteran Affairs, VA Boston Healthcare System, Boston, MA, USA.
¹⁴ Department of Veterans Affairs Medical Center, Bedford, MA, USA.
¹⁵ Center for Biomedical Imaging, Boston University School of Medicine, Boston, MA, USA.
¹⁶ Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA.

PMID: 29843242
PMCID: PMC6081639
DOI: 10.3233/JAD-180017

A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology

Michael L Alosco et al. J Alzheimers Dis. 2018.

. 2018;63(4):1347-1360.

doi: 10.3233/JAD-180017.

Authors

Affiliations

¹ Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA, USA.
² Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
³ Department of Neuropsychology, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA.
⁴ National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, USA.
⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁶ Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA.
⁷ Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
⁸ Neurology Service, VA Boston Healthcare System, Boston, MA, USA.
⁹ Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA, USA.
¹⁰ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
¹¹ Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA.
¹² Department of Neurology, University of California at Davis Health System, Sacramento, CA, USA.
¹³ U.S. Department of Veteran Affairs, VA Boston Healthcare System, Boston, MA, USA.
¹⁴ Department of Veterans Affairs Medical Center, Bedford, MA, USA.
¹⁵ Center for Biomedical Imaging, Boston University School of Medicine, Boston, MA, USA.
¹⁶ Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA.

PMID: 29843242
PMCID: PMC6081639
DOI: 10.3233/JAD-180017

Abstract

Background: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility.

Objective: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP.

Methods: The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy.

Results: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04).

Conclusions: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

Keywords: Alzheimer’s disease; Alzheimer’s disease neuropathology; cerebrovascular disease; dementia; magnetic resonance imaging; white matter hyperintensities.

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Conflict of interest statement

CONFLICT OF INTEREST

RAS is a paid consultant to Eli Lilly (Indianapolis, IN, USA), Avanir Pharmaceuticals (Aliso Viejo, CA), and Biogen (Cambridge, MA, USA). He is a member of the Board of Directors of King-Devick Technologies, Inc. (Chicago, IL, USA), and he receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, FL, USA). CD is a paid consultant to Novartis Pharmaceuticals (Basel, Switzerland). For the remaining authors, there are no conflicts of interest to declare.

Figures

**Figure 1.**
Exemplary White Matter Hyperintensity Burden in a Participant with Alzheimer’s Disease Neuropathology. The below is a T2 FLAIR sequence from a selected participant who had Alzheimer’s disease neuropathology. Participant was selected to exemplify the pattern and high burden of WMH in AD.

See this image and copyright information in PMC

References

1. Jack CR Jr., Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS, Petersen RC, Scheltens P, Sperling RA, Dubois B (2016) A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 87, 539–47. - PMC - PubMed
1. Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, Mormino E, Chhatwal J, Amariglio R, Papp K, Marshall G, Albers M, Mauro S, Pepin L, Alverio J, Judge K, Philiossaint M, Shoup T, Yokell D, Dickerson B, Gomez-Isla T, Hyman B, Vasdev N, Sperling R. (2016) Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol 79, 110–9. - PMC - PubMed
1. Kang JH, Korecka M, Figurski MJ, Toledo JB, Blennow K, Zetterberg H, Waligorska T, Brylska M, Fields L, Shah N, Soares H, Dean RA, Vanderstichele H, Petersen RC, Aisen PS, Saykin AJ, Weiner MW, Trojanowski JQ, Shaw LM, Alzheimer’s Disease Neuroimaging I. (2015) The Alzheimer’s Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans. Alzheimers Dement 11, 772–91. - PMC - PubMed
1. Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, Holtta M, Rosen C, Olsson C, Strobel G, Wu E, Dakin K, Petzold M, Blennow K, Zetterberg H. (2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15, 673–84. - PubMed
1. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Cedarbaum J, Green RC, Harvey D, Jack CR, Jagust W, Luthman J, Morris JC, Petersen RC, Saykin AJ, Shaw L, Shen L, Schwarz A, Toga AW, Trojanowski JQ, Alzheimer’s Disease Neuroimaging I. (2015) 2014 Update of the Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception. Alzheimers Dement 11, e1–120. - PMC - PubMed

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A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology

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A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology

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Conflict of interest statement

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