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December 10, 2019; 93 (24) Article

Cerebrospinal fluid dynamics disorders

Relationship to Alzheimer biomarkers and cognition

Jonathan Graff-Radford, Jeffrey L. Gunter, David T. Jones, Scott A. Przybelski, Christopher G. Schwarz, John Huston, Val Lowe, Benjamin D. Elder, Mary M. Machulda, Nathaniel B. Gunter, Ronald C. Petersen, Kejal Kantarci, Prashanthi Vemuri, Michelle M. Mielke, David S. Knopman, Neill R. Graff-Radford, Clifford R. Jack
First published November 12, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008616
Jonathan Graff-Radford
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Jeffrey L. Gunter
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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David T. Jones
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Scott A. Przybelski
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Christopher G. Schwarz
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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John Huston
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Val Lowe
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Benjamin D. Elder
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Mary M. Machulda
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Nathaniel B. Gunter
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Ronald C. Petersen
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Kejal Kantarci
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Prashanthi Vemuri
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Michelle M. Mielke
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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David S. Knopman
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Neill R. Graff-Radford
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Clifford R. Jack
From the Departments of Neurology (J.G.-R., D.T.J., R.C.P., D.S.K.), Radiology (J.L.G., C.G.S., J.H., V.L., N.B.G., K.K., P.V., C.R.J.), Health Sciences Research (S.A.P., M.M. Mielke), Neurologic Surgery (B.D.E.), and Psychiatry and Psychology (M.M. Machulda), Mayo Clinic, Rochester, MN; and Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL.
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Citation
Cerebrospinal fluid dynamics disorders
Jonathan Graff-Radford, Jeffrey L. Gunter, David T. Jones, Scott A. Przybelski, Christopher G. Schwarz, John Huston, Val Lowe, Benjamin D. Elder, Mary M. Machulda, Nathaniel B. Gunter, Ronald C. Petersen, Kejal Kantarci, Prashanthi Vemuri, Michelle M. Mielke, David S. Knopman, Neill R. Graff-Radford, Clifford R. Jack
Neurology Dec 2019, 93 (24) e2237-e2246; DOI: 10.1212/WNL.0000000000008616

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Abstract

Objective To 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.

Methods We 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.

Results Of 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.

Conclusion The 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.

Glossary

Aβ42=
β-amyloid42;
AD=
Alzheimer disease;
AT(N)=
amyloid-tau-neurodegeneration;
CDD=
CSF dynamics disorder;
DESH=
disproportionately enlarged subarachnoid space hydrocephalus;
FLAIR=
and fluid-attenuated inversion recovery;
HCTS=
high-convexity tight sulci;
MCALT=
Mayo Clinic Adult Lifespan Template;
MCSA=
Mayo Clinic Study of Aging;
MPRAGE=
magnetization-prepared rapid gradient-echo;
NPH=
normal-pressure hydrocephalus;
PiB=
Pittsburgh compound B;
SUVR=
standard uptake value ratio

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • CME Course: NPub.org/cmelist

  • Received February 12, 2019.
  • Accepted in final form June 19, 2019.
  • © 2019 American Academy of Neurology
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