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Hippocampal calcifications: risk factors and association with cognitive functioning E.J.M. de Brouwer, R. Kockelkoren, J.J. Claus, A. de Jonghe, M. Geerlings, T.E.F. Jongsma, W.P.Th.M. Mali, J. Hendrikse, P.A. de Jong, H.L. Koek University of

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Hippocampal calcifications: risk factors and association with cognitive functioning

E.J.M. de Brouwer, R. Kockelkoren, J.J. Claus, A. de Jonghe, M. Geerlings, T.E.F. Jongsma, W.P.Th.M. Mali, J. Hendrikse, P.A. de Jong, H.L. Koek

University of Utrecht, the Netherlands

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CONFLICT OF INTEREST DISCLOSURE

I have no potential conflict of interest to report

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Introduction

  • Dementia is a global health problem
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Introduction

  • Multifactorial etiology: Alzheimer pathology, vascular lesions,

Lewy bodies and inflammation

  • Most research focuses on neurodegeneration
  • Little research about vascular pathology in the hippocampus
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SLIDE 5

Introduction

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SLIDE 6

Introduction

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SLIDE 7

Introduction

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Hypothesis

  • Vasculopathy with fibrosis and calcification
  • Hippocampal atrophy
  • Leading to cognitive decline
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Aim

  • To determine risk factors for hippocampal calcifications

(HCC)

  • To determine the association between hippocampal

calcifications and cognition

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SLIDE 10

Methods

  • Outpatient memory clinic Tergooi hospital, the

Netherlands

  • April 2009 – april 2015
  • 2000 patients
  • Cognitive tests: CAMCOG, VAT, CDT, GDS
  • CT scan of the head
  • Multidisciplinary meeting: neurologist, geriatrician,

neuropsychologist

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SLIDE 11

Methods

  • Diagnosis

– Subjective cognitive impairment (SCI) – Mild cognitive impairment (MCI) – Alzheimer dementia (AD) – Vascular dementia (VaD) – Other dementia (incl. FTD, PD, LBD) – Other diagnosis (a neurologic or psychiatric disorder)

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SLIDE 12

Methods

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SLIDE 13

Statistics

  • Logistic regression analysis

– Age/sex adjusted – Adjusted for age, sex, hypertension, diabetes mellitus, hyperlipidemia, smoking

  • Linear regression analysis

– Age/sex adjusted – Adjusted for age, sex and education level

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Patient characteristics

Characteristic Total, n= 1991 (100%) HCC present, n= 380 (19.1%) HCC absent, n= 1611 (80.9%) P-value Age, median (yrs) 80 81 79 <0.01 Gender, male % 40.3 43.2 39.6 0.22 Education level, mean 4.34 4.20 4.37 0.05 Cerebral infarct % 5.2 3.4 5.6 0.10 TIA, % 5.8 6.6 5.6 0.47 Hypertension % 33.9 33.9 33.9 1.00 Diabetes mellitus % 15.9 20.8 14.8 0.01 Hyperlipidaemia % 7.7 7.1 7.8 0.75 Smoking % Current 11.5 13.4 11.0 0.39 Former 22.8 22.9 22.8 Never 65.6 63.7 66.1

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Patient characteristics

Characteristic Total, n= 1991 (100%) HCC present, n= 380 (19.1%) HCC absent, n= 1611 (80.9%) P-value Age, median (yrs) 80 81 79 <0.01 Gender, male % 40.3 43.2 39.6 0.22 Education level, mean 4.34 4.20 4.37 0.05 Cerebral infarct % 5.2 3.4 5.6 0.10 TIA, % 5.8 6.6 5.6 0.47 Hypertension % 33.9 33.9 33.9 1.00 Diabetes mellitus % 15.9 20.8 14.8 0.01 Hyperlipidaemia % 7.7 7.1 7.8 0.75 Smoking % Current 11.5 13.4 11.0 0.39 Former 22.8 22.9 22.8 Never 65.6 63.7 66.1

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Patient characteristics

Characteristic Total, n= 1991 (100%) HCC present, n= 380 (19.1%) HCC absent, n= 1611 (80.9%) P-value Age, median (yrs) 80 81 79 <0.01 Gender, male % 40.3 43.2 39.6 0.22 Education level, mean 4.34 4.20 4.37 0.05 Cerebral infarct % 5.2 3.4 5.6 0.10 TIA, % 5.8 6.6 5.6 0.47 Hypertension % 33.9 33.9 33.9 1.00 Diabetes mellitus % 15.9 20.8 14.8 0.01 Hyperlipidaemia % 7.7 7.1 7.8 0.75 Smoking % Current 11.5 13.4 11.0 0.39 Former 22.8 22.9 22.8 Never 65.6 63.7 66.1

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Patient characteristics

Characteristic Total, n= 1991 (100%) HCC present, n= 380 (19.1%) HCC absent, n= 1611 (80.9%) P-value MTA score, mean 1.6 1.8 1.6 <0.01 Fazekas score, mean 1.0 1.1 1.0 0.54 Diagnosis % SCI 16.7 14.5 17.2 0.22 MCI 24.6 23.9 24.8 0.79 AD 41.6 45.5 40.7 0.09 VaD 2.8 2.9 2.8 0.86 Other dementia 2.7 1.8 2.9 0.37 Other diagnosis 11.6 11.3 11.7 0.93 MMSE, median 23 22 23 0.39 CAMCOG, median 76 75 76 0.04

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Patient characteristics

Characteristic Total, n= 1991 (100%) HCC present, n= 380 (19.1%) HCC absent, n= 1611 (80.9%) P-value MTA score, mean 1.6 1.8 1.6 <0.01 Fazekas score, mean 1.0 1.1 1.0 0.54 Diagnosis % SCI 16.7 14.5 17.2 0.22 MCI 24.6 23.9 24.8 0.79 AD 41.6 45.5 40.7 0.09 VaD 2.8 2.9 2.8 0.86 Other dementia 2.7 1.8 2.9 0.37 Other diagnosis 11.6 11.3 11.7 0.93 MMSE, median 23 22 23 0.39 CAMCOG, median 76 75 76 0.04

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Risk factors for presence of HCC

Univariable model Age/sex adjusted model Multivariable model Risk factors OR CI P OR CI P OR CI P Age 1.04 1.03-1.06 <0.01 1.05 1.03-1.06 <0.01 1.05 1.03-1.07 <0.01 Gender 0.86 0.69-1.08 0.20 0.78 0.62-0.98 0.03 0.81 0.64-1.03 0.08 Hypertension 1.00 0.79-1.27 0.98 0.95 0.75-1.21 0.68 0.91 0.71-1.17 0.46 Diabetes Mellitus 1.51 1.14-2.01 <0.01 1.47 1.10-1.95 <0.01 1.49 1.12-2.00 <0.01 Smoking* Current 1.27 0.90-1.78 0.17 1.51 1.06-2.16 0.02 1.50 1.05-2.14 0.03 Former 1.04 0.80-1.37 0.76 1.04 0.78-1.38 0.79 1.03 0.78-1.40 0.84 Hyperlipidaemia 0.90 0.59-1.39 0.64 0.91 0.59-1.41 0.67 0.89 0.57-1.39 0.60 * Smoking: compared with never smoked

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Risk factors for presence of HCC

Univariable model Age/sex adjusted model Multivariable model Risk factors OR CI P OR CI P OR CI P Age 1.04 1.03-1.06 <0.01 1.05 1.03-1.06 <0.01 1.05 1.03-1.07 <0.01 Gender 0.86 0.69-1.08 0.20 0.78 0.62-0.98 0.03 0.81 0.64-1.03 0.08 Hypertension 1.00 0.79-1.27 0.98 0.95 0.75-1.21 0.68 0.91 0.71-1.17 0.46 Diabetes Mellitus 1.51 1.14-2.01 <0.01 1.47 1.10-1.95 <0.01 1.49 1.12-2.00 <0.01 Smoking* Current 1.27 0.90-1.78 0.17 1.51 1.06-2.16 0.02 1.50 1.05-2.14 0.03 Former 1.04 0.80-1.37 0.76 1.04 0.78-1.38 0.79 1.03 0.78-1.40 0.84 Hyperlipidaemia 0.90 0.59-1.39 0.64 0.91 0.59-1.41 0.67 0.89 0.57-1.39 0.60 * Smoking: compared with never smoked

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Association between HCC and cognition

Univariable model Age/sex adjusted model Multivariable model Cognitive tests Beta CI P Beta CI P Beta CI P CAMCOG

  • 1.40
  • 3.28-0.48

0.14 0.30

  • 1.48-2.07

0.74 0.86

  • 0.81-2.53

0.32 VAT

  • 0.66
  • 1.15- -0.17

<0.01

  • 0.19
  • 0.65-0.27

0.43

  • 0.12
  • 0.57-0.34

0.62 MMSE

  • 0.19
  • 0.82-0.45

0.56 0.38

  • 0.23-0.98

0.22 0.54

  • 0.04-1.12

0.07 CDT

  • 0.06
  • 0.17-0.04

0.19 0.02

  • 0.08-0.12

0.95 0.04

  • 0.06-0.14

0.45

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SLIDE 22

Conclusion

  • Increasing age, diabetes mellitus and current smoking

were associated with hippocampal calcifications

  • No association of hippocampal calcifications with

cognition

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SLIDE 23

Questions?

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SLIDE 24

Thank you!

My colleagues: Remko Kockelkoren2 MD Jules J. Claus3 MD PhD Annemarieke de Jonghe4 MD PhD Mirjam I. Geerlings5 PhD Thomas E.F. Jongsma6 MD Willem P.Th.M. Mali2 MD PhD Jeroen Hendrikse2 MD PhD Pim A. de Jong2 MD PhD Huiberdina L. Koek1 MD PhD

1 Department of Geriatrics, University Medical Center, Utrecht, The Netherlands 2 Department of Radiology, University Medical Center, Utrecht, The Netherlands 3 Department of Neurology, Tergooi hospital, Hilversum, The Netherlands 4 Department of Geriatrics, Tergooi hospital, Hilversum, The Netherlands 5 Julius Center for Health Sciences and Primary Care, Department of Epidemiology, University Medical

Center, Utrecht, The Netherlands

6 Department of Radiology, Tergooi hospital, Hilversum, The Netherlands

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Risk factors for presence of HCC

Univariable analysis Age/sex adjusted analysis Multivariable analysis Model 1 Model 2 Model 3 Risk factors OR CI P OR CI P OR CI P Age 1.04 1.03-1.06 <0.001 1.05 1.03-1.06 <0.001 1.05 1.03-1.07 <0.001 Gender 0.86 0.69-1.08 0.204 0.78 0.62-0.98 0.032 0.81 0.64-1.03 0.083 Hypertension 1.00 0.79-1.27 0.984 0.95 0.75-1.21 0.681 0.91 0.71-1.17 0.464 Diabetes Mellitus 1.51 1.14-2.01 0.004 1.47 1.10-1.95 0.009 1.49 1.12-2.00 0.007 Smoking Never (ref) * * * * * * * * * Current 1.27 0.90-1.78 0.173 1.51 1.06-2.16 0.022 1.50 1.05-2.14 0.025 Former 1.04 0.80-1.37 0.760 1.04 0.78-1.38 0.788 1.03 0.78-1.40 0.835 Hyperlipidaemia 0.90 0.59-1.39 0.638 0.91 0.59-1.41 0.669 0.89 0.57-1.39 0.604 MTA score 1.23 1.10-1.38 <0.001 1.04 0.92-1.19 0.530 1.04 0.91-1.19 0.555 Fazekas score 1.08 0.95-1.23 0.222 0.93 0.81-1.07 0.292 0.92 0.80-1.06 0.250

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Association between HCC and cognition measured by CAMCOG domains

Univariable analysis Age/sex adjusted Multivariable adjusted Model 1 Model 2 Model 3 Cognitive tests Beta CI P Beta CI P Beta CI P CAMCOG TOTAL

  • 1.40
  • 3.28-0.48

0.144 0.30

  • 1.48-2.07

0.743 0.86

  • 0.81-2.53

0.315 Orientation

  • 0.16
  • 0.42-0.15

0.356 0.16

  • 0.11-0.43

0.249 0.21

  • 0.06-0.47

0.123 Memory

  • 0.43
  • 1.07-0.20

0.178 0.08

  • 0.52-0.68

0.788 0.23

  • 0.35-0.81

0.435 Memory section

  • 0.58
  • 1.45-0.29

0.191 0.22

  • 0.59-1.04

0.590 0.42

  • 0.37-1.21

0.295 Language

  • 0.18
  • 0.61-0.25

0.412 0.05

  • 0.37-0.48

0.804 0.17

  • 0.23-0.58

0.397 Attention 0.04

  • 0.21-0.28

0.795 0.15

  • 0.10-0.39

0.238 0.19

  • 0.04-0.43

0.104 Praxis

  • 0.18
  • 0.45-0.09

0.194

  • 0.01
  • 0.27-0.25

0.951 0.07

  • 0.19-0.32

0.610 Calculation

  • 0.02
  • 0.08-0.04

0.506 0.01

  • 0.05-0.07

0.732 0.02

  • 0.04-0.08

0.547 Abstract reasoning

  • 0.18
  • 0.45-0.10

0.205

  • 0.02
  • 0.29-0.25

0.874 0.05

  • 0.20-0.31

0.698 Perception

  • 0.40
  • 0.60- -0.20

<0.001

  • 0.20
  • 0.39-0.01

0.035

  • 0.16
  • 0.35-0.02

0.084 Not memory section

  • 0.85
  • 2.02-0.32

0.153 0.04

  • 1.08-1.17

0.941 0.40

  • 0.65-1.46

0.456

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Association between severity of HCC and cognition measured by CAMCOG domains

Univariable analysis Age/sex adjusted analysis CAMCOG domains Beta CI p Beta CI P CAMCOG TOTAL

  • 0.267 -1.367-0.834

0.635 0.386

  • 0.649-1.421

0.464 Orientation 0.014

  • 0.153-0.182

0.868 0.135

  • 0.022-0.292

0.091 Memory

  • 0.086 -0.455-0.284

0.650 0.104

  • 0.246-0.454

0.560 Memory section

  • 0.068 -0.575-0.439

0.793 0.237

  • 0.237-0.712

0.326 Language 0.003

  • 0.248-0.254

0.979 0.094

  • 0.154-0.341

0.458 Attention 0.057

  • 0.086-0.199

0.434 0.091

  • 0.049-0.231

0.202 Praxis

  • 0.048 -0.204-0.108

0.549 0.019

  • 0.134-0.171

0.811 Calculation 0.007

  • 0.028-0.043

0.687 0.020

  • 0.015-0.055

0.263 Abstract reasoning

  • 0.052 -0.212-0.108

0.525 0.010

  • 0.147-0.168

0.900 Perception

  • 0.202 -0.318- -0.086

0.001

  • 0.118
  • 0.228- -0.009

0.034 Not memory section

  • 0.212 -0.896-0.472

0.544 0.134

  • 0.523-0.791

0.690 VAT

  • 0.260 -0.545-0.025

0.074

  • 0.071
  • 0.339-0.196

0.602 MMSE 0.062

  • 0.309-0.433

0.742 0.288

  • 0.064-0.640

0.109 CDT

  • 0.002 -0.062-0.059

0.959 0.030

  • 0.029-0.088

0.322

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Severe hippocampal calcification vs not severe or absent calcification

Univariable analysis Age/sex adjusted analysis CAMCOG domains Beta CI p Beta CI P CAMCOG TOTAL 4.791

  • 0.333-9.915

0.067 3.308

  • 1.494-8.110

0.177 Orientation 0.770

  • 0.004-1.544

0.051 0.619

  • 0.102-1.341

0.092 Memory 1.439

  • 0.284-3.161

0.102 0.885

  • 0.739-2.508

0.285 Memory section 2.284

  • 0.078-4.647

0.058 1.549

  • 0.653-3.751

0.168 Language 0.714

  • 0.455-1.883

0.231 0.511

  • 0.636-1.657

0.382 Attention 0.686 0.023-1.349 0.042 0.522

  • 0.128-1.173

0.115 Praxis 0.490

  • 0.231-1.211

0.183 0.364

  • 0.337-1.065

0.309 Calculation 0.125

  • 0.041-0.291

0.139 0.105

  • 0.058-0.268

0.207 Abstract reasoning 0.371

  • 0.375-1.116

0.330 0.263

  • 0.469-0.994

0.481 Perception

  • 0.017 -0.557-0.523

0.951

  • 0.111
  • 0.615-0.393

0.666 Not memory section 2.490

  • 0.697-5.676

0.126 1.723

  • 1.325-4.772

0.268 VAT 0.508

  • 0.811-1.827

0.450 0.206

  • 1.025-1.438

0.742 MMSE 1.766 0.039-3.493 0.045 1.361

  • 0.273-2.994

0.102 Klok 0.390 0.108-0.673 0.007 0.328 0.058-0.599 0.018