High cognitive activity

Very few studies have investigated the effects of cognitive activity on brain MRI measures. One study showed that greater cognitive activity and physical activity were related to lower WML volumes independently (57). Higher cognitive activity in midlife and currently predicted lower WML volumes. Cognitive and physical activity was hypothesized to reduce Aβdependent and -independent pathways for AD development, which may help in maintaining brain integrity.

1.5.10 Depression

A study of depressive and non-depressive AD patients with GM volume loss showed that AD patients with comorbid depression had greater GM volume loss mainly in the sensory and motor areas and right thalamus (58). Another study of subclinical depression and structural brain alterations showed that middle-aged men (age ≈51 years) with depressive symptoms had association with volume loss in hippocampus at the age of 59 years (59). A systematic review reported that early-onset depression was associated to reversible hippocampus atrophy, whereas late-onset depression appeared to indicate early neurodegeneration and cerebral abnormalities including WMH (60). A longitudinal study of 9 years showed that depressed mood predicted more WMLs in men and women, and somatic symptoms also predicted increased WML volume in men (61).

1.5.11 High cholesterol

A study found that higher HDL-cholesterol was associated with higher hippocampal volume in elderly patients aged 75-85 years. Thus, high HDL levels may be protective against dementia and hippocampus atrophy. This was thought to be due to brain lipoproteins and cholesterols facilitation for synaptic plasticity, although the association may also have been explained by reverse causality. No associations were found between total cholesterol or LDL-cholesterol and hippocampus volume (62). A similar association was not found in a larger sample (63). Midlife total serum cholesterol levels were not associated with cortical thickness in late life in the CAIDE study (51), although lipid-lowering medication seemed to be protective against WML (52).

A pilot study of cholesterol-lowering treatment in AD patients found a significant shrinkage in right hippocampus with atorvastatin therapy compared to placebo group, but no statistically significant reduction in total hippocampus volume was found. Atorvastatin therapy improved some cognitive measures compared to placebo (64). Another study found that low LDL-cholesterol levels were associated to smaller GM volumes in frontal and posterior cingulate in participants with hypertension, and in addition hypertensive participants had highest periventricular WMH (65).

1.5.12 Alcohol

One study reported that, while some regions of the brain were unharmed by the effects of alcoholism, regions at risk were the prefrontal cortex and subjacent white matter, cerebellar sites and white matter structures and tracts (66). MRI scans from people with excessive alcohol use showed smaller gray matter volumes in the cerebral cortex, and older alcoholics had greater shrinkage of gray and white matter volumes in frontal lobes compared to younger alcoholics. Also, abstinence from alcohol even in the shorter-term seemed to be linked to some improvement in volumes of cortical gray matter, overall brain tissue and hippocampal structures, although the mechanisms for brain tissue volume loss through excessive alcohol use, or the restoration by abstinence are not exactly known.

One review reported that MRI studies in general found a negative linear effect of alcohol consumption on brain volumes, although there appeared to be a U-shaped relationship with more white matter integrity in elderly low to moderate drinkers (67). The negative effects of alcohol seemed more pronounced in men. Another review (68) on postmortem and in vivo neuroimaging studies described that longitudinal studies suggested benefits of alcohol abstinence on cortical gray matter, overall brain, and hippocampal volumes. Longer-term abstinence was related to benefits on brain volumes especially in frontal and temporal regions.

Two other studies reported a U-shaped association between WML burden and alcohol intake (69), and an association between alcohol dependence and lower gray matter volumes in mesocorticolimbic system, possibly linked to neural changes which could lead to impulsive behavior (70).

2. Aims and relevance of this study

Due to the current lack of effective disease-modifying drugs, it is important to focus on prevention of dementia through lifestyle-related modifications. This study aimed to investigate

associations between LIBRA dementia risk score in midlife and late-life, and brain MRI findings from the CAIDE 1998 and 2005-2008 follow-ups. This study is relevant to dementia prevention programs because the LIBRA score contains modifiable risk and protective factors, and thus emphasizes the potential for dementia risk reduction.

3 Materials and methods 3.1 CAIDE study

Cardiovascular Risk Factors, Aging and Dementia (CAIDE) is a follow-up study that was based on random population-based samples of middle-aged individuals in 1972, 1977, 1982 and 1987 from Eastern Finland (part of the FINMONICA study and North Karelia Project for cardiovascular disease prevention). The study design has been previously described in detail (7, 8, 22, 32, 51, 52, 71), and is summarized at www.uef.fi/caide. Participants in the study were re-examined first in 1998 (2000 individuals were invited, and 1449 participated) and then in 2005-2008 (1426 of the initial 2000 individuals were still alive and living in the Kuopio and Joensuu areas, and 909 participated). All visits included assessments of sociodemographic, vascular, lifestyle and other health-related factors. For the LIBRA score, CAIDE data on all factors except diet and cognitive activity were available.

In 1998 and 2005-2008, CAIDE re-examinations also included detailed cognitive assessments and dementia and MCI diagnoses. These were done with a three-step protocol: screening, clinical phase and differential diagnostic phase. Screening in the first re-examination led to further evaluation in participants with ≤24 points on Mini-Mental State Examination (MMSE) (72). In the second re-examination, for screening; participants with ≤24 points or ≥3 point decline in MMSE or if participants had <70% delayed recall in the CERAD word list (73) or concerns for individual’s cognition lead for further evaluations. Clinical phase, in both re-examinations, consisted of medical and neuropsychological assessments. Differential diagnostic phase included MRI/CT for brain imaging, blood tests and cerebrospinal fluid (CSF) analysis if needed. Primary diagnosis was verified by a review board including the study physician, neuropsychologist, senior neuropsychologist and a senior neurologist. Based on available information diagnoses for dementia and MCI were ascertained by established criteria (74-76).

3.2 Assessment of LIBRA factors in the CAIDE study

The descriptions for assessment of the LIBRA factors in the CAIDE study are shown in Table 2.

Each variable was categorized, and each category was assigned points according to the LIBRA

index described in Table 1. The total LIBRA score was obtained by calculating the sum of all points for a specific CAIDE participant.

Low/moderate alcohol intake was based on answers to the question “Do you use alcohol?” with the following alternative answers: once or twice per year or less frequently, 3-4 times a year or approximately once in two months were given –1 LIBRA point; other alternatives such as not using alcohol, approximately once per month, once or twice per month, once per week, once or twice per week were given 0 LIBRA points. For alcohol the LIBRA weight was negative for low or moderate consumption because it was considered a protective factor.

Coronary heart disease was based on self-report of myocardial infarction or angina pectoris diagnosed by a physician, or a record of diagnosed ischemic heart disease or atrial fibrillation or flutter in the Finnish hospital discharge register based on ICD codes. In ICD-10 codes I20-I25 (ischemic heart diseases) and I48 (atrial fibrillation or flutter), in ICD 9 codes 410-414 (ischemic heart diseases) and 427.3A (atrial fibrillation or flutter) and in ICD 8 codes 410-414 (ischemic heart diseases) and 427.92 (atrial fibrillation) were given 1 LIBRA point. Absence of these ICD codes or self-report of no coronary heart disease were coded as 0.

Physical inactivity was based on the question “How often do you participate in leisure time physical activity that lasts at least 20-30 minutes and causes breathlessness and sweating”. Answer alternatives once a week, 2-3 times a month, a few times a year or less frequently, or unable to exercise due to injury or sickness were given 1.1 LIBRA points. The other answer alternatives (daily or 2-3 times a week) were given the value of 0.

Chronic kidney disease was based on ICD codes for chronic renal failure, proteinuria or chronic nephritis from the Finnish hospital discharge register: in ICD 10 codes N18 (chronic renal failure) and R80 (proteinuria), in ICD 9 codes 585 (chronic renal failure) and 791.0 (proteinuria), in ICD 8 code 582 (chronic nephritis). Diabetes was based on self-report for history of diabetes diagnosed by a physician or a record of diabetes in the Finnish hospital discharge register based in ICD codes: in ICD 10 codes E10-14, in ICD 9 code 250 and in ICD 8 code 250. These alternatives were given the value of 1.1.

Cholesterol was based on total serum cholesterol. Levels equal or higher than 6.50 mmol/l were coded as 1.4 LIBRA points, and levels lower than 6.50 mmol/l were coded as 0. Smoking was based on the question “Have you ever smoked?”; answering yes was coded as 1.5 points, and answering no was coded as 0. Midlife obesity was based on measuring body-mass-index; BMI same or higher than 30 kg/m² was given the value of 1.6 points, otherwise it was coded as 0 (if BMI data were available).

Midlife hypertension was defined based on measuring systolic and diastolic blood pressure from participants’ right arm after being seated for 5 minutes. Systolic blood pressure over 140 mmHg or

diastolic blood pressure over 90 mmHg were given the value of 1.6 points, and all other alternatives were given the value of 0 (if blood pressure data were available).

Healthy diet was based on CAIDE healthy diet index which was previously published (71), based on a questionnaire covering healthy and unhealthy dietary components. Data on dietary habits was collected only for a smaller subsample of CAIDE participants, and thus was not available for the present study.

Depressive symptoms were assessed based on two statements about hopelessness; “I feel it is impossible to reach goals that I would like to strive for” and “The future seems hopeless to me, and I can’t believe that things are changing for the better”, which participants were able to answer with 5 alternative options (Likert scale): 0-absolutely agree, 1-somewhat agree, 2-cannot say, 3- somewhat disagree or 4-absolutely disagree. Answers of “somewhat agree” or “absolutely agree” to both statements were coded as 2.1 LIBRA points. All other alternatives were coded as 0 and missing values as missing. Data on cognitive activity were not available, and this variable was not included in the LIBRA score calculations.

Table 2 Assessment of LIBRA factors from the CAIDE study.

Risk/protective

factor CAIDE assessment Low/moderate

alcohol intake Frequency of alcohol consumption question with alternative answers: once or twice per year or less frequently, 3-4 times a year, or approximately once in two months were given -1 LIBRA points.

Answer options not using alcohol, approximately once per month, once or twice per month, once per week, once or twice per week, daily were coded as 0.

Missing values were coded as missing.

Coronary

heart disease Self-report of myocardial infarction or angina pectoris diagnosed by physician, or records of diagnoses of ischemic heart disease or atrial fibrillation based on the Finnish Hospital Discharge Register ICD codes (ICD 10, ICD 9 or ICD 8, listed in the text above) were given 1 LIBRA point. Absence of self-reported or register-based coronary heart disease was coded as 0.

Physical

inactivity Answering to the question “How often do you participate in leisure time physical activity that lasts at least 20-30 minutes and causes breathlessness and sweating” with alternatives once a week, 2-3 times a month, a few times a year or less frequently or unable to exercise due to injury or sickness were given the value 1.1. Alternatives daily or 2-3 times a week were given value 0.

Missing values were coded as missing.

Chronic

kidney disease This variable was based on record of certain ICD codes from the Finnish

hospital discharge register (listed in text above); diagnoses in ICD-10, ICD-9 or ICD-8 of chronic renal failure, proteinuria or chronic nephritis were given the value of 1.1. Absence of these diagnostic codes was given the value of 0.

Diabetes Self-report of diabetes diagnosed by a physician or record of diagnoses of diabetes based on the Finnish Hospital Discharge Register of certain ICD codes (listed in text above) were given the value of 1.1. Absence of diabetes was coded as 0.

Cholesterol Serum cholesterol values < 6.5 mmol/l were coded as 0, values ≥ 6.50 mmol/l were coded as 1.4, and missing values as missing.

Smoking If participants had ever been smoking they were given value 1.5 if not value 0 and missing values were coded as missing

Midlife obesity If participants body-mass index was ≥ 30 kg/m² they were given value 1.6, all other values were given value 0 and missing values coded as missing

Midlife

hypertension If participants had either SBP ≥ 140 mmHg or DBP ≥ 90 mmHg they were given value 1, if less than these value 0 and missing values as missing.

Healthy diet Not available Depressive

symptoms Measuring hopelessness was based on two questions: “I feel it is impossible to reach goals that I would like to strive for” and “The future seems hopeless to me, and I can’t believe that things are changing for the better”. Participants rated their agreement or disagreement to the questions using Likert scale: 0-absolutely agree, 1-somewhat agree, 2-cannot say, 3- somewhat disagree or 4-absolutely disagree. Replies of “somewhat agree” or “4-absolutely agree” were coded as 2.1. All other alternatives were coded as 0 and missing values as missing.

High cognitive

activity Not available

3.3 MRI assessments in the CAIDE study

In 1998, MRI scans were taken only from individuals who needed further evaluation in the Kuopio cohort (39 with dementia, 31 with MCI) and 42 cognitively normal controls (total 112 participants). In 2005-2008 MRI scans were conducted in 113 participants from Kuopio (during the differential diagnostic phase), of which 69 did not have dementia and were considered for this study. Figure 1 below shows the number of participants included in the present study based on availability of both MRI and LIBRA data.

T1-weighted images were acquired using a three-dimensional magnetization prepared rapid acquisition gradient echo (3DMPRAGE) sequence on 1.5T MR scanners. One MRI scanner was used in the first re-examination (Siemens Magnetom Vision), and two scanners were used in the second re-examination (Siemens Magnetom Vision or Siemens Avanto). Axial fluid-attenuated inversion recovery images (FLAIR) were available from both re-examinations. The imaging parameters for both sequences and image check procedures have been previously described (32, 51, 52).

In the first re-examination, GM volume was measured using FSL FAST (FMRIB’s Automated Segmentation Tool) (77). WML were assessed from FLAIR images using the Wahlund

semi-quantitative visual rating scale (78). The lesions were rated separately from zero to three for five brain regions (frontal, parieto-occipital, temporal, infratentorial and basal ganglia) in both hemispheres. MTA was rated from zero (no atrophy) to four (end-stage atrophy) bilaterally from T1-weighted images according to the Scheltens visual rating scale (79).

In the second re-examination, brain volumes and cortical thickness were assessed with the FreeSurfer software package, version 5.0 (http://surfer.nmr.mgh.harvard.edu/) (80). WML volumes were calculated using CASCADE, an automatic pipeline developed at Karolinska Institute, Stockholm, Sweden (81, 82). Visual MTA assessment was done using the Scheltens scale. Alzheimer’s disease signature cortical thickness was calculated as the average cortical thickness of left and right entorhinal, inferior temporal, middle temporal and fusiform regions (83).

Figure 1 demonstrating design of this study with baseline CAIDE population and MRI populations in 1998 and 2005-2008 with available midlife LIBRA score.

3.4 Statistical analyses

Analyses were conducted using SPSS software version 23. Level of significance was p<0.05 in all analyses.

1) Midife LIBRA and MRI measures in 1998

MRI measures included WML visual rating total score (continuous variable, zero-skewness log-transformed), total gray matter volume (continuous variable, TIV-adjusted and zero-skewness log-transformed), and MTA visual rating (dichotomous, average of left and right MTA 0 or 1 versus 1.5 and above). Linear regression models or binary logistic regression models with MRI measures as dependent variables were used for continuous or dichotomous variables, respectively. Model 1 was adjusted for follow-up time, and model 2 was additionally adjusted for age in midlife, diagnosis, gender and education.

2) Midlife LIBRA and MRI measures in 2005-2008

MRI measures included WML visual rating total score (continuous variable, zero-skewness log-transformed), total gray matter volume (continuous variable, TIV-adjusted and zero-skewness log-transformed), medial temporal atrophy visual rating (dichotomous, average of left and right MTA 0 or 1 versus 1.5 and above), hippocampus volume (continuous variable, TIV-adjusted and skewness log-transformed) and AD signature thickness (continuous variable, zero-skewness log-transformed). Linear regression models or binary logistic regression models with MRI measures as dependent variables were used for continuous or dichotomous variables, respectively. Model 1 was adjusted for follow-up time from midlife to 2005-2008 and scanner type, except for visually rated MTA. Model 2 was additionally adjusted for age in midlife, gender and education.

3) 1998 LIBRA and MRI measures in 1998

MRI measures included WML visual rating total score (continuous variable, zero-skewness log-transformed), total gray matter volume (continuous variable, TIV-adjusted and zero-skewness log-transformed), and MTA visual rating (dichotomous, average of left and right MTA 0 or 1 versus 1.5 and above). Linear regression models or binary logistic regression models with MRI measures as dependent variables were used for continuous or dichotomous variables, respectively. Model 1 was unadjusted, and model 2 was adjusted for age in 1998, gender and education.

4)1998 LIBRA and MRI measures in 2005-2008

MRI measures included WML visual rating total score (continuous variable, zero-skewness transformed), total gray matter volume (continuous variable, TIV-adjusted zero-skewness

log-transformed), medial temporal atrophy visual rating (dichotomous, average of left and right MTA 0 or 1 versus 1.5 and above), hippocampus volume (continuous variable, TIV-adjusted skewness log-transformed) and AD signature thickness (continuous variable, zero-skewness log-transformed). Linear regression models or binary logistic regression models with MRI measures as dependent variables were used for continuous or dichotomous variables, respectively. Model 1 was adjusted for follow-up time, and model 2 was additionally adjusted for age in 1998, gender and education.

4 Results

4.1. Population characteristics

Characteristics of participants with available LIBRA score and MRI are shown in Table 3. In the CAIDE 1998 MRI population participants were older than in 2005-2008 MRI population, with mean (SD) age in midlife 51.09 (4.61) years vs 47.33 (4.69) years, and had less years of education 6.96 (2.53) vs 7.53 (2.46). In the 1998 MRI population participants had higher midlife LIBRA score mean (SD) 3.98 (2.04) vs. 3.57 (1.68), and more participants had depression N (%) 12 (14.6) vs. 4 (8.9), midlife hypertension 63 (76.8) vs. 30 (66.7), midlife obesity 21 (25.6) vs.

10 (22.2), high cholesterol 58 (70.7) vs. 29 (64.4) and coronary heart disease 8 (9.8) vs. 3 (6.7) when compared to the MRI population in 2005-2008.

Table 3. Characteristics of the 1998 and 2005-2008 CAIDE MRI populations with available data on LIBRA score

N CAIDE 1998 MRI

population N CAIDE 2005-2008 MRI population

Midlife examination

Age 82 51.1 (4.6) 45 47.3 (4.7)

Women (N. %) 82 50 (61) 45 28 (62)

Education. years 82 7.0 (2.5) 45 7.5 (2.5) APOE4 carriers (N, %) 81 32 (40) 44 16 (36) Follow-up time, years 82 22,9 (2,4) 45 30,8 (2,5) Low/moderate alcohol intake

(N, %) 82 26 (32) 45 13 (29)

Coronary heart disease (N, %) 82 8 (9.8) 45 3 (6.7) Physical inactivity (N, %) 82 51 (62) 45 28 (62)

Chronic kidney disease (N, %) 82 0 0

Diabetes (N, %) 82 1 (1) 45 1 (2)

High cholesterol (N, %) 82 58 (71) 45 29 (64)

Smoking (N, %) 82 31 (38) 45 17 (38)

Midlife obesity (N, %) 82 21 (26) 45 10 (22) Midlife hypertension (N, %) 82 63 (77) 45 30 (67)

Depression (N, %) 82 12 (14) 45 4 (8)

LIBRA score 82 4.0 (2.0) 45 3.6 (1.7)

MRI measures 1998 examination 2005-2008 examination

Hippocampus vol. N.A. 44 6.70 (1.22)

Total gray matter vol. 64 342 (56) 44 508 (61)

TIV 64 1386 (126) 44 154 (173)

AD signature thickness N.A. 44 2.56 (0.32)

MTA* 65 1,0 (0,0-2,5) 45 1,0 (0,0-2,5)

Deep WML N.A. N.A.

Periventricular WML N.A. N.A.

WML (Wahlund)* 82 5,0 (0,0-22,0) N.A.

WML volume N.A. 45 31.4 (28.6)

Values are means (SD) unless otherwise specified. * Median (range)

In the CAIDE 1998 re-examination, participants with available LIBRA score were younger compared to participants without complete data on LIBRA score (mean (SD) 51.09 (4.61) vs.

56.17 (5.00), p<0.001) (Table 4). Participants with available LIBRA score had longer follow-up time compared to those without available LIBRA score (22.93 (2.38) vs. 16.72 (4.51), p=<0.001). Lower percentage of women had available LIBRA score compared to participants without LIBRA (number (percentage) 50 (60.98) vs. 23 (76.67), p=0.123)

Table 4 - Comparison between participants with and without available data on LIBRA score in the CAIDE 1998 MRI population

N LIBRA score

available N LIBRA score

not available P-value

Age 82 51,1 (4,6) 30 56,2 (5.0) <0.001

Women (N. %) 82 50 (61) 30 23 (77) 0.123

Education. years 82 7.0 (2.5) 29 7.0 (3.0) 0.949 Follow-up time, years 82 22.9 (2.4) 30 16.7 (4.5) <0.001 Total gray matter

volume ⁶⁴ 0.36 (0.03) 26 0.36 (0.02) 0.640

Visually rated white

matter lesions ^{82 6.0 (4,4) 30 6.4 (4.0) 0.642} More severe medial

temporal atrophy (N, %) 65 14 (22) 26 8 (31) 0.353

Values are means (SDs) unless otherwise specified. P-values are shown from t-test for continuous variables, and chi2 test for categorical variables.

In the CAIDE 2005-2008 re-examination, participants with available LIBRA score were younger

In the CAIDE 2005-2008 re-examination, participants with available LIBRA score were younger

In document Does a midlife dementia risk score relate to late-life structural brain changes on MRI? (sivua 14-0)