White matter hyperintensities and within-person variability in community-dwelling adults aged 60–64 years

Estimates of white matter hyperintensities (WMH) derived from T2-weighted MRI were investigated in relation to cognitive performance in 469 healthy community-dwelling adults aged 60–64 years. Frontal lobe WMH but not WMH from other brain regions (temporal, parietal, and occipital lobes, anterior and posterior horn, periventricular body) were associated with elevated within-person reaction time (RT) variability (trial to trial fluctuations in RT performance) but not performance on several other cognitive tasks including psychomotor speed, memory, and global cognition. The findings are consistent with the view that elevated within-person variability is related to neurobiological disturbance, and that attentional mechanisms supported by the frontal cortex play a key role in this type of variability

Cognitive Deficits Are Associated with Frontal and Temporal Lobe White Matter Lesions in Middle-Aged Adults Living in the Community

BACKGROUND The association between brain white matter lesions and cognitive impairment in old age is well established. However, little is known about this association in midlife. As this information will inform policy for early preventative healthcare initiatives, we investigated non-periventricular frontal, temporal, parietal and occipital lobe white matter hyperintensities (WMH) in relation to cognitive function in 428 (232 women) community-dwelling adults aged 44 to 48 years. RESULTS Frontal white matter lesions were significantly associated with greater intraindividual RT variability in women, while temporal WMH were associated with face recognition deficits in men. Parietal and occipital lobe lesions were unrelated to cognitive performance. These findings did not differ when education and a range of health variables, including vascular risk factors, were taken into account. CONCLUSION Gender differences in WMH-cognition associations are discussed, and we conclude that small vessel disease is present in midlife and has functional consequences which are generally not recognized. Preventative strategies should, therefore, begin early in life.David Bunce's collaboration in this work was supported by the Leverhulme Trust and the British Academy. The study was funded by NHMRC of Australia Unit Grant No. 973302, Program Grant No. 179805, NHMRC project grant No. 157125, grants from the Australian Rotary Health Research Fund and the Australian Brewers Foundation. Nicolas Cherbuin is funded by NHMRC Research Fellowship No. 471501. Kaarin Anstey is funded by NHMRC Research Fellowship No. 366756. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Classification and characterization of periventricular and deep white matter hyperintensities on MRI: A study in older adults.

White matter hyperintensities (WMH) are frequently divided into periventricular (PWMH) and deep (DWMH), and the two classes have been associated with different cognitive, microstructural, and clinical correlates. However, although this distinction is widely used in visual ratings scales, how to best anatomically define the two classes is still disputed. In fact, the methods used to define PWMH and DWMH vary significantly between studies, making results difficult to compare. The purpose of this study was twofold: first, to compare four current criteria used to define PWMH and DWMH in a cohort of healthy older adults (mean age: 69.58 ± 5.33 years) by quantifying possible differences in terms of estimated volumes; second, to explore associations between the two WMH sub-classes with cognition, tissue microstructure and cardiovascular risk factors, analysing the impact of different criteria on the specific associations. Our results suggest that the classification criterion used for the definition of PWMH and DWMH should not be considered a major obstacle for the comparison of different studies. We observed that higher PWMH load is associated with reduced cognitive function, higher mean arterial pressure and age. Higher DWMH load is associated with higher body mass index. PWMH have lower fractional anisotropy than DWMH, which also have more heterogeneous microstructure. These findings support the hypothesis that PWMH and DWMH are different entities and that their distinction can provide useful information about healthy and pathological aging processes

Cognitive Deficits Are Associated with Frontal and Temporal Lobe White Matter Lesions in Middle-Aged Adults Living in the Community

Background: The association between brain white matter lesions and cognitive impairment in old age is well established. However, little is known about this association in midlife. As this information will inform policy for early preventative healthcare initiatives, we investigated non-periventricular frontal, temporal, parietal and occipital lobe white matter hyperintensities (WMH) in relation to cognitive function in 428 (232 women) community-dwelling adults aged 44 to 48 years. Results: Frontal white matter lesions were significantly associated with greater intraindividual RT variability in women, while temporal WMH were associated with face recognition deficits in men. Parietal and occipital lobe lesions were unrelated to cognitive performance. These findings did not differ when education and a range of health variables, including vascular risk factors, were taken into account. Conclusion: Gender differences in WMH-cognition associations are discussed, and we conclude that small vessel disease is present in midlife and has functional consequences which are generally not recognized. Preventative strategies should, therefore, begin early in life

Different patterns of white matter degeneration using multiple diffusion indices and volumetric data in mild cognitive impairment and Alzheimer patients

Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia

Associations between reaction time measures and white matter hyperintensities in very old age.

In old age, a relationship has been reported between intraindividual variability (IIV) in reaction time and white matter integrity as evidenced by white matter hyperintensities (WMH). However, it is unclear how far such associations are due to incipient neurodegenerative pathology in the samples investigated. The present study examined the relationship between IIV and WMH in older individuals (N=526) drawn from the Sydney Memory and Ageing Study. Using a complex reaction time (RT) task, greater IIV and mean-RT were related to a higher WMH burden in the frontal lobe. Critically, significant associations remained having taken future dementia into account suggesting that they were not explained by incipient dementia. Additionally, independent measures of executive function accounted for the association between RT metrics and WHM. The results are consistent with the view that frontally-supported cognitive processes are involved in IIV-WMH relations, and that RT measures are sensitive to compromise in white matter structures in non-demented older individuals

Cardiovascular health and brain aging : a population-based MRI study

Deterioration of brain structure and cognitive function occurs as individuals reach advanced age. The former can be observed through various markers of cerebral small vessel disease on magnetic resonance imaging (MRI) scans and the later can be assessed by neuropsychological tests and clinical examinations. In addition, maintaining a favorable cardiovascular health (CVH) status may contribute to delaying brain aging. Having a higher cognitive reserve (CR) capacity may contribute to preserving cognitive function even in the presence of brain damage. In this thesis, we aimed to examine the progression and interrelationships of MRI markers of structural brain aging and the association between the progression of these markers and cognitive decline. Furthermore, we aimed to investigate whether maintaining a favorable CVH status would be related to a slower deterioration of brain structure and whether having a higher CR capacity would be associated with a lower risk of cognitive deterioration and death. Data were derived from the population-based Swedish National study on Aging and Care in Kungsholmen from 2001–2004 to 2016–2019 and the MRI sub-study from 2001–2003 to 2007–2010. Study I: This six-year follow-up study showed that the progression rate of cerebral small vessel disease markers including expansion rates of white matter hyperintensities (WMHs) and lateral ventricles, incidence of lacunes, and shrinkage rate of gray matter volume, but not the progression rate of perivascular spaces (PVSs), steadily increased with aging (P < 0.05). The progression rate of regional WMHs was faster in males than in females and in people without a university degree than those with a degree (P < 0.05). In addition, a higher load of microvascular lesions (i.e., WMHs, PVSs, and lacunes) at baseline was related to faster progression of both microvascular lesions (WMHs and lacunes) and gray matter atrophy (P < 0.05). Study II: This follow-up study showed that a greater burden of WMHs at baseline was associated with a faster decline in executive function, letter fluency, perceptual speed, and global cognition over 15 years (P < 0.05), but not in episodic or semantic memory. The faster deterioration in category fluency was linked to greater periventricular WMHs at baseline only in people carrying the APOE-ε4 allele (multivariable-adjusted β-coefficients and 95% confidence interval [CI]: -0.018, -0.031– -0.004). Accelerated decline in perceptual speed over 15 years was linked to a faster increase in deep and periventricular WMHs during the first six years, and accelerated decline in executive function and global cognition was linked to a faster increase in deep WMHs during the first six years (P < 0.05). Study III: This six-year follow-up study showed that compared to the unfavorable global CVH profile, the intermediate-to-favorable profiles were associated with a slower accumulation of WMHs (multivariable-adjusted β-coefficients and 95% CI: -0.019, -0.035– -0.002 and -0.018, - 0.034– -0.001, respectively). Intermediate-to-favorable biological CVH profiles were associated with a slower WMH increase among people aged 60–72 years, but not in those aged 78 years and above. Furthermore, a higher metabolic genetic risk was linked to a faster accumulation of WMHs in people with intermediate-to-favorable global or behavioral CVH profiles, but not in those with favorable CVH profiles (P for both interactions = 0.001). Study IV: This 15-year follow-up study revealed that a higher composite CR score, which was estimated from early-life education, midlife work complexity, late-life leisure activities, and late-life social network, was associated with a reduced risk of transition from normal cognition to cognitive impairment, no dementia (CIND) (multivariable-adjusted hazards ratio and 95% CI: 0.78, 0.72–0.85) and death (0.85, 0.79–0.93) and from CIND to death (0.82, 0.73–0.91), but not from CIND to dementia neither from CIND to normal cognition (P > 0.05). The risk of transitions from normal cognition to CIND or death did not change after controlling for brain aging markers, while the risk of transition from CIND to death became not significant. Furthermore, a higher CR score was associated with a lower risk of transition from CIND to death among people aged 60–72 years (0.65, 0.54–0.77) while not among those aged 78 years and above (0.87, 0.75–1.01) (P for interaction = 0.010). Conclusions: First, the deterioration of brain structure accelerates with advancing age. Cerebral microvascular lesions are associated with accelerated brain atrophy. Second, WMHs are linked to an accelerated decline in multiple cognitive domains except memory. A faster accumulation of WMHs in deep brain regions is associated with an accelerated decline in perceptual speed and executive function. Third, having a favorable CVH profile is associated with a slower progression of structural brain aging attributable to metabolic genetic risk. Finally, having a greater CR capacity might play a crucial role in preserving cognitive health and reducing mortality rate in the prodromal phase of dementia, independent of brain aging markers. The association between higher CR capacity and lower likelihood of transition from CIND to death exists particularly among people in the early stage of older adulthood

노인에서 조절 중인 고혈압이 대뇌백질고강도신호와 인지기능에 미치는 영향

학위논문(박사) -- 서울대학교대학원 : 자연과학대학 뇌인지과학과, 2021.8. 이의지.연구배경 및 목적: 고혈압은 인지장애의 위험인자이다. 또한, 고혈압은 대뇌백질고강도신호 (WMH)의 위험인자이고 WMH는 인지장애의 위험인자이지만, WMH의 고혈압과 인지기능간의 매개효과는 아직 충분히 검증된 적이 없다. 고혈압환자에서 WMH가 인지장애를 매개한다면, WMH의 존재나 크기는 인지장애를 판단할 수 있는 중요한 지표가 될 것이다. 하지만 건강한 노인의 WMH 확률지도 (WMHPM)나 WMHPM을 활용한 인지장애에 대한 연구는 아직까지 진행된바 없다. 본 연구에서는 두 개의 가설을 검증하고자 한다. 1) 비치매 노인에서의 WMH가 조절된 고혈압이 인지기능에 미치는 영향을 조정하는가? 2) WMHPM를 사용하여 추정된 WMH 나이가 조절된 고혈압 노인의 현재의 인지장애와 미래의 인지저하를 예측할 수 있는가? 연구방법: 본 연구는 주요 정신학적 또는 신경학적 질환이 없는 890명의 지역사회 거주 60세 이상의 비치매 노인을 대상으로 진행하였다. 그 중 368명이 2년후 추적검사를 하였다. WMHPM은 300명의 주요 정신학적 또는 신경학적 질환이 없고 인지기능이 정상인 건강한 60세 이상 지역사회 거주노인으로 구성하였다. 대상자의 혈압은 좌위 자세에서 자동혈압측정기를 이용하여 세 번 측정값의 평균값을 이용하였다. 조절된 고혈압 (cHT)은 고혈압병력이 있고 측정된 수축기 혈압이 140 mm Hg 미만이면서 이완기 혈압은 90 mm Hg 미만인 자로 정의하였다. 낮은 수축기 혈압 (LSBP)는 측정된 수축기 혈압이 110 mm Hg 이하인 자로 정의하였고, 낮은 이완기 혈압 (LDBP)는 측정된 이완기 혈압이 60 mm Hg 이하인 자로 정의하였다. 인지기능은 CERAD-K 신경심리검사, 전두엽기능평가, 숫자외우기 검사를 시행하였다. CERAD-TS 점수를 계산하였다. WMH 추출은 3.0T 액체감쇠역전회복 자기공명영상을 이용하였다. 개인의 WMH 영상과 5개의 연령대의 WMHPM 사이의 최저 편차 값을 계산하여 개인의 WMH 연령을 계산하였다. WMH연령이 실제연령과 같을 시 normal WMH 나이, 높을 시 older WMH 나이, 낮을 시 younger WMH 나이로 분류하였다. WMH가 고혈압이 인지기능에 미치는 영향을 조정하는지 Baron과 Kenny 방법으로 매개효과를 검증하였다. 로지스틱회귀분석을 이용하여 고혈압과 WMH나이가 인지장애에 미치는 영향을 분석하였다. 연구결과: cHT (p < .001), LSBP (p = .018)와 상호작용 (p < .001)은 WMH용적의 커짐과 관련이 있다. WMH용적은 인지기능의 낮은 수행점수와 관련이 있었다 (모든 인지검사: p < .001). WMH는 수축기 혈압이 1 mm Hg 감소할 때 인지기능점수가 0.016 ~ 0.030 포인트 감소하는 관계에 매개하였다. Younger 혹은 normal WMH 나이에 비해 older WMH 나이 군이 모든 인지기능 검사에서 낮은 수행능력을 보였다. (모든 인지검사: p < .001; DST: p = .002 for DST). cHT (p = .002), LSBP (p = .003), LDBP (p = .013), 상호작용 (p = .010)이 older WMH와 관련이 있었다. cHT군 중 older WMH 나이인 사람들은 정상혈압을 가진 normal 혹은 younger WMH 나이인 사람들에 비해 2년후 인지기능저하가 빠르고 경도인지장애가 발병할 확률이 8배 높았다. 결론: cHT 환자에서 LSBP는 WMH 용적을 증가시킴으로써 인지기능저하와 관련이 있었다. 건강한 노인의 WMHPM을 사용하면 임상환경에서 WMH 연령을 추정하여 인지저하 위험이 있는 고혈압환자를 구별해낼 수 있다.Background and Objectives: Hypertension, even when controlled, is associated with cognitive impairment. Although hypertension is also associated with white matter hyperintensity (WMH) and WMH is associated with cognitive impairments, the mediation role of WMH in the association of hypertension with cognitive impairments has never been directly investigated. If WMH shows to mediate the cognitive impairments in participants with controlled hypertension, presence or volume of WMH may be a good biomarker of those who are at risk of cognitive impairments. However, neither the WMH probability map (WMHPM) of healthy older adults nor the predictive validity of WMH age estimated by WMHPM for cognitive impairments has been investigated. This study examined two main hypotheses; 1) Does cerebral WMH mediate the effect of controlled hypertension on cognitive function in nondemented older adults?; 2) Does WMH age estimated using the WMHPM predict current cognitive impairment and future cognitive decline in older adults with controlled hypertension? Methods: We recruited 890 community-dwelling nondemented Koreans aged 60 years or older; 505 from the participants of the Korean Longitudinal Study on Cognitive Aging and Dementia and 385 from the visitors to the Dementia Clinic of the Seoul National University Bundang Hospital. Among them, 368 participants completed 2-year follow-up assessment. We constructed WMHPM using 300 community-dwelling cognitively and physically healthy Koreans aged 60 years or older; 228 from the KLOSCAD and 72 from the Gwangju Alzheimer’s & Related Dementias Study. We defined controlled hypertension (cHT) as having history of hypertension, however, office-measured systolic blood pressure (SBP) less than 140 mm Hg and office-measured diastolic blood pressure (DBP) less than 90 mm Hg; low systolic blood pressure (LSBP) as having office-measured SBP of 110 mm Hg or below; low diastolic blood pressure (LDBP) as having office-measured DBP of 60 mm Hg or below. We measured blood pressure three times in a sitting position using an automated blood pressure monitoring device. We evaluated cognitive performance using the CERAD-K Neuropsychological Assessment Battery, Frontal Assessment Battery and Digit Span Test. We calculated Consortium to Establish a Registry for Alzheimer Disease neuropsychological battery total score (CERAD-TS). We segmented and quantified WMH from 3.0 Tesla fluid attenuated inversion recovery magnetic resonance images. We estimated WMH age using the WMHPM by calculating the lowest deviance between individual’s WMH and each of the 5 age-banded WMHPMs. We classified the participants into three WMH age group; normal WMH age group whose WMH age is equal to their chronological age, younger WMH age group whose WMH age is younger than their chronological age, and the older WMH age group whose WMH age is older than their chronological age. We analyzed the mediation role of WMH on the effect of controlled hypertension on cognitive function using Baron and Kenny method of mediation analysis. We examined the effect of controlled hypertension and WMH age on the risk of incident mild cognitive impairment (MCI) using logistic regression analysis. Results: cHT (p < .001), LSBP (p = .018), and their interaction (p < .001) were associated with WMH volume, and WMH volume was associated with negative cognitive performance (p < .001 for all cognitive performance). WMH mediated the association of LSBP on the performance of neuropsychological tests with 1 mm Hg decrease of SBP affect 0.016 to 0.030 points decrease in various cognitive tests. Compared to the younger or normal WMH age groups, the older WMH age group performed worse in all neuropsychological tests (p = .002 for DST; p < .001 for other tests). cHT (p = .002), LSBP (p = .003), LDBP (p = .013) and their interaction (p = .010) were associated with older WMH age. The cHT with the older WMH age group showed the faster cognitive decline and 8 times higher risk of incident MCI after two years than normotensive participants with the normal or younger WMH age. Conclusion: In the cHT patients, LSBP was associated with worse cognitive performance by increasing WMH volume. If we use WMHPM of healthy older adults, we can identify older adults with controlled hypertension who are at risk of cognitive decline by estimating their WMH age in clinical settings.1. Introduction 1 1.1. Study Background 1 1.2. Purpose of Research 3 2. Methods 4 2.1. Study population 4 2.1.1. Hypothesis 1. Does cerebral WMH mediate the effect of controlled hypertension on cognitive function in nondemented older adults 4 2.1.2. Hypothesis 2. Does WMH age estimated using the WMH probability map (WMHPM) predict current cognitive impairment and future cognitive decline in older adults with controlled hypertension 4 2.2. Research ethics 5 2.3. Assessments 6 2.4. Diagnoses 6 2.5. Acquisition of brain MRI 7 2.6. Processing of brain MRI 7 2.7. Segmentation of WMH. 8 2.8. Visual rating of WMH 8 2.9. Construction of WMHPM 9 2.10. Estimation of WMH age 9 2.11. Statistical analyses 10 3. Results 12 3.1. Hypothesis 1. Does cerebral WMH mediate the effect of controlled hypertension on cognitive function in nondemented older adults 12 3.2. Hypothesis 2. Does WMH age estimated using the WMH probability map (WMHPM) predict current cognitive impairment and future cognitive decline in older adults with controlled hypertension 14 4. Discussions 17 5. Conclusions 24 Bibliography 49 국문초록 57박

Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise

Corrected by: Erratum: Molecular Psychiatry (2016) 21, 1645–1645; doi:10.1038/mp.2016.57; published online 19 April 2016. Following publication of the above article, the authors noticed that the second author’s name was presented incorrectly. The author’s name should have appeared as M Fiatarone Singh. The publisher regrets the error.Physical and cognitive exercise may prevent or delay dementia in later life but the neural mechanisms underlying these therapeutic benefits are largely unknown. We examined structural and functional magnetic resonance imaging (MRI) brain changes after 6 months of progressive resistance training (PRT), computerized cognitive training (CCT) or combined intervention. A total of 100 older individuals (68 females, average age=70.1, s.d.±6.7, 55-87 years) with dementia prodrome mild cognitive impairment were recruited in the SMART (Study of Mental Activity and Resistance Training) Trial. Participants were randomly assigned into four intervention groups: PRT+CCT, PRT+SHAM CCT, CCT+SHAM PRT and double SHAM. Multimodal MRI was conducted at baseline and at 6 months of follow-up (immediately after training) to measure structural and spontaneous functional changes in the brain, with a focus on the hippocampus and posterior cingulate regions. Participants' cognitive changes were also assessed before and after training. We found that PRT but not CCT significantly improved global cognition (F(90)=4.1, P<0.05) as well as expanded gray matter in the posterior cingulate (Pcorrected <0.05), and these changes were related to each other (r=0.25, P=0.03). PRT also reversed progression of white matter hyperintensities, a biomarker of cerebrovascular disease, in several brain areas. In contrast, CCT but not PRT attenuated decline in overall memory performance (F(90)=5.7, P<0.02), mediated by enhanced functional connectivity between the hippocampus and superior frontal cortex. Our findings indicate that physical and cognitive training depend on discrete neuronal mechanisms for their therapeutic efficacy, information that may help develop targeted lifestyle-based preventative strategies.Molecular Psychiatry advance online publication, 22 March 2016; doi:10.1038/mp.2016.19.C Suo, M Fiatarone Singh, N Gates, W Wen, P Sachdev, H Brodaty, N Saigal, GC Wilson, J Meiklejohn, N Singh, BT Baune, M Baker, N Foroughi, Y Wang, Y Mavros, A Lampit, I Leung, and MJ Valenzuel

Automated measurement of brain and white matter lesion volume in type 2 diabetes mellitus

Aims/hypothesis: Type 2 diabetes mellitus has been associated with brain atrophy and cognitive decline, but the association with ischaemic white matter lesions is unclear. Previous neuroimaging studies have mainly used semiquantitative rating scales to measure atrophy and white matter lesions (WMLs). In this study we used an automated segmentation technique to investigate the association of type 2 diabetes, several diabetes-related risk factors and cognition with cerebral tissue and WML volumes. Subjects and methods: Magnetic resonance images of 99 patients with type 2 diabetes and 46 control participants from a population-based sample were segmented using a k-nearest neighbour classifier trained on ten manually segmented data sets. White matter, grey matter, lateral ventricles, cerebrospinal fluid not including lateral ventricles, and WML volumes were assessed. Analyses were adjusted for age, sex, level of education and intracranial volume. Results: Type 2 diabetes was associated with a smaller volume of grey matter (-21.8 ml; 95% CI -34.2, -9.4) and with larger lateral ventricle volume (7.1 ml; 95% CI 2.3, 12.0) and with larger white matter lesion volume (56.5%; 95% CI 4.0, 135.8), whereas white matter volume was not affected. In separate analyses for men and women, the effects of diabetes were only significant in women. Conclusions/interpretation: The combination of atrophy with larger WML volume indicates that type 2 diabetes is associated with mixed pathology in the brain. The observed sex differences were unexpected and need to be addressed in further studies. © 2007 Springer-Verlag