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Late-life depression (LLD) increases risk for dementia and brain pathology, but possibly this is only true for one or more symptom profiles of LLD. In 4354 participants (76±5 years; 58% female) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we identified five LLD symptom profiles, based on the Geriatric Depression Scale-15 (no LLD(57%); apathy(31%); apathy with emptiness(2%), mild LLD(8%) and severe LLD(2%)). Cox regression analyses showed that severe LLD, mild LLD and apathy increased risk of dementia up to 12 years, compared to no LLD. Additionally, hippocampal volume loss and white matter lesion increase, were assessed on 1.5 T MR images, at baseline and after 5 years follow-up. Only severe LLD showed increased WML volume over time, but not on hippocampal volume loss. WML increase over time mediated partially the relation between mild LLD and dementia but not for the other symptom profiles. It appears that hippocampal atrophy and LLD are independent predictors for dementia incidence, whereas for mild LLD the risk for dementia is partially mediated by WML changes.

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: –0.23 to –0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: –0.29 to –0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time ( p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF ( p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.

BACKGROUND: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear.OBJECTIVE: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis.METHODS: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia.RESULTS: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66-2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55-1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34-2.08).CONCLUSION: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia.

ObjectiveTo determine whether white matter hyperintensity (WMH) markers on MRI are associated with long-term risk of mortality and ischemic stroke.MethodsWe included consecutive patients with manifest arterial disease enrolled in the Second Manifestations of Arterial Disease–Magnetic Resonance (SMART-MR) study. We obtained WMH markers (volume, type, and shape) from brain MRI scans performed at baseline using an automated algorithm. During follow-up, occurrence of death and ischemic stroke was recorded. Using Cox regression, we investigated associations of WMH markers with risk of mortality and ischemic stroke, adjusting for demographics, cardiovascular risk factors, and cerebrovascular disease.ResultsWe included 999 patients (59 ± 10 years; 79% male) with a median follow-up of 12.5 years (range 0.2–16.0 years). A greater periventricular or confluent WMH volume was independently associated with a greater risk of vascular death (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.13–1.47) for a 1-unit increase in natural log-transformed WMH volume and ischemic stroke (HR 1.53, 95% CI 1.26–1.86). A confluent WMH type was independently associated with a greater risk of vascular (HR 1.89, 95% CI 1.15-3.11) and nonvascular death (HR 1.65, 95% CI 1.01–2.73) and ischemic stroke (HR 2.83, 95% CI 1.36-5.87). A more irregular shape of periventricular or confluent WMH, as expressed by an increase in concavity index, was independently associated with a greater risk of vascular (HR 1.20, 95% CI 1.05–1.38 per SD increase) and nonvascular death (HR 1.21, 95% CI 1.03–1.42) and ischemic stroke (HR 1.28, 95% CI 1.05–1.55).ConclusionsWMH volume, type, and shape are associated with long-term risk of mortality and ischemic stroke in patients with manifest arterial disease.

We determined the occurrence and association of cortical cerebral microinfarcts (CMIs) at 7 T MRI with risk factors, neuroimaging markers of small and large vessel disease, and cognitive functioning. Within the Medea-7T study, a diverse cohort of older persons with normal cognition, patients with vascular disease, and memory clinic patients, we included 386 participants (68 ± 9 years) with available 7 T and 1.5 T/3T brain MRI, and risk factor and neuropsychological data. CMIs were found in 10% of participants and were associated with older age (RR = 1.79 per +10 years, 95%CI 1.28–2.50), history of stroke or TIA (RR = 4.03, 95%CI 2.18–7.43), cortical infarcts (RR = 5.28, 95%CI 2.91–9.55), lacunes (RR = 5.66, 95%CI 2.85–11.27), cerebellar infarcts (RR = 2.73, 95%CI 1.27–5.84) and decreased cerebral blood flow (RR = 1.35 per −100 ml/min, 95%CI 1.00–1.83), after adjustment for age and sex. Furthermore, participants with >2 CMIs had 0.5 SD (95%CI 0.05–0.91) lower global cognitive performance, compared to participants without CMIs. Our results indicate that CMIs on 7 T MRI are observed in vascular and memory clinic patients with similar frequency, and are associated with older age, history of stroke or TIA, other brain infarcts, and poorer global cognitive functioning.

Neurodegenerative and neurovascular diseases lead to heterogeneous brain abnormalities. A combined analysis of these abnormalities by phenotypes of the brain might give a more accurate representation of the underlying aetiology. We aimed to identify different MRI phenotypes of the brain and assessed the risk of future stroke and mortality within these subgroups. In 1003 patients (59 ± 10 years) from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, different quantitative 1.5T brain MRI markers were used in a hierarchical clustering analysis to identify 11 distinct subgroups with a different distribution in brain MRI markers and cardiovascular risk factors, and a different risk of stroke (Cox regression: from no increased risk compared to the reference group with relatively few brain abnormalities to HR = 10.34; 95% CI 3.80↔28.12 for the multi-burden subgroup) and mortality (from no increased risk compared to the reference group to HR = 4.00; 95% CI 2.50↔6.40 for the multi-burden subgroup). In conclusion, within a group of patients with manifest arterial disease, we showed that different MRI phenotypes of the brain can be identified and that these were associated with different risks of future stroke and mortality. These MRI phenotypes can possibly classify individual patients and assess their risk of future stroke and mortality.

Lacunes and white matter hyperintensities (WMHs) are features of cerebral small vessel disease (CSVD) that are associated with poor functional outcomes. However, how the two are related remains unclear. In this study, we examined the association between lacunes and several WMH features in patients with a history of vascular disease. A total of 999 patients (mean age 59 ± 10 years) with a 1.5 T brain magnetic resonance imaging (MRI) scan were included from the SMART-MR study. Lacunes were scored visually and WMH features (volume, subtype and shape) were automatically determined. Analyses consisted of linear and Poisson regression adjusted for age, sex, and total intracranial volume (ICV). Patients with lacunes (n = 188; 19%) had greater total (B = 1.03, 95% CI: 0.86 to 1.21), periventricular/confluent (B = 1.08, 95% CI: 0.89 to 1.27), and deep (B = 0.71, 95% CI: 0.44 to 0.97) natural log-transformed WMH volumes than patients without lacunes. Patients with lacunes had an increased risk of confluent type WMHs (RR = 2.41, 95% CI: 1.98 to 2.92) and deep WMHs (RR = 1.41, 95% CI: 1.22 to 1.62) and had a more irregular shape of confluent WMHs than patients without lacunes, independent of total WMH volume. In conclusion, we found that lacunes on MRI were associated with WMH features that correspond to more severe small vessel changes, mortality, and poor functional outcomes.

Background and Purpose— Cerebral small-vessel disease and cerebral blood flow (CBF) are interrelated. However, the direction of the relationship is unknown, and longitudinal studies are scarce. We investigated the longitudinal relationship between CBF and white matter hyperintensities (WMHs) and lacunes, as representatives of cerebral small-vessel disease, in patients with manifest arterial disease. Methods— Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, 1.5T brain magnetic resonance imaging, including an MR angiography, was obtained at baseline and after on ≈3.9 years of follow-up in 575 patients with manifest arterial disease (mean age, 57±10 years). Longitudinal associations of WMHs and lacunes with parenchymal CBF (pCBF; per 100-mL brain volume) were estimated using regression analyses, adjusted for age, sex, follow-up time, and baseline brain measures. Results— Baseline pCBF was not associated with progression of WMHs and lacunes over time. However, periventricular and deep WMHs at baseline were associated with decline in pCBF; mean (95% confidence interval) decline in pCBF per % intracranial volume increase in periventricular and deep WMH volume was −0.70 (−1.40 to −0.00) and −1.01 (−1.64 to −0.38) mL/min per 100-mL brain volume, respectively. These associations were partly explained by cardiovascular risk factors but remained significant for deep WMHs (mean decline [95% confidence interval] in pCBF per % intracranial volume increase in deep WMH volume was −0.92 [−1.56 to −0.28] mL/min per 100-mL brain volume). Lacunes were not associated with change in pCBF. Conclusions— In patients with manifest arterial disease, baseline periventricular and deep WMH volumes were associated with decline in pCBF over time, but baseline pCBF was not associated with progression of WMHs and lacunes over time.

Objective: To estimate the association between hippocampal and total brain volume and the course of depressive symptoms over eight years of follow-up in patients with a history of vascular disease. Method: Within the SMART-Medea study, 636 participants (62 ± 10 years) had a 1.5-tesla brain MRI obtaining hippocampal and total brain volumes. Depressive symptoms were assessed with the Patient Health Questionnaire-9 biannually during eight-year follow-up. Generalized estimating equation models with robust standard errors were used to assess the associations of hippocampal and total brain volumes with depressive symptoms during follow-up adjusting for age, sex, education, and intracranial volume. An interaction term between volume and time (6-month intervals) was included to examine whether the course of depressive symptoms differed according to hippocampal and total brain volume. Results: The mean PHQ-9 score was 2.8 ± 3.5. Smaller hippocampal volumes were associated with an increasing course of depressive symptom levels, while larger volumes were associated with decreasing levels (P-value interaction = 0.07). Smaller total brain volume was associated with consistently higher levels of depressive symptoms, but not with change in course of depressive symptoms (P-value interaction = 0.45). Conclusion: Smaller hippocampal volume but not total brain volume is associated with poorer course of depressive symptoms over eight years of follow-up.

Objective: To examine the cross-sectional and prospective associations between arterial stiffness and structural brain changes within the Second Manifestations of Arterial Disease–Magnetic Resonance (SMART-MR) study, a prospective cohort study among patients with manifest arterial disease. Methods: Distension measurements of the common carotid arteries and a brain MRI were performed in 526 patients (mean age 59 ± 10 years). After a mean follow-up of 4.1 years (range 3.6–5.8), brain MRI was repeated in 308 patients. Brain segmentation was used to quantify total brain volume, cortical gray matter volume, ventricular volume, and white matter lesion (WML) volume (relative to intracranial volume). Infarcts were rated visually. Results: Cross-sectional multivariable regression analyses showed that 1 SD decrease in carotid distension, indicating increased arterial stiffness, was associated with smaller relative total brain and cortical gray matter volumes (B = −0.24%, 95% confidence interval [CI] −0.44 to −0.04%, and B = −0.47%, 95% CI −0.75 to −0.19%), with larger WML volume (B = 0.09%, 95% CI −0.01 to 0.19%), and with higher risk of having nonlacunar (cortical or large subcortical) brain infarcts (relative risk = 1.44, 95% CI 1.14 to 1.81). However, our prospective findings showed that carotid distension was not significantly associated with progression of brain atrophy, WML volume, or brain infarcts. Conclusion: In this population of patients with manifest arterial disease, stiffening of the carotid arteries was cross-sectionally associated with more brain atrophy, WML volume, and nonlacunar infarcts, but did not lead to changes in brain volumes or infarcts after 4 years.

Aims It has been suggested that in patients with type 2 diabetes mellitus (T2DM), brain atrophy is most pronounced in the hippocampus, but this has not been investigated systematically. The present pooled analysis of three studies examined if hippocampal atrophy is more prominent than global brain atrophy in patients with T2DM relative to controls. Methods Data were derived from a cohort study of patients with vascular disease (SMART-Medea (T2DM = 120; no T2DM = 502)), and from two case–control studies (UDES1 (T2DM = 61; controls = 30) and UDES2 (T2DM = 54; controls = 53)). In SMART-Medea and UDES1, hippocampal volume was obtained by manual tracing on 1.5 Tesla (T) MRI scans. Total brain and intracranial volume (ICV) were determined by an automated segmentation method. In UDES2, hippocampal and total brain volume were determined by FreeSurfer and ICV by manual segmentation on 3 T MRI scans. Results The pooled analyses, adjusted for age and sex, showed a significant negative relation between T2DM and total brain-to-ICV ratio (standardized mean difference = − 1.24%, 95% CI: − 1.63; − 0.86), but not between T2DM and hippocampal-to-ICV ratio (0.00%, 95% CI: − 0.01; 0.00) or between T2DM and hippocampal-to-total brain volume ratio (0.01%, 95% CI: − 0.01; 0.02). In patients with T2DM no associations were found between brain volume measures and HbA1c or memory. Conclusion Patients with T2DM had greater brain atrophy but not hippocampal atrophy, compared to controls. These findings do not support specific vulnerability of the hippocampus in patients with T2DM.