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1.  Carotid Artery Atherosclerosis, MRI Indices of Brain Ischemia and Aging and Cognitive Impairment: The Framingham Study 
Background and Purpose
Carotid atherosclerosis has been associated with increased risk of stroke, and poorer cognitive performance in older adults. The relation of carotid atherosclerosis to cognitive impairment and MRI indices of ischemia and aging in midlife is less clear.
Methods
We studied 1,975 Framingham Offspring Study participants free of stroke and dementia with available carotid ultrasound, brain MRI and neuropsychological testing. We related common and internal carotid artery intima-media thickness (ICA-IMT and CCA-IMT respectively) and internal carotid stenosis (CAS) to large white matter hyperintensity (>1-SD above age-specific mean; LWMH), total brain volume (TCBV), hippocampal volume, silent cerebral infarcts (SCI) and neuropsychological measures of verbal memory, executive function and non-verbal memory measures.
Results
We observed that ICA-IMT, but not CCA-IMT, was associated with higher prevalence of SCI (OR 1.21, 95% CI 1.03–1.43, p<0.05), LWMH (OR 1.19, 95% CI 1.03–1.38, p<0.05), lower TCBV (−0.05 per SD, p<0.05) and poorer performance in verbal memory (−0.06 per SD; p<0.05) and non-verbal memory measures (−0.08 per SD; p<0.01), but not with hippocampal volume. CAS ≥25% was associated with a higher prevalence of LWMH (adjusted OR 1.77, 95% CI 1.25–2.53) and lower TCBV (−0.11 per SD, p=0.042) but not with SCI or hippocampal volume. CAS ≥50% was associated with higher prevalence of SCI (OR 2.53, 95% CI 1.17 – 5.44), LWMH (OR 2.35, 95% CI 1.08–5.13) and poorer performance on executive function (−0.39 per SD; p<0.05) but not with TCBV or hippocampal volume.
Conclusions
Carotid atherosclerosis markers were associated with MRI indices of brain ischemia and aging and with cognitive impairment in a community-based sample of middle-aged adults. Our data suggest that ICA-IMT may be a better marker for cognitive impairment than CCA-IMT.
doi:10.1161/STROKEAHA.108.535245
PMCID: PMC2705324  PMID: 19265054
Carotid atherosclerosis; brain MRI; cognitive performance
2.  Association of Carotid Artery Atherosclerosis with Circulating Biomarkers of Extracellular Matrix Remodeling: The Framingham Offspring Study 
Objective
To relate circulating biomarkers of extracellular matrix (ECM) turnover to site-specific measures of carotid artery atherosclerosis on duplex ultrasound.
Background
Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) regulate ECM remodeling, a key feature of atherosclerosis, and their circulating concentrations can be assayed. MMP-9, TIMP-1 and protocollagen-III n-terminal propeptide (PIIINP) may relate differentially to the severity of atherosclerosis at different carotid artery sites. However, data examining this premise are sparse.
Design/Methods
We related circulating MMP-9, TIMP-1 and/or PIIINP concentrations to carotid atherosclerosis on duplex ultrasound in1006 Framingham Offspring (mean age 58 years, 56% women) who attended a routine examination from 1995–1998. We used multivariable regression to relate MMP-9 (detectable versus undetectable), and TIMP-1 and PIIINP (age- and sex-specific quartiles) to internal carotid artery stenosis (>25%), and log-transformed common and internal carotid intima-media thickness (CC-IMT, IC-IMT, respectively).
Results
Detectable MMP-9 was associated with carotid stenosis (OR 1.71, p=0.032) but not with IMT. Higher TIMP-1 was associated with carotid stenosis (OR for Q4 versus Q1-3, 1.63, p=0.022) and a higher IC-IMT (β 0.057 ±0.025, Q4 versus Q1-3, p=0.023). Higher PIIINP (Q4 versus Q1-3) showed a borderline association with carotid stenosis (OR 1.45 for Q4 versus Q1-3, p=0.095) but not with IMT. TIMP-1 was not associated with CC-IMT.
Conclusions
In our community-based sample of middle-aged to older adults, higher circulating biomarkers of matrix remodeling were associated with a greater prevalence of carotid stenosis, and subclinical atherosclerosis in the IC artery. Our findings are consistent with regional differences in matrix remodeling in the carotid artery.
doi:10.1016/j.jstrokecerebrovasdis.2008.06.002
PMCID: PMC2613480  PMID: 18984437
Carotid artery; atherosclerosis; matrix proteins; intima media thickness; stenosis
3.  Prevalence and Correlates of Silent Cerebral Infarcts in the Framingham Offspring Study 
Background and Purpose
Prior estimates of the prevalence of silent cerebral infarction (SCI) on magnetic resonance imaging (MRI) in community-based samples have varied between 5.8 and 17.7% depending on age, ethnicity, presence of co-morbidities and imaging techniques. We document the prevalence and risk factors associated with SCI at midlife in the community-based Framingham sample.
Methods
2040 Framingham Offspring (53% F; mean age 62±9 yrs) who attended the 6th examination (1996–98), underwent volumetric brain MRI (1999–2005) and were free of clinical stroke at MRI, constituted our study sample. We examined the age- and sex-specific prevalence and the clinical correlates of SCI using multivariable logistic regression models.
Results
At least one SCI was present in 10.7% of participants. 84% had a single lesion. SCI were largely located in the basal ganglia (52%), other subcortical (35%) and cortical areas (11%). Prevalent SCI was associated with the Framingham Stroke Risk Profile score (OR: 1.27; 95% CI: 1.10 – 1.46); Stage I hypertension by JNC-VII criteria (OR:1.56; CI:1.15 – 2.11)), an elevated plasma homocysteine in the highest quartile (OR: 2.23; CI: 1.42 – 3.51), atrial fibrillation (OR: 2.16; CI: 1.07 – 4.40), carotid stenosis >25% (OR: 1.62; 1.13 – 2.34)) and increased carotid intimal-medial thickness above the lowest quintile (OR: 1.65; CI: 1.22 – 2.24).
Conclusion
The prevalence and distribution of SCI in the Framingham Offspring.is comparable to prior estimates. Risk factors previously associated with clinical stroke were also found to be associated with midlife SCI. Our results support current guidelines emphasizing early detection and treatment of stroke risk factors.
doi:10.1161/STROKEAHA.108.516575
PMCID: PMC2712254  PMID: 18583555
cerebral infarction; magnetic resonance imaging; risk factors; prevalence; hypertension

Results 1-3 (3)