[Show abstract][Hide abstract] ABSTRACT: The evidence on the clinical significance of cerebral white matter changes (WMC) has mounted over the past few decades. WMC are recognized as one of the neuroimaging features of cerebral small vessel disease, and are associated with various disturbances and a poor prognosis. The Leukoaraiosis and Disability (LADIS) Study has contributed substantially to this body of knowledge. LADIS is a European multicenter collaboration aimed at assessing the role of WMC as an independent predictor of the transition to disability in initially non-disabled patients aged 65-84 years. Besides the demonstration that severe WMC cause a more than double risk of transition from an autonomous to a dependent status after 3 years of follow-up, the LADIS Study has also provided evidence on the role of WMC in relation to the decline of cognitive and motor performances, depressive symptoms associated with aging and cerebrovascular diseases, the presence of urinary disturbances, and various neurological abnormalities. The possible role of other lesions (lacunar infarcts, cerebral atrophy, corpus callosum morphology) and microstructural abnormalities (diffusion-weighted imaging changes in normal appearing brain tissue and in WMC) has also been investigated. In the present article, we review the main results of the LADIS Study and offer some considerations for future developments in the field, paying attention to the potential use of WMC progression as a surrogate marker in intervention trials in cerebral small vessel diseases. We also discuss some therapeutic perspectives regarding the beneficial impact of physical activity on the risk of vascular cognitive impairment in patients with WMC. Geriatr Gerontol Int 2015; 15 (Suppl. 1): 10-16.
Preview · Article · Dec 2015 · Geriatrics & Gerontology International
[Show abstract][Hide abstract] ABSTRACT: White matter lesions (WML) are the main brain imaging surrogate of cerebral small-vessel disease. A new MRI tissue segmentation method, based on a discriminative clustering approach without explicit model-based added prior, detects partial WML volumes, likely representing very early-stage changes in normal-appearing brain tissue. This study investigated how the different stages of WML, from a “pre-visible” stage to fully developed lesions, predict future cognitive decline. MRI scans of 78 subjects, aged 65–84 years, from the Leukoaraiosis and Disability (LADIS) study were analyzed using a self-supervised multispectral segmentation algorithm to identify tissue types and partial WML volumes. Each lesion voxel was classified as having a small (33%), intermediate (66%), or high (100%) proportion of lesion tissue. The subjects were evaluated with detailed clinical and neuropsychological assessments at baseline and at three annual follow-up visits. We found that voxels with small partial WML predicted lower executive function compound scores at baseline, and steeper decline of executive scores in follow-up, independently of the demographics and the conventionally estimated hyperintensity volume on fluid-attenuated inversion recovery images. The intermediate and fully developed lesions were related to impairments in multiple cognitive domains including executive functions, processing speed, memory, and global cognitive function. In conclusion, early-stage partial WML, still too faint to be clearly detectable on conventional MRI, already predict executive dysfunction and progressive cognitive decline regardless of the conventionally evaluated WML load. These findings advance early recognition of small vessel disease and incipient vascular cognitive impairment.
Full-text · Article · Dec 2015 · Frontiers in Neuroscience
[Show abstract][Hide abstract] ABSTRACT: The term cerebral small vessel disease (SVD) refers to a group of pathologic processes with various etiologies that affect small arteries, arterioles, venules, and capillaries of the brain. Magnetic resonance imaging (MRI) correlates of SVD are lacunes, recent small subcortical infarcts, white-matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy. Endothelial dysfunction is thought to have a role in the mechanisms leading to SVD-related brain changes, and the study of endothelial dysfunction has been proposed as an important step for a better comprehension of cerebral SVD. Among available methods to assess endothelial function in vivo, measurement of molecules of endothelial origin in peripheral blood is currently receiving selective attention. These molecules include products of endothelial cells that change when the endothelium is activated, as well as molecules that reflect endothelial damage and repair. This review examines the main molecular factors involved in both endothelial function and dysfunction, and the evidence linking endothelial dysfunction with cerebral SVD, and gives an overview of clinical studies that have investigated the possible association between endothelial circulating biomarkers and SVD-related brain changes.Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 June 2015; doi:10.1038/jcbfm.2015.116.
No preview · Article · Jun 2015 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Apolipoprotein E (APOE) increases the risk for Alzheimer's disease (ɛ4 allele) and cerebral amyloid angiopathy (ɛ2 and ɛ4), but its role in small vessel disease (SVD) is debated. Here we studied the effects of APOE on white matter hyperintensity volume (WMHV) in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a nonamyloidogenic angiopathy and inherited early-onset form of pure SVD. Four hundred and eighty-eight subjects were recruited through a multicenter consortium. Compared with APOE ɛ3/ɛ3, WMHV was increased in APOE ɛ2 (P=0.02) but not APOE ɛ4. The results remained significant when controlled for genome-wide genetic background variation. Our findings suggest a modifying influence of APOE ɛ2 on WMHV caused by pure SVD.Journal of Cerebral Blood Flow & Metabolism advance online publication, 29 April 2015; doi:10.1038/jcbfm.2015.85.
No preview · Article · Apr 2015 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
A number of studies have suggested associations between dementia and depression in older adults. One reason could be that these disorders share structural correlates, such as white matter lesions (WMLs) and cortical atrophy. No study has examined whether these lesions precede both dementia and depression independently of each other in the general population.
Whether WMLs and cortical atrophy on computed tomography predict dementia and depression was investigated in a population-based sample of 70-year-olds (n = 380) followed over 10 years. Exclusion criteria were dementia, major depression, history of stroke and a Mini-Mental State Examination score below 26 at baseline in 2000-2001. Dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised, and depression according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Primary outcomes included dementia and major depression at 10-year follow-up.
Adjusted logistic regression models, including both WMLs and temporal lobe atrophy, showed that moderate to severe WMLs [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.23-12.76] and temporal lobe atrophy (OR 2.93, 95% CI 1.13-7.60) predicted dementia during a 10-year follow-up independently of major depression. Similarly, both moderate to severe WMLs (OR 3.84, 95% CI 1.25-11.76) and temporal lobe atrophy (OR 2.52, 95% CI 1.06-5.96) predicted depression even after controlling for incident dementia.
White matter lesions and temporal lobe atrophy preceded 10-year incidence of both dementia and depression in 70-year-olds. Shared structural correlates could explain the reported associations between dementia and depression. These brain changes may represent independent and complementary pathways to dementia and depression. Strategies to slow progression of vascular pathology and neurodegeneration could indirectly prevent both dementia and depression in older adults.
No preview · Article · Jan 2015 · European Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence suggests vascular risk factors (VRF) play a role in the pathogenesis of Alzheimer’s disease (AD). Epidemiological studies have found associations between VRF and risk of AD. Treating VRF in patients with AD offers a potential treatment option but ineffective treatments should be avoided in this group who are frequently on multiple medications and in whom compliance may be challenging.
Studies containing information on the treatment of VRF in patients with a diagnosis of AD were identified using a defined search strategy. Randomised controlled trials and observational studies were included.
The pre-specified search strategy retrieved 11,992 abstract articles, and 25 papers including those identified on review of reference lists and reviews met the inclusion criteria. Of these, 11 were randomised controlled trials (RCTs) and 14 observational studies. Observational studies suggested that a VRF package and treatment of hypertension and statin therapy may be associated with improved outcome but these studies suffered from potential bias. The few RCTs performed were mostly small with short duration follow-up, and do not provide clear evidence either way.
Observational data raises the possibility that treating VRF could alter the rate of decline in AD. However RCT data are not yet available to support this hypothesis and to alter clinical practice. RCTs in larger numbers of individuals with longer follow-up, ideally in the early stages of AD, are required to address this potentially important treatment question.
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Montreal Cognitive Assessment (MoCA) has been proposed as a screening tool in vascular cognitive impairment. Diffusion tensor imaging is sensitive to white matter microstructural damage. We investigated if diffusion tensor imaging-derived indices are more strongly associated with performances on MoCA or on the widely used mini mental state examination in patients with mild cognitive impairment and small vessel disease.
Mild cognitive impairment patients with moderate/severe degrees of white matter hyperintensities on MRI were enrolled. Lacunar infarcts, cortical atrophy, medial temporal lobe atrophy and median values of mean diffusivity and fractional anisotropy of the cerebral white matter were studied and correlated with cognitive tests performances.
Seventy-six patients (mean age 75.1±6.8 years, mean years of education 8.0±4.3) were assessed. In univariate analyses, a significant association of both MoCA and mini mental state examination scores with age, education, cortical atrophy, and medial temporal lobe atrophy was found, whereas mean diffusivity and fractional anisotropy were associated with MoCA. In partial correlation analyses, adjusting for all demographic and neuroimaging variables, both mean diffusivity and fractional anisotropy were associated only with MoCA (mean diffusivity: r= -0.275, P=0.023; fractional anisotropy: r=0.246, P=0.043).
In patients with mild cognitive impairment and small vessel disease, diffusion tensor imaging-measured white matter microstructural damage is more related to MoCA than mini mental state examination performances. MoCA is suited for the cognitive screening of patients with small vessel disease.
[Show abstract][Hide abstract] ABSTRACT: Mild cognitive impairment (MCI) is an abnormal condition defined by the presence of cognitive decline not severe enough to fit dementia criteria. According to Winblad et al.'s criteria, the clinical distinction of MCI subtypes (amnestic/non-amnestic, single/multiple domain) is based on the cognitive profiling (conventional diagnosis) and infers possible different MCI etiologies. MCI prodromic of vascular dementia (Vasc-MCI) is thought to be characterized by a multiple domain profile. In our outpatient clinic (the "Florence VAS-COG clinic"), the diagnosis of MCI and of its different subtypes (vascular, degenerative, mixed) is based on a comprehensive evaluation of clinical and neuroimaging features (pragmatic diagnosis).
No preview · Article · Nov 2014 · Aging - Clinical and Experimental Research
[Show abstract][Hide abstract] ABSTRACT: The objective of the study is to detail clinical and NOTCH3 gene mutational spectrum in a large group of Italian CADASIL patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial cerebral small vessels disease caused by mutations in the NOTCH3 gene on 19p13 usually presenting in young or middle adulthood. Characteristic features include migraine, recurrent lacunar stroke, subcortical dementia, mood disturbances and leukoencephalopathy. The disorder is often overlooked and misdiagnosed. CADASIL prevalence and disease burden is still undetermined. We retrospectively reviewed demographic, clinical, and mutational characteristic of all CADASIL patients diagnosed from January 2002 to December 2012 in three referral centers for neurogenetic and cerebrovascular diseases in central Italy. 229 NOTCH3 positive subjects were identified. Mean age at diagnosis was 57.8 ± 14.7 years, and 48.6 ± 17.1 years at first symptom onset. Most frequent clinical symptoms were ischemic events (59 %) and psychiatric disturbances (48 %). The highest percentage of mutations were found on exons 4 and 19 (20.6 and 17.6 % respectively), the remaining being dispersed over the entire EGF-like region of the NOTCH3 gene. 209 patients resided in a circumscribed geographic area which included three regions of the central Italy, yielding a minimum prevalence of 4.1 per 100.000 adult inhabitants. This is the most extensive study on CADASIL in Italy. Clinical phenotype showed several peculiarities in frequency and presentation of the main disease manifestations. Our study enlarges the number of pathogenic NOTCH3 mutations and due to the heterogeneous mutational spectrum observed suggests that full sequencing of exons 2-24 is mandatory for CADASIL screening in the Italian population.
No preview · Article · Oct 2014 · Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Small vessel disease (SVD) represents a common often progressive condition in elderly people contributing to cognitive disability. The relationship between cerebrospinal fluid (CSF) biomarkers and imaging correlates of SVD was investigated, and the findings were hypothesized to be associated with a neuropsychological profile of SVD.
CSF SVD-related biomarkers [neurofilament light (NF-L), myelin basic protein (MBP), soluble amyloid precursor protein-β (sAPPβ), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinase (TIMP)] were analysed in 46 non-demented elderly with imaging findings of SVD. We assessed the relationship between the CSF biomarkers and white matter hyperintensity (WMH) volume, diffusion-weighted imaging and atrophy as well as their association with neuropsychological profiles.
The WMH volume correlated with ventricular dilation, which was associated with executive function and speed and attention. Increased WMH and ventricular dilation were related to increased CSF levels of TIMP-1, NF-L and MBP and to decreased sAPPβ. A positive correlation was found between the CSF biomarker MMP-9 and WMH progression.
The link between progressive WMH and MMP-9 suggests an involvement of the enzyme in white matter degeneration. CSF TIMP-1, NF-L, MBP and sAPPβ may function as biological markers of white matter damage.
[Show abstract][Hide abstract] ABSTRACT: Objectives
Physical activity reduces the risk of cognitive decline but may affect cognitive domains differently. We examined whether physical activity modifies processing speed, executive function and memory in a population of non-dementia elderly subjects with age-related white matter changes (ARWMC).Methods
Data from the Leukoaraiosis And DISability (LADIS) study, a multicenter, European prospective cohort study aimed at examining the role of ARWMC in transition to disability, was used. Subjects in the LADIS study were clinically assessed yearly for 3 years including MRI at baseline and 3-year follow-up. Physical activity was assessed at baseline, and cognitive compound scores at baseline and 3-year assessment were used.ResultsTwo-hundred-eighty-two subjects (age, y (mean (SD)): 73.1 (±5.1); gender (f/m): 164/118); MMSE (mean (SD)): 28.3 (±1.7)) who had not progressed to MCI or dementia, were included. Multiple variable linear regression analysis with baseline MMSE, education, gender, age, stroke, diabetes and ARWMC rating as covariates revealed that physical activity was associated with better scores at baseline and 3-year follow-up for executive function (baseline: β: 0.39, 95% CI: 0.13-0.90, p = 0.008; follow-up: β: 0.24, 95% CI: 0.10-0.38, p = 0.001) and processing speed (baseline: β: 0.48, 95% CI: 0.14-0.89, p = 0.005; follow-up: β: 0.15, 95% CI: 0.02-0.29, p = 0.02) but not memory. When including baseline cognitive score as a covariate in the analysis of 3-year follow-up scores, executive function remained significant (β: 0.11, 95% CI: 0-0.22, p = 0.04).Conclusion
Our findings confirm previous findings of a positive effect of physical activity on cognitive functions in elderly subjects, and further extends these by showing that the association is also present in patients with ARWMC.
No preview · Article · Oct 2014 · International Journal of Geriatric Psychiatry