Nicola Moscufo

Cognitive profile and brain morphological changes in obstructive sleep apnea

Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short- and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory-Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences.

Functional interaction of a novel cellular protein with the papillomavirus E2 transactivation domain.

The transactivation domain (AD) of bovine papillomavirus type 1 E2 stimulates gene expression and DNA replication. To identify cellular proteins that interact with this 215-amino-acid domain, we used a transactivation-defective mutant as bait in the yeast two-hybrid screen. In vitro and in vivo results demonstrate that the cDNA of one plasmid isolated in this screen encodes a 37-kDa nuclear protein that specifically binds to an 82-amino-acid segment within the E2 AD. Mutants with point mutations within this E2 domain were isolated based on their inability to interact with AMF-1 and were found to be unable to stimulate transcription. These mutants also exhibited defects in viral DNA replication yet retained binding to the viral E1 replication initiator protein. Overexpression of AMF-1 stimulated transactivation by both wild-type E2 and a LexA fusion to the E2 AD, indicating that AMF-1 is a positive effector of the AD of E2. We conclude that interaction with AMF-1 is necessary for the transcriptional activation function of the E2 AD in mammalian cells.

Average Daily Blood Pressure, Not Office Blood Pressure, Is Associated With Progression of Cerebrovascular Disease and Cognitive Decline in Older People

Background— High blood pressure (BP) is a risk factor for cerebrovascular disease, including stroke. Little is known about the importance of BP on the progression of microvascular disease of the brain, which has been associated with functional decline in mobility and cognition in older people. Methods and Results— This was a prospective cohort of subjects 75 to 89 years of age to determine relations among vascular risk factors, white matter hyperintensity volume, and functional status. Ninety-nine subjects were enrolled through the use of a balanced 3×3 matrix stratified by age and mobility performance, and 72 subjects completed all sets of baseline and follow-up studies at 2 years. Subjects were excluded if there were medications or systemic or neurological diseases that could compromise mobility. Ambulatory and clinic BP monitoring, magnetic resonance imaging, gait studies, and neuropsychological testing were performed at baseline and after 24 months. Brain classification into normal white matter and T2-hyperintense white matter hyperintensity volume was performed with semiautomated segmentation. Quantitative measures of mobility and cognitive function were obtained longitudinally. Increased ambulatory systolic BP, but not clinic systolic BP, from baseline to 24 month follow-up was associated with increased white matter hyperintensity volume over that same period, as well as measures of executive function/processing speed. Similar associations were observed for 24-hour BP, awake BP, and sleep BP but not for the surge between the sleep and awake time at the 24-month time point. Conclusions— These data demonstrate for the first time the importance of 24-hour systolic BP in the progression of brain white matter hyperintensity volume burden associated with impairment of cognitive function in older people. The 24-hour systolic BP may be a potential target for intervention in the elderly to reduce vascular disease of the brain and impairment of function.

White Matter Hyperintensities Predict Functional Decline in Voiding, Mobility, and Cognition in Older Adults

OBJECTIVES: To compare magnetic resonance imaging data with functional assessments of mobility, urinary control, and cognition to determine common or distinctive features in the distribution of brain white matter hyperintensities (WMHs) associated with functional decline and impairment.

Modulation of human immunodeficiency virus 1 replication by interferon regulatory factors.

Transcription of the human immunodeficiency virus (HIV)-1 is controlled by the cooperation of virally encoded and host regulatory proteins. The Tat protein is essential for viral replication, however, expression of Tat after virus entry requires HIV-1 promoter activation. A sequence in the 5′ HIV-1 LTR, containing a binding site for transcription factors of the interferon regulatory factors (IRF) family has been suggested to be critical for HIV-1 transcription and replication. Here we show that IRF-1 activates HIV-1 LTR transcription in a dose-dependent fashion and in the absence of Tat. This has biological significance since IRF-1 is produced early upon virus entry, both in cell lines and in primary CD4+ T cells, and before expression of Tat. IRF-1 also cooperates with Tat in amplifying virus gene transcription and replication. This cooperation depends upon a physical interaction that is blocked by overexpression of IRF-8, the natural repressor of IRF-1, and, in turn is released by overexpression of IRF-1. These data suggest a key role of IRF-1 in the early phase of viral replication and/or during viral reactivation from latency, when viral transactivators are absent or present at very low levels, and suggest that the interplay between IRF-1 and IRF-8 may play a key role in virus latency.

Localization of Brain White Matter Hyperintensities and Urinary Incontinence in Community-Dwelling Older Adults

BACKGROUND Because white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) may be linked to geriatric syndromes involving mobility, cognition, and affect, we postulated that involvement of areas critical to bladder control could influence urinary incontinence (UI). METHODS One hundred community-dwelling individuals (75-89 years) were recruited into three groups stratified by age and gender reflecting normal and mildly and moderately impaired mobility. Baseline incontinence status and related symptoms were evaluated in 97 individuals using validated instruments (3IQ, Urinary Incontinence Severity Index, Urogenital Distress Inventory, Incontinence Impact Questionnaire). Regional WMH was measured using an MRI brain imaging segmentation pipeline and WM tract-based parcellation atlas. RESULTS Sixty-two (64%) of the participants were incontinent, mostly with urgency (37; 60%) and moderate-severe symptoms (36; 58%). Incontinent individuals were more likely to be women with worse scores for depression and mobility. WMH located in right inferior frontal regions predicted UI severity, with no significant relationship with incontinence, incontinence type, bother, or functional impact. As regards WM tracts, WMH within regions normally occupied by the anterior corona radiata predicted severity and degree of bother, cingulate gyrus predicted incontinence and severity, whereas cingulate (hippocampal portion) and superior fronto-occipital fasciculus predicted severity. CONCLUSIONS Presence of WMH in right inferior frontal regions and selected WM tracts predicts incontinence, incontinence severity, and degree of bother. Our observations support the findings of recent functional MRI studies indicating a critical role for the cingulum in bladder control, while also suggesting potential involvement of other nearby WM tracts such as anterior corona radiata and superior fronto-occipital fasciculus.

Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage

White matter hyperintensities (WMH) in elderly individuals with vascular diseases are presumed to be due to ischemic small vessel diseases; however, their etiology is unknown. We examined the cross-sectional relationship between cerebrovascular hemodynamics and white matter structural integrity in elderly individuals with vascular risk factors. White matter hyperintensity volumes, fractional anisotropy (FA), and mean diffusivity (MD) were obtained from MRI in 48 subjects (75±7years). Pulsatility index (PI) and dynamic cerebral autoregulation (dCA) was assessed using transcranial Doppler ultrasound of the middle cerebral artery. Dynamic cerebral autoregulation was calculated from transfer function analysis (phase and gain) of spontaneous blood pressure and flow velocity oscillations in the low (LF, 0.03 to 0.15 Hz) and high (HF, 0.16 to 0.5 Hz) frequency ranges. Higher PI was associated with greater WMH (P<0.005). Higher phase across all frequency ranges was associated with greater FA and lower MD (P<0.005). Lower gain was associated with higher FA in the LF range (P=0.001). These relationships between phase and FA were significant in the territories limited to the middle cerebral artery as well as across the entire brain. Our results show a strong relationship between impaired cerebrovascular hemodynamics (PI and dCA) and loss of cerebral white matter structural integrity (WMH and DTI metrics) in elderly individuals.

Brain regional lesion burden and impaired mobility in the elderly

This study investigated the relationship of brain white matter (WM) lesions affecting specific neural networks with decreased mobility in ninety-nine healthy community-dwelling subjects ≥75 years old prospectively enrolled by age and mobility status. We assessed lesion burden in the genu, body and splenium of corpus callosum; anterior, superior and posterior corona radiata; anterior and posterior limbs of internal capsule; corticospinal tract; and superior longitudinal fasciculus. Burden in the splenium of corpus callosum (SCC) demonstrated the highest correlation particularly with walking speed (r=0.4, p<10(-4)), and in logistic regression it was the best regional predictor of low mobility performance. We also found that independent of mobility, corona radiata has the largest lesion burden with anterior (ACR) and posterior (PCR) aspects being the most frequently affected. The results suggest that compromised inter-hemispheric integration of visuospatial information through the SCC plays an important role in mobility impairment in the elderly. The relatively high lesion susceptibility of ACR and PCR in all subjects may obscure the importance of these lesions in mobility impairment.

Neurovascular Coupling is Impaired in Slow Walkers: The MOBILIZE Boston Study

Neurovascular coupling may be involved in compensatory mechanisms responsible for preservation of gait speed in elderly people with cerebrovascular disease. Our study examines the association between neurovascular coupling in the middle cerebral artery and gait speed in elderly individuals with impaired cerebral vasoreactivity.

Rapid buildup of brain white matter hyperintensities over 4 years linked to ambulatory blood pressure, mobility, cognition, and depression in old persons.

BACKGROUND Brain white matter hyperintensities (WMH) are associated with functional decline in older people. We performed a 4-year cohort study examining progression of WMH, its effects on mobility, cognition, and depression with the role of clinic and 24-hour ambulatory systolic blood pressure as a predisposing factor. METHODS Ninety-nine subjects, 75-89 years were stratified by age and mobility, with the 67 completing 4-years comprising the cohort. Mobility, cognition, depressive symptoms, and ambulatory blood pressure were assessed, and WMH volumes were determined by quantitative analysis of magnetic resonance images. RESULTS WMH increased from 0.99±0.98% of intracranial cavity volume at baseline to 1.47±1.2% at 2 years and 1.74±1.30% after 4 years. Baseline WMH was associated with 4-year WMH (p < .0001), explaining 83% of variability. Small, but consistent mobility decrements and some evidence of cognitive decline were noted over 4 years. Regression analyses using baseline and 4-year WMHs were associated with three of five mobility measures, two of four cognitive measures and the depression scale, all performed at 4 years. Increases in ambulatory systolic blood pressure but not clinic systolic blood pressure during the initial 2 years were associated with greater WMH accrual during those years, while ambulatory systolic blood pressure was related to WMH at 4 years. CONCLUSION Declines in mobility, cognition, and depressive symptoms were related to WMH accrual over 4 years, and WMH was related to out-of-office blood pressure. This suggests that prevention of microvascular disease, even in asymptomatic older persons, is fundamental for preserving function. There may be value in tighter 24-hour blood pressure control in older persons although this requires further investigation.