Jillian Prestopnik

Blood–Brain Barrier Permeability Abnormalities in Vascular Cognitive Impairment

Background and Purpose— Disruption of the blood–brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood–brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood–brain barrier permeability in vascular cognitive impairment. Method— We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems. Results— Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects (P<0.05). Patient age did not correlate with either the blood–brain barrier permeability or albumin index. Highest albumin index values were seen in the SIVD group (P<0.05) and were significantly increased over multiple and lacunar infarcts. Ki values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts. Conclusions— There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood–brain barrier damage and development of white matter hyperintensities.

Matrix Metalloproteinases Are Associated With Increased Blood–Brain Barrier Opening in Vascular Cognitive Impairment

Background and Purpose— Subcortical ischemic vascular disease (SIVD) is a major form of vascular cognitive impairment (VCI) due to small vessel disease. Matrix metalloproteinases (MMPs) are neutral proteases that disrupt the blood–brain barrier and degrade myelin basic protein under conditions of neuroinflammation. Brain tissues and cerebrospinal fluid (CSF) of patients with VCI have increased levels of MMPs. We hypothesized that patients with SIVD have increased MMPs in the CSF, which are associated with increased CSF albumin. Methods— We studied 60 patients with suspected VCI. Twenty-five were classified as SIVD, whereas other groups included mixed Alzheimer disease and VCI, multiple strokes, and leukoaraiosis when white matter lesions were present and the diagnosis of VCI was uncertain. MMP-2 and MMP-9 in CSF and plasma were measured by gel zymography and indexed to CSF and plasma albumin. MMP-3 activity was measured by fluorescent assay. Results— We found reduced MMP-2 index (P<0.001) in the CSF for the full group of patients (SIVD, multiple strokes, mixed Alzheimer disease and VCI, and leukoaraiosis) compared with control subjects, whose CSF was obtained during spinal anesthesia. MMP-3 activity was increased in VCI compared with control subjects (P<0.01). In SIVD, MMP-2 index showed a negative correlation with albumin index, which was absent with the MMP-9 index. Combining MMP-2 index and MMP-3 activity separated the patients with SIVD from the control subjects with high specificity (P<0.0005). Conclusions— Our results support the hypothesis that MMPs are associated with increased CSF albumin and suggest that they may contribute to the pathophysiology of SIVD.

Comparison of Family Therapy Outcome with Alcohol-Abusing, Runaway Adolescents.

Treatment evaluation for alcohol problem, runaway adolescents and their families is rare. This study recruited primary alcohol problem adolescents (N = 119) and their primary caretakers from two runaway shelters and assigned them to (a) home-based ecologically based family therapy (EBFT), (b) office-based functional family therapy (FFT), or (c) service as usual (SAU) through the shelter. Findings showed that both home-based EBFT and office-based FFT significantly reduced alcohol and drug use compared with SAU at 15-month postbaseline. Measures of family and adolescent functioning improved over time in all groups. However, significant differences among the home- and office-based interventions were found for treatment engagement and moderators of outcome.

Six‐ and Twelve‐Month Outcomes among Homeless Youth Accessing Therapy and Case Management Services through an Urban Drop‐in Center

RESEARCH OBJECTIVE To evaluate the impact of case management and individual therapy offered through a drop-in center for homeless youth on substance use, mental health, housing, education, employment, and medical care utilization. STUDY POPULATION All youth (n=172) between the ages of 14-24 who accessed treatment services through an urban, southwestern drop-in center were included. DATA SOURCE Semistructured and self-report questionnaires were administered to youth between October 2002 and April 2005. STUDY DESIGN A repeated measures design was utilized. Youth were assessed at baseline, 6 months, and 12 months postbaseline. Hierarchical linear modeling was used to test the hypotheses. PRINCIPAL FINDINGS Statistically significant improvements were found in substance abuse, mental health, and percent days housed up to 12 months postbaseline. Decreased alcohol and drug use was associated with an increase in housing. However, most youth did not acquire permanent housing, and education, employment, and medical service utilization did not significantly change over time. CONCLUSIONS While treatment offered through drop-in centers for homeless youth can positively impact homeless youth, policy, funding, and service provision need greater focus, collaboration, and support if youth homelessness is to be successfully addressed.

Long-Term Blood–Brain Barrier Permeability Changes in Binswanger Disease

Background and Purpose— The blood–brain barrier (BBB) is disrupted in small vessel disease patients with lacunes and white matter hyperintensities (WMHs). The relationship of WMHs and regional BBB permeability changes has not been studied. We hypothesized that BBB disruption occurs in normal appearing WM and regions near the WMHs. To test the hypothesis, we repeated BBB permeability measurements in patients with extensive WMHs related to Binswanger disease. Methods— We selected a subset of 22 Binswanger disease subjects from a well-characterized larger prospective vascular cognitive impairment cohort. We used 16 age-matched controls for comparison. The abnormal WM permeability (WMP) was measured twice for several years using dynamic contrast–enhanced magnetic resonance imaging. WMP maps were constructed from voxels above a predetermined threshold. Scans from first and second visits were coregistered. WM was divided into 3 regions: normal appearing WM, WMH ring, and WMH core. The ring was defined as 2 mm on each side of the WMH border. WMP was calculated in each of the 3 specific regions. We used paired t test, ANOVA, and Fisher exact test to compare individual changes. Results— WMP was significantly higher in subjects than in controls (P<0.001). There was no correlation between WMH load and WMP. High permeability regions had minimal overlap between first and second scans. Nine percent of WMP was within the WMHs, 49% within the normal appearing WM, and 52% within the WMH ring (P<0.001; ANOVA). Conclusions— Increased BBB permeability in normal appearing WM and close to the WMH borders supports a relationship between BBB disruption and the development of WMHs.

Office versus Home-Based Family Therapy for Runaway, Alcohol Abusing Adolescents: Examination of Factors Associated with Treatment Attendance

Abstract There is a dearth of research examining treatment engagement and attendance among runaway youth and their families. Such research is needed in order to inform treatment providers on factors associated with engagement and maintenance of these difficult to engage families into counseling. This study examined differential treatment attendance for alcohol abusing runaway youth residing at a local shelter. A traditional office-based family systems approach, Functional Family Therapy (FFT), was compared to a non-traditional, home-based, multisystemic family therapy approach, Ecologically Based Family Therapy (EBFT). As expected, treatment engagement and attendance was significantly higher for those assigned to EBFT (N = 37) compared to FFT (N = 40). Predictors of treatment attendance (income, family chaos, externalization problems and level of youth substance use) were examined within each treatment modality. Findings suggest that home-based (compared to office-based) treatment modalities may significantly increase treatment attendance and engagement of runaway youth and their families. Non-traditional forms of treatment may need to be considered in order to best meet the needs of highly chaotic and disorganized family systems.

1H-MR spectroscopy metabolite levels correlate with executive function in vascular cognitive impairment

Background White matter hyperintensities (WMHs) are associated with vascular cognitive impairment (VCI) but fail to correlate with neuropsychological measures. As proton MR spectroscopy (1H-MRS) can identify ischaemic tissue, we hypothesised that MRS detectable brain metabolites would be superior to WMHs in predicting performance on neuropsychological tests. Methods 60 patients with suspected VCI underwent clinical, neuropsychological, MRI and CSF studies. They were diagnosed as having subcortical ischaemic vascular disease (SIVD), multiple infarcts, mixed dementia and leukoaraiosis. We measured brain metabolites in a white matter region above the lateral ventricles with 1H-MRS and WMH volume in this region and throughout the brain. Results We found a significant correlation between both total creatine (Cr) and N-acetylaspartyl compounds (NAA) and standardised neuropsychological test scores. Cr levels in white matter correlated significantly with executive function (p=0.001), attention (p=0.03) and overall T score (p=0.007). When lesion volume was added as a covariate, NAA also showed a significant correlation with executive function (p=0.003) and overall T score (p=0.015). Furthermore, while metabolite levels also correlated with total white matter lesion volume, adjusting the Cr levels for lesion volume did not diminish the strength of the association between Cr levels and neuropsychological scores. The lowest metabolite levels and neuropsychological scores were found in the SIVD group. Finally, lesion volume alone did not correlate significantly with any neuropsychological test score. Conclusion These results suggest that estimates of neurometabolite levels provide additional and useful information concerning cognitive function in VCI not obtainable by measurements of lesion load.

Perceptions of the Family Environment and Youth Behaviors: Alcohol-Abusing Runaway Adolescents and Their Primary Caretakers

Research suggests family disturbance is highly correlated to adolescents running away from home. However, given methodological challenges, few studies assess parent report of the family situation and instead, rely primarily on adolescent self-report. This article reports the findings of parents’ and runaway adolescents’ reports on several behavioral dimensions. Substance-using runaway adolescents completed measures about their family environment and adolescent problem behaviors. Of 119 adolescents, 49 of their parents also completed measures at intake. Adolescents perceived a more negative family environment than did their parents, and parents rated their youth as having more externalizing problems than did the youth themselves. Findings are consonant with prior research showing a relationship between parental distress and child problems. Contrary to prior findings, this sample of parents did not report significant alcohol use, and there was no relationship between their use and their child’s use. Implications for future research and family therapy are discussed.

Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials

Objectives Vascular cognitive impairment (VCI) is a heterogeneous group of cerebrovascular diseases secondary to large and small vessel disease. We hypothesised that biomarkers obtained early in the disease could identify a homogeneous subpopulation with small vessel disease. Methods We obtained disease markers in 62 patients with VCI that included neurological findings, neuropsychological tests, multimodal MR and cerebrospinal fluid measurements of albumin ratio, matrix metalloproteinases (MMPs), amyloid-β1–42 and phosphorylated-τ181. Proton MR spectroscopic imaging showed ischaemic white matter and permeability of the blood-brain barrier (BBB) was measured with dynamic contrast-enhanced MRI. We constructed a 10-point Binswanger disease score (BDS) with subjective and objective disease markers. In addition, an objective set of biomarkers was used for an exploratory factor analysis (EFA) to select patients with BD. Patients were followed for an average of 2 years to obtain clinical consensus diagnoses. Results An initial BDS of 6 or greater was significantly correlated with a final diagnosis of BD (p<0.05; area under the curve (AUC)=0.79). EFA reduced nine objective biomarkers to four factors. The most predictive of BD was the factor containing the inflammatory biomarkers of increased BBB permeability, elevated albumin index and reduced MMP-2 index (factor 2; AUC=0.78). Both measures independently predicted a diagnosis of BD, and combining them improved the diagnostic accuracy. Conclusions Biomarkers predicted the diagnosis of the BD type of subcortical ischaemic vascular disease. Using pathophysiological biomarkers to select homogeneous groups of patients needs to be tested in targeted treatment trials.

Imaging of Subacute Blood–Brain Barrier Disruption After Methadone Overdose

Methadone intoxication can cause respiratory depression, leading to hypoxia with subsequent coma and death. Delayed postanoxic leukoencephalopathy (DAL) has been reported with intoxication by carbon monoxide, narcotics, and other toxins.