MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.

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.

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-ß1-42 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.

Blood-Brain Barrier Permeability Is Associated With Cognitive Functioning in Normal Aging and Neurodegenerative Diseases.

BACKGROUND: The purpose of this study was to investigate the relationship between blood-brain barrier (BBB) permeability and cognitive functioning in healthy older adults and individuals with neurodegenerative diseases. METHODS AND RESULTS: A total of 124 participants with Alzheimer disease, cerebrovascular disease, or a mix Alzheimer's and cerebrovascular diseases and 55 controlparticipants underwent magnetic resonance imaging and neuropsychological testing. BBB permeability was measured with dynamic contrast-enhanced magnetic resonance imaging and white matter injury was measured using a quantitative diffusion-tensor imaging marker of white matter injury. Structural equation modeling was used to examine the relationships between BBB permeability, vascular risk burden, white matter injury, and cognitive functioning. Vascular risk burden predicted BBB permeability (r=0.24, P<0.05) and white matter injury (r=0.38, P<0.001). BBB permeability predicted increased white matter injury (r=0.34, P<0.001) and increased white matter injury predicted lower cognitive functioning (r=-0.51, P<0.001). CONCLUSIONS: The study provides empirical support for a vascular contribution to white matter injury and cognitive impairment, directly or indirectly via BBB permeability. This highlights the importance of targeting modifiable vascular risk factors to help mitigate future cognitive decline.

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 ((1)H-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 (1)H-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.

Changes in intrinsic functional brain networks following blast-induced mild traumatic brain injury.

OBJECTIVE: Blast-induced mild traumatic brain injuries (mTBI) commonly go undetected by computed tomography and conventional magnetic resonance imaging (MRI). This study was used to investigate functional brain network abnormalities in a group of blast-induced mTBI subjects using independent component analysis (ICA) of resting state functional MRI (fMRI) data. METHODS: Twenty-eight resting state networks of 13 veterans who sustained blast-induced mTBI were compared with healthy controls across three fMRI domains: blood oxygenation level-dependent spatial maps, time course spectra and functional connectivity. RESULTS: The mTBI group exhibited hyperactivity in the temporo-parietal junctions and hypoactivity in the left inferior temporal gyrus. Abnormal frequencies in default-mode (DMN), sensorimotor, attentional and frontal networks were detected. In addition, functional connectivity was disrupted in six network pairs: DMN-basal ganglia, attention-sensorimotor, frontal-DMN, attention-sensorimotor, attention-frontal and sensorimotor-sensorimotor. CONCLUSIONS: The results suggest white matter disruption across certain attentional networks. Additionally, given their elevated activity relative to controls', the temporo-parietal junctions of blast mTBI subjects may be compensating for diffuse axonal injury in other cortical regions.

A trichotomy method for defining homogeneous subgroups in a dementia population.

INTRODUCTION: Diagnosis of dementia in the aging brain is confounded by the presence of multiple pathologies. Mixed dementia (MX), a combination of Alzheimer's disease (AD) proteins with vascular disease (VD), is frequently found at autopsy, and has been difficult to diagnose during life. This report develops a method for separating the MX group and defining preclinical AD (presence of AD factors with normal cognition) and preclinical VD subgroups (presence of white matter damage with normal cognition). METHODS: Clustering was based on three diagnostic axes: (1) AD factor (ADF) derived from cerebrospinal fluid proteins (Aß42 and pTau), (2) VD factor (VDF) calculated from mean free water and peak width of skeletonized mean diffusivity in the white matter, and (3) Cognition (Cog) based on memory and executive function. The trichotomy method was applied to an Alzheimer's Disease Neuroimaging Initiative cohort (N = 538). RESULTS: Eight biologically defined subgroups were identified which included the MX group with both high ADF and VDF (9.3%) and a preclinical VD group (3.9%), and a preclinical AD group (13.6%). Cog is significantly associated with both ADF and VDF, and the partial-correlation remains significant even when the effect of the other variable is removed (r(Cog, ADF/VDF removed) = 0.46, p < 10-28 and r(Cog, VDF/ADF removed) = 0.24, p < 10-7 ). DISCUSSION: The trichotomy method creates eight biologically characterized patient groups, which includes MX, preclinical AD, and preclinical VD subgroups. Further longitudinal studies are needed to determine the utility of the 3-way clustering method with multimodal biological biomarkers.

Albuminuria, cognition, and MRI biomarkers of cerebrovascular disease in American Indians of the Zuni Pueblo.

Background: Elevated urine albumin to creatinine ratio (UACR) is associated with cerebrovascular disease and cognitive impairment in older adults, though few studies have evaluated these relationships in midlife. This is particularly important to assess in American Indian populations, which are disproportionately impacted by diabetes and kidney disease. Additionally, evidence suggests that biomarkers may perform differently in underrepresented groups, thus, it is crucial to validate biomarkers in this unique population. Methods: Twenty-five participants from the Zuni Pueblo underwent neuropsychological assessment and an MRI that included fluid attenuated inversion recovery (FLAIR) and diffusion imaging to calculate recently developed MRI markers of cerebrovascular small vessel disease (Peak width of Skeletonized Mean Diffusivity (PSMD), mean free-water fraction (mFW), white matter hyperintensity (WMH)). Results: Regression analyses indicated no significant associations between UACR, MRI biomarkers and cognitive outcomes. Analyses of covariance indicated that the Zuni Indian cohort exhibited reduced white matter damage relative to an existing cohort of older adults with vascular cognitive impairment when accounting for age, sex, and education. Slower processing speed was associated with greater white matter disease across all measures examined. Conclusions: Our pilot study validated the use of MRI biomarkers of cerebrovascular disease in this unique cohort of American Indians.

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.

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. K(i) 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.

Inflammatory Biomarkers Aid in Diagnosis of Dementia.

Dual pathology of Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) commonly are found together at autopsy, but mixed dementia (MX) is difficult to diagnose during life. Biological criteria to diagnose AD have been defined, but are not available for vascular disease. We used the biological criteria for AD and white matter injury based on MRI to diagnose MX. Then we measured multiple biomarkers in CSF and blood with multiplex biomarker kits for proteases, angiogenic factors, and cytokines to explore pathophysiology in each group. Finally, we used machine learning with the Random forest algorithm to select the biomarkers of maximal importance; that analysis identified three proteases, matrix metalloproteinase-10 (MMP-10), MMP-3 and MMP-1; three angiogenic factors, VEGF-C, Tie-2 and PLGF, and three cytokines interleukin-2 (IL-2), IL-6, IL-13. To confirm the clinical importance of the variables, we showed that they correlated with results of neuropsychological testing.

Biomarkers identify the Binswanger type of vascular cognitive impairment.

Binswanger's disease is a form of subcortical ischemic vascular disease (SIVD-BD) with extensive white matter changes. To test the hypothesis that biomarkers could improve classification of SIVD-BD, we recruited 62 vascular cognitive impairment and dementia (VCID) patients. Multimodal biomarkers were collected at entry into the study based on clinical and neuropsychological testing, multimodal magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. The patients' diagnoses were confirmed by long-term follow-up, and they formed a "training set" to test classification methods, including (1) subcortical ischemic vascular disease score (SIVDS), (2) exploratory factor analysis (EFA), (3) logistic regression (LR), and (4) random forest (RF). A subsequently recruited cohort of 43 VCID patients with provisional diagnoses were used as a "test" set to calculate the probability of SIVD-BD based on biomarkers obtained at entry. We found that N-acetylaspartate (NAA) on proton magnetic resonance spectroscopy (1H-MRS) was the best variable for classification, followed by matrix metalloproteinase-2 in CSF and blood-brain barrier permeability on MRI. Both LR and RF performed better in diagnosing SIVD-BD than either EFA or SIVDS. Two-year follow-up of provisional diagnosis patients confirmed the accuracy of statistically derived classifications. We propose that biomarker-based classification methods could diagnose SIVD-BD patients earlier, facilitating clinical trials.

A Multimodal Approach to Stratification of Patients with Dementia: Selection of Mixed Dementia Patients Prior to Autopsy.

Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) are major causes of dementia, and when combined lead to accelerated cognitive loss. We hypothesized that biomarkers of neurodegeneration and neuroinflammation could be used to stratify patients into diagnostic groups. Diagnosis of AD can be made biologically with detection of amyloid and tau proteins in the cerebrospinal fluid (CSF) and vascular disease can be identified with diffusion tensor imaging (DTI). We recruited patients with cognitive complaints and made an initial clinical diagnosis. After one year of follow-up we made a biological diagnosis based on the use of biomarkers obtained from DTI, CSF AD, and inflammatory proteins, and neuropsychological testing. Patients with AD had primarily findings of neurodegeneration (CSF showing increased tau and reduced amyloid), while patients with neuroinflammation had abnormal DTI mean diffusion (MD) in the white matter. Using the biological biomarkers resulted in many of the clinically diagnosed AD patients moving into mixed dementia (MX). Biomarkers of inflammation tended to be higher in the MX than in either the AD or VCID, suggesting dual pathology leads to increased inflammation, which could explain accelerated cognitive decline in that group.

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.

Treatment outcome for street-living, homeless youth.

Comprehensive intervention for homeless, street living youth that addresses substance use, social stability, physical and mental health issues has received very little attention. In this study, street living youth aged 14-22 were recruited from a drop-in center and randomly assigned to the Community Reinforcement Approach (CRA) or treatment as usual (TAU) through a drop-in center. Findings showed that youth assigned to CRA, compared to TAU, reported significantly reduced substance use (37% vs. 17% reduction), depression (40% vs. 23%) and increased social stability (58% vs. 13%). Youth in both conditions improved in many other behavioral domains including substance use, internalizing and externalizing problems, and emotion and task oriented coping. This study indicates that homeless youth can be engaged into treatment and respond favorably to intervention efforts. However, more treatment development research is needed to address the barriers associated with serving these youth.

Visual imagery scanning in young adults with intellectual disability.

Fifteen young adults with intellectual disability and 17 college students learned the locations of 5 landmarks on an island map and then scanned from one landmark to another. In the perception condition, the landmarks were visible; in the imagery condition, they were not. The rate of scanning over distance was similar for perception and imagery conditions, but overall scan times were slower in the imagery condition. Participants with intellectual disability required slightly more trials to learn the landmark locations and had generally slower scan times. Both groups were identical in rate of scanning for both perception and imagery conditions. Results suggest that persons with intellectual disability have no particular deficit in image inspection and, perhaps, relatively good imagery capacities.

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.

Imaging of subacute blood-brain barrier disruption after methadone overdose.

BACKGROUND: 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. OBJECTIVE: To investigate the metabolic derangement of the white matter (WM) and blood-brain barrier (BBB) after DAL caused by methadone overdose. DESIGN, SETTING, AND PATIENTS: Case report of 2 patients with DAL after a single dose of "diverted" methadone used for pain control. RESULTS: In both cases brain magnetic resonance imaging (MRI) revealed initial extensive bilateral restricted diffusion lesions within the WM. Follow-up MRI using proton magnetic resonance spectroscopic imaging ((1) H-MRSI) showed markedly lower N-acetylaspartate and higher choline within the WM. BBB permeability, calculated by Patlak graphical analysis of MRI T1 data obtained after contrast agent injection, showed disruption of the BBB within the WM lesions, which persisted longer than a year in 1 patient. Neuropsychological evaluation showed executive dysfunction in both patients. After 1 year, one patient recovered whereas the second remained impaired. CONCLUSIONS: Methadone overdose can cause DAL with profound disturbances of neural metabolism and the BBB. The time course of these disturbances can be monitored with MR methods.

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.

Dual and multiple diagnosis among substance using runaway youth.

Although research on runaway and homeless youth is increasing, relatively little is known about the diagnostic profile of runaway adolescents. The current study examined patterns of psychiatric dual and multiple diagnosis among a sample (N=226) of treatment-engaged substance-abusing youth (ages 13 to 17) who were residing at a runaway shelter. As part of a larger treatment outcome study, the youths' psychiatric status was assessed using the DSM-IV based computerized diagnostic interview schedule for children [CDISC; (1)]. The majority of the youth in our sample met criteria for dual or multiple diagnosis (60%) with many having more than one substance-use diagnosis (56%). The severity of mental-health and substance-use problems in this sample of substance-abusing runaways suggests the need for continued development of comprehensive services. The range and intensity of diagnoses seen indicates a need for greater focus on treatment development and strategies to address their multiple areas of risk.