Overcoming Barriers to Latino Participation in Alzheimer's Disease Research.

There is a critical need to increase Latino participation in research on Alzheimer's disease and related disorders (ADRD). Applying principles of community-based participatory research, we convened a community advisory board (CAB) to identify barriers and recommend strategies to increase participation of older Latinos in a longitudinal observational research study of ADRD at the Shiley-Marcos Alzheimer's Disease Research Center. Six major barriers were identified and programmatic changes to overcome them were implemented. Changes resulted in a nearly three-fold increase in the number of Latino individuals recruited, with the proportion of all newly recruited participants who were Latino increasing from 12.2% to 57.4%. Newer Latino recruits were more representative of the elderly Latino population in San Diego County than those recruited pre-CAB and remained highly agreeable to blood draw and neuroimaging, though less so to lumbar puncture and autopsy. Results demonstrate the value of CAB involvement in enhancing diversity in ADRD research.

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.

Clinical use of computed tomographic perfusion for the diagnosis and prediction of lesion growth in acute ischemic stroke.

BACKGROUND: Computed tomography perfusion (CTP) mapping in research centers correlates well with diffusion-weighted imaging (DWI) lesions and may accurately differentiate the infarct core from ischemic penumbra. The value of CTP in real-world clinical practice has not been fully established. We investigated the yield of CTP-derived cerebral blood volume (CBV) and mean transient time (MTT) for the detection of cerebral ischemia and ischemic penumbra in a sample of acute ischemic stroke (AIS) patients. METHODS: We studied 165 patients with initial clinical symptoms suggestive of AIS. All patients had an initial noncontrast head CT, CTP, CT angiogram (CTA), and follow-up magnetic resonance imaging (MRI) of the brain. The obtained perfusion images were used for image processing. CBV, MTT, and DWI lesion volumes were visually estimated and manually traced. Statistical analysis was conducted using R and SAS software. RESULTS: All normal DWI sequences had normal CBV and MTT studies (N = 89). Seventy-three patients had acute DWI lesions. CBV was abnormal in 23.3% and MTT was abnormal in 42.5% of these patients. There was a high specificity (91.8%) but poor sensitivity (40.0%) for MTT maps predicting positive DWI. The Spearman correlation was significant between MTT and DWI lesions (ρ = 0.66; P > .0001) only for abnormal MTT and DWI lesions >0 cc. CBV lesions did not correlate with final DWI. CONCLUSIONS: In real-world use, acute imaging with CTP did not predict stroke or DWI lesions with sufficient accuracy. Our findings argue against the use of CTP for screening AIS patients until real-world implementations match the accuracy reported from specialized research centers.

Incremental treatments with laser therapy augments good behavioral outcome in the rabbit small clot embolic stroke model.

Transcranial near-infrared laser therapy (TLT) improves behavioral outcome in animal stroke models when applied as single treatment within the 24 h of the stroke onset. It is unknown if the multiple TLT treatments have an added beneficial effect. We aim to determine whether multiple irradiations with TLT would have further improvement in behavioral outcomes in the rabbit small clot embolic stroke model (RSCEM). Using the RSCEM, two and three TLT treatments (7.5-20 mW/cm(2)) were compared against single laser treatment alone (7.5-10.8 mW/cm(2)). Two sham irradiation groups were added for the control curves. The double treatment group received TLT at 3 and 5 h and the triple treatment group at 2, 3, and 4 h after embolization. Behavioral analysis was conducted 24 h after embolization using a dichotomized behavioral score. The determination of the effective clot amount (milligrams) that produces neurological deficits in 50 % of the rabbits (P 50) was used to compare TLT treatments with the sham. The P 50 for double treatment was 5.47 ± 0.90, with n = 39; the corresponding P 50 value for a single treatment was 3.87 ± 0.73, with n = 38; and the corresponding control curve was 3.25 ± 0.4, n = 32. The P 50 for triple treatment was 5.91 ± 0.49, with n = 23; the corresponding P 50 value for a single treatment was 3.09 ± 0.59, with n = 15, and the corresponding control curve was 1.71 ± 0.26, with n = 17. The triple treatment had 91 % improvement when compared with the single treatment and 245 % improvement when compared with the sham. The present study suggests that the additional TLT treatments provide further behavioral improvement when given during the acute ischemic stroke phase.

Vertebral artery dissection in rheumatoid arthritis with cervical spine disease.

A 59-year-old woman with long-standing active rheumatoid arthritis presented with posterior circulation ischemic stroke after vertebral dissection. She had severe multilevel degenerative changes of her cervical spine. She did not have classic stroke risk factors nor evidence of atherosclerotic disease or other systemic diseases. The most likely mechanism appears to be injury of the artery wall by an osteophyte, causing dissection that resulted in thrombosis and subsequent embolic strokes.

Glycosylated hemoglobin for diagnosis of prediabetes in acute ischemic stroke patients.

BACKGROUND: Prediabetes (PD) is an independent risk factor for stroke. The American Diabetes Association (ADA) has recently published new guidelines recommending glycosylated hemoglobin A1c (HbA1c) as a marker to diagnose diabetes and PD. Diagnosis of diabetes Mellitus (DM) is often made at the time of hospitalization for stroke. Less is known about identifying PD in acute ischemic stroke (AIS) patients. We aim to investigate the frequency of new-onset PD in the hospitalized AIS patients using the new ADA guidelines. METHODS: We retrospectively studied 362 AIS patients from our local database. Stroke risk factors, type of stroke, and white matter hyperintensities (WMHs) were all collected. Based on the 2010 ADA guidelines, patients were classified as prediabetics, with HbA1c levels of 5.7%-6.4%; diabetics, with HbA1c levels more than 6.5%; and normoglycemic, HbA1c levels less than 5.7%. We used SAS 9.3 for analysis. RESULTS: On admission, 279 (78%) AIS patients had HbA1c values collected. Stratifying by HbA1c, 113 (31%) AIS patients were given the diagnosis of DM and 109 (30%) were given the diagnosis of PD. From the 166 patients with no DM history, 53% had PD and 15% had DM. Patients with DM and PD were more likely to have hypertension (P<.001) and hyperlipidemia (P=.05). The likelihood of new-onset PD increased with age (P<.01). No differences were found by the type of stroke or WMH. CONCLUSION: Diabetes and PD are highly prevalent in the hospitalized ischemic stroke (IS) patients. Our results suggest a need for routine HbA1c testing in all patients with IS. Further larger studies need to confirm these findings.

Diffusion-weighted imaging-fluid attenuated inversion recovery mismatch in nocturnal stroke patients with unknown time of onset.

BACKGROUND: More than a quarter of patients with ischemic stroke (IS) are excluded from thrombolysis because of an unknown time of symptom onset. Recent evidence suggests that a mismatch between diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) imaging could be used as a surrogate for the time of stroke onset. We compared used the DWI-FLAIR mismatch and the FLAIR/DWI ratio to estimate the time of onset in a group of patients with nocturnal strokes and unknown time of onset. METHODS: We used a prospectively collected acute IS patient database with MRI as the initial imaging modality. Nineteen selected nocturnal stroke patients with unknown time of onset were compared with 22 patients who had an MRI scan within 6 hours from stroke onset (control A) and 19 patients who had an MRI scan between 6 and 12 hours (control B). DWI and FLAIR signal was rated as normal or abnormal. FLAIR/DWI ratio was calculated from independent DWI and FLAIR ischemic lesion volumes using semiautomatic software. RESULTS: The DWI-FLAIR mismatch was different among groups (unknown 43.7%; control A 63.6%; control B 10.5%; Fisher-Freeman-Halton test; P = .001). There were significant differences in FLAIR/DWI ratio among the 3 groups (unknown 0.05 ± 0.12; control A 0.17 ± 0.15; control B 0.04 ± 0.06; Kruskal-Wallis test; P < .0001). Post-hoc pairwise comparisons revealed that FLAIR/DWI ratio from the unknown group was significantly different from the control B group (P = .0045) but not different from the control A group. DWI volumes were not different among the 3 groups. CONCLUSIONS: A large proportion of patients with nocturnal IS and an unknown time of stroke initiation have a DWI-FLAIR mismatch, suggesting a recent onset of stroke.

Intravenous tissue plasminogen activator for patients with minor ischemic stroke.

BACKGROUND: Patients with minor ischemic stroke (MIS) are frequently excluded from thrombolytic therapy. Denial of therapy to these patients, however, remains controversial. We compared outcomes in patients with MIS who received intravenous (IV) tissue plasminogen activator (t-PA) with those who were not treated. METHODS: We selected adult patients with stroke onset within 3 hours from a prospectively collected stroke registry. MIS was defined as an admission National Institutes of Health Stroke Scale (NIHSS) score ≤ 5. The primary outcome was a 90-day modified Rankin scale (mRS) score of 0 to 1. Secondary outcomes were a Barthel index (BI) score ≥ 95 at 90 days, symptomatic intracranial hemorrhage (SICH), and death. Multivariable logistic regression was performed to determine the association between outcomes adjusting for age, history of diabetes, and NIHSS score at admission. Reasons for t-PA exclusion were obtained. RESULTS: We identified 133 patients with MIS; 59 patients received IV t-PA. The NIHSS score (mean ± SD) at admission was higher in the t-PA treated group (3.4 ± 1.4 v 1.9 ± 1.3 in the untreated group; P < .0001). Other baseline characteristics were not significantly different between the 2 groups. At 90 days, 57.6% of patients in the t-PA group and 68.9% of patients in the untreated group had a mRS score of 0 to 1 (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.39-2.2; P = .87). A BI score of 95 to 100 was achieved in 75% of patients in the IV t-PA group versus 78.9% in the untreated group (OR 1.18, 95% CI 0.43-3.23; P = .74). There were 3 deaths (5.1%) in the IV t-PA group and 3 deaths (4.1%) in the control group. CONCLUSIONS: In our sample, patients with MIS treated with IV t-PA have similar outcomes as patients not receiving thrombolysis. A randomized trial or larger observational study is needed confirm or reject these findings.

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.

The evolution of transcranial laser therapy for acute ischemic stroke, including a pooled analysis of NEST-1 and NEST-2.

Intravenous tissue plasminogen activator is the only proven therapy for acute ischemic stroke. Not enough patients are eligible for treatment and additional new therapies are needed. Recently, laser technology has been applied to acute ischemic stroke. This noninvasive technique uses near-infrared wavelengths applied to the scalp within 24 h of symptom onset. The mechanism is incompletely understood but may involve increased mitochondrial adenosine triphosphate production. Animal models demonstrated safety and efficacy warranting randomized controlled trials in humans. NEST-1 (phase 2) and NEST-2 (phase 3) confirmed the safety of transcranial laser therapy, although efficacy was not found in NEST-2. Pooled analysis of NEST-1 and NEST-2 revealed a significantly improved success rate in patients treated with laser therapy. Further phase 3 testing is planned and may create a new paradigm for the treatment of acute ischemic stroke.

Alberta Stroke Program Early CT Score (ASPECTS) in patients with wake-up stroke.

One-quarter of ischemic strokes occur during sleep, and affected patients are excluded from thrombolytic therapy because of an unknown time of stroke onset. It has been suggested that early ischemic changes detected on computed tomography (CT) are similar in patients with acute stroke and patients who recently awoke with stroke. We compared head CT scans using the Alberta Stroke Program Early CT Score (ASPECTS) in patients who were likely to suffer their stroke during sleep (awoke group) and a control group of patients with stroke of known onset time. Patients were recruited from a prospectively collected acute stroke database. The awoke group was defined as all ischemic stroke patients who were "last seen normal" more than 4 hours ago, arrived between 4 a.m. and 10 a.m., and underwent head CT within 15 hours of the time last seen normal. The control group was randomly selected from patients who underwent head CT within 4 hours of stroke onset. The ASPECTS evaluations were performed by investigators blinded to patient group and time of onset. A modified Rankin Scale (mRS) score was available in 15 awoke patients and 46 control patients at 90 days after stroke. Twenty-eight awoke patients and 68 control patients had suitable imaging for the ASPECTS. Baseline demographic characteristics and risk factors were similar in the 2 groups. The dichotomized ASPECTS analysis (≤7 vs 8-10) showed no significant differences between the groups. ASPECTS was 8-10 in 89.3% the awoke group and 95.6% in the control group (P=.353). There was a trend toward higher 90-day mRS score (0-1) in the awoke group versus controls (73% vs 45%; P=.079). Initial ASPECTS was similar in patients with wake-up stroke and those with 4 hours of symptoms. This suggests that a subset of wake-up stroke patients might be suitable for thrombolytic therapy.

Memantine and Acetylcholinesterase Inhibitor Use in Alzheimer's Disease Clinical Trials: Potential for Confounding by Indication.

BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly prescribed medications for Alzheimer's disease (AD). Their concurrent use in AD randomized clinical trials (RCTs) is generally allowed but their effect in outcome measures is unsettled. OBJECTIVE: To evaluate whether use of AChEIs and/or memantine across AD RCTs are associated with different rates of cognitive/functional decline. METHODS: We pooled data from 5 RCTs of mild to moderate AD conducted by the Alzheimer's Disease Cooperative Study (ADCS) between 2002-2013. 1,423 participants with MMSE of 14-26 and completion of 12-18 months follow-up visits were analyzed. Trials did not randomize with respect to AChEIs or memantine. We defined 4 groups: AChEI (27%), memantine (16%), AChEIs+memantine (46%), and non-users (11%). Outcome measures were change in ADAS-cog-11, ADCS-ADL, and MMSE from baseline to 18 months. Fisher's exact test, Wilcoxon signed rank, and Spearman's tests were used to identify confounding variables. Mixed model repeated measures were used for adjustments and pairwise tests for comparing change in scores. RESULTS: Age, apolipoprotein E, and initial MMSE were identified as covariates. Memantine and/or AChEIs users had greater impairment at entry than non-users. There was a significant decline on the ADAS-cog-11 in the memantine (estimate -4.2 p < 0.0001) and AChEIs+memantine groups (estimate -3.5 p < 0.0001) than non-users, while there was significantly more decline in MMSE (estimate 2.5 p < 0.0001) and ADCS-ADL in the AChEIs+memantine group (estimate 4.3 p < 0.0001)Conclusion: Memantine monotherapy or combined with AChEIs are associated with more rapid cognitive and functional decline than non-users. We postulated a potential selection bias by indication.

Clinical-Neuropathological Correlations of Alzheimer's Disease and Related Dementias in Latino Volunteers.

Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer's disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer's Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of Apolipoprotein E. We calculated the sensitivity and specificity of the clinical diagnosis of AD against the primary pathological diagnosis. Of the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity for autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved.

The Cerebrovascular-Chronic Kidney Disease Connection: Perspectives and Mechanisms.

Chronic kidney disease (CKD) is an independent risk factor for the development of cerebrovascular disease, particularly small vessel disease which can manifest in a variety of phenotypes ranging from lacunes to microbleeds. Small vessel disease likely contributes to cognitive dysfunction in the CKD population. Non-traditional risk factors for vascular injury in uremia include loss of calcification inhibitors, hyperphosphatemia, increased blood pressure variability, elastinolysis, platelet dysfunction, and chronic inflammation. In this review, we discuss the putative pathways by which these mechanisms may promote cerebrovascular disease and thus increase risk of future stroke in CKD patients.

Taeniasis and cysticercosis in housemaids working in affluent neighborhoods in Lima, Peru.

Taenia solium taeniasis/cysticercosis is endemic in most developing countries, where it is an important cause of epileptic seizures and other neurologic symptoms. In industrialized countries, cysticercosis results from travel or immigration of tapeworm carriers from endemic areas. In both endemic and nonendemic countries, housemaids commonly immigrate from cysticercosis-endemic areas and can transmit the infection if they carry the adult tapeworm. Between July 2001 and July 2002, 1,178 housemaids (961 of them work in the top five most affluent districts of Lima, a metropolis of 8 million inhabitants considered nonendemic for cysticercosis) were evaluated for serum antibodies to Taenia solium and stool microscopy for taeniasis and cysticercosis. The serosurvey revealed a prevalence of cysticercosis-specific antibodies of 14.6% (95% CI: 12.6-16.6%), and stool microscopy detected 12 T. solium tapeworm carriers, for a prevalence of taeniasis of 1.2% (95% CI: 0.6-1.8%). A nonrandom sample of 26 seropositive housemaids was examined by brain CT and 50% of them had brain lesions compatible with neurocysticercosis, mainly calcifications. From the families who used a tapeworm-carrier housemaid, cysticercosis antibodies were detected in 6 (23%) of 26 persons who agreed to participate. One seropositive member of the employer families was symptomatic for seizures and had brain calcifications. The prevalence of tapeworm infections in this housemaid group is similar to levels in endemic areas, constituting a source of neurocysticercosis infection.

Binswanger's disease: toward a diagnosis agreement and therapeutic approach.

Binswanger's disease (BD) is a progressive form of cerebral small vessel disease affecting the white matter and other subcortical structures. Clinical and imaging characteristics, neuropsychological profile and cerebrospinal fluid analysis aid in making the diagnosis. BD shares features of other small vessel diseases and degenerative neurological conditions, which makes diagnosis difficult. However, with recent developments in MRI methods and serum/cerebrospinal fluid biomarkers, we have gained a greater understanding of the complex pathophysiology of the disease that will guide us to a more certain diagnosis. There is growing evidence that the white matter injury in BD is related to endothelial dysfunction with a secondary inflammatory response leading to breakdown of the neurovascular unit. This review summarizes current and future research directions, including pathophysiological mechanisms and potential therapeutic approaches.

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.