T2 Protect AD: Achieving a rapid recruitment timeline in a multisite clinical trial for individuals with mild to moderate Alzheimer's disease.

Introduction: The reporting of approaches facilitating the most efficient and timely recruitment of Alzheimer's disease (AD) patients into pharmacologic trials is fundamental to much-needed therapeutic progress. Methods: T2 Protect AD (T2), a phase 2 randomized placebo-controlled trial of troriluzole in mild to moderate AD, used multiple recruitment strategies. Results: T2 exceeded its recruitment target, enrolling 350 participants between July 2018 and December 2019 (randomization rate: 0.87 randomizations/site/month, or 3-fold greater than recent trials of mild to moderate AD). The vast majority (98%) of participants were enrolled during a 10-month window of intense promotion in news media, TV and radio advertisements, and social media. The distribution of primary recruitment sources included: existing patient lists at participating sites (72.3%), news media (12.3%), physician referral (6.0%), word of mouth (3.1%), and paid advertising (2.9%). Discussion: The rapid recruitment of participants with mild to moderate AD was achieved through a range of approaches with varying success.

Using Biomarkers to Predict Memantine Effects in Alzheimer's Disease: A Proposal and Proof-Of-Concept Demonstration.

Memantine's benefits in Alzheimer's disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual's clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.

Case 279: Central-Variant Posterior Reversible Encephalopathy Syndrome.

HistoryA 25-year-old woman with recently diagnosed systemic lupus erythematosus and class IV lupus nephritis confirmed with biopsy and treated with mycophenolate mofetil presented with a 2-day history of progressively worsening edema of her face and lower extremities. She had no antecedent infection or vaccination. She was admitted to the hospital and treated with methylprednisolone, furosemide, and C1 esterase inhibitor. On hospital day 2, she experienced a witnessed generalized tonic-clonic seizure. At that time, she became hypoxic and was intubated for airway protection. Her laboratory study results preceding the seizure were remarkable for hyponatremia, with a blood sodium level of 122 mEq/L (122 mmol/L) (normal range, 135-145 mEq/L [134-145 mmol/L]), which was corrected to 137 mEq/L (137 mmol/L) over 48 hours. Same-day cerebrospinal fluid analysis was unremarkable, and unenhanced head CT findings (not shown) were normal, with no evidence of intracranial hemorrhage or edema.Her subsequent hospital course was complicated by renal failure requiring continuous renal replacement therapy, hypertension (systolic blood pressure ranging from 140 to 190 mm Hg), anemia requiring blood transfusions, thrombocytopenia, and pneumonia. She remained intubated with a limited neurologic examination due to sedative medications until hospital day 10. After extubation, she was noted to have a right gaze preference. She was able to speak in short phrases and follow simple commands. Neurologic examination was notable for drowsiness, right gaze deviation, direction-changing torsional nystagmus, horizontal ophthalmoplegia, and generalized symmetric weakness without upper motor neuron signs. The following day (hospital day 11), unenhanced MRI of the brain was performed along with MR angiography of the brain. Biopsy of the temporal artery was normal, without evidence of inflammation.

Case 279.

HistoryA 25-year-old woman with recently diagnosed systemic lupus erythematosus and class IV lupus nephritis confirmed with biopsy and treated with mycophenolate mofetil presented with a 2-day history of progressively worsening edema of her face and lower extremities. She had no antecedent infection or vaccination. She was admitted to the hospital and treated with methylprednisolone, furosemide, and C1 esterase inhibitor. On hospital day 2, she experienced a witnessed generalized tonic-clonic seizure. At that time, she became hypoxic and was intubated for airway protection. Her laboratory study results preceding the seizure were remarkable for hyponatremia, with a blood sodium level of 122 mEq/L (122 mmol/L) (normal range, 135-145 mEq/L [134-145 mmol/L]), which was corrected to 137 mEq/L (137 mmol/L) over 48 hours. Same-day cerebrospinal fluid analysis was unremarkable, and unenhanced head CT findings (not shown) were normal, with no evidence of intracranial hemorrhage or edema.

Mapping a Reliable Stroke Onset Time Course Using Signal Intensity on DWI Scans.

BACKGROUND AND PURPOSE: Identifying a last known well (LKW) time surrogate for acute stroke is vital to increase stroke treatment. Diffusion-weighted imaging (DWI) signal intensity initially increases from onset of stroke but mapping a reliable time course to the signal intensity has not been demonstrated. METHODS: We retrospectively reviewed stroke code patients between 1/2016 and 6/2017 from the prospective; Institutional review board (IRB) approved University of California San Diego Stroke Registry. Patients who had magnetic resonance imaging of brain from onset, with or without intervention, are included. All ischemic strokes were confirmed and timing from onset to imaging was calculated. Raw DWI intensity is measured using IMPAX software and compared to contralateral side for control for a relative DWI intensity (rDWI). LKW and magnetic resonance imaging (MRI) time were collected by chart review. Correlation is assessed using Pearson correlation coefficient between DWI intensity, rDWI, and time to MRI imaging. 1.5T, 3T, and combined modalities were examined. RESULTS: Seventy-eight patients were included in this analysis. Overall, there was statistically significant positive correlation (.53, P < .001) between DWI intensity and LKW time irrespective of scanner strength. Using 1.5T analyses, there was good correlation (.46, P < .001). 3T MRI analysis further showed comparatively stronger positive correlation (.66, P < .001). CONCLUSIONS: There is good correlation between DWI intensity and minutes from onset to MRI. This suggests a time-dependent DWI intensity response and supports the potential use of DWI intensity measurements to extrapolate an LKW time. Further studies are being pursued to increase both experience and generalizability.

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.

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.

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.

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.

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.

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.

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.

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.

Transcranial laser therapy for acute ischemic stroke: a pooled analysis of NEST-1 and NEST-2.

BACKGROUND: NeuroThera Effectiveness and Safety Trials (NEST) 1 and 2 have demonstrated safety of transcranial laser therapy (TLT) for human treatment in acute ischemic stroke. NEST 1 study suggested efficacy of TLT but the following NEST 2, despite strong signals, missed reaching significance on its primary efficacy endpoint. In order to assess efficacy in a larger cohort, a pooled analysis was therefore performed. METHODS: The two studies were first compared for heterogeneity, and then a pooled analysis was performed to assess overall safety and efficacy, and examined particular subgroups. The primary endpoint for the pooled analysis was dichotomized modified Rankin scale (mRS) 0-2 at 90 days. RESULTS: Efficacy analysis for the intention-to-treat population was based on a total of 778 patients. Baseline characteristics and prognostic factors were balanced between the two groups. The TLT group (n = 410) success rate measured by the dichotomized 90-day mRS was significantly higher compared with the sham group (n = 368) (P = 0·003, OR: 1·67, 95% CI: 1·19-2·35). The distribution of scores on the 90-day mRS was significantly different in TLT compared with sham (P = 0·0005 Cochran-Mantel-Haenszel). Subgroup analysis identified moderate strokes as a predictor of better treatment response. CONCLUSIONS: This pooled analysis support the likelihood that transcranial laser therapy is effective for the treatment of acute ischemic stroke when initiated within 24 h of stroke onset. If ultimately confirmed, transcranial laser therapy will change management and improve outcomes of far more patients with acute ischemic stroke.

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.