16 research outputs found

    Widespread extrahippocampal NAA/(Cr+Cho) abnormalities in TLE with and without mesial temporal sclerosis

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    MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE

    Parietal gray matter volume loss is related to spatial processing deficits in long-term abstinent alcoholic men. Alcohol Clin Exp Res 33:1806–14. Neurocognitive findings in binge drinking 7 by guest on D ecem ber 4

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    Abstract Background. We previously demonstrated relatively intact cognitive function (with the exception of suggestive evidence for persistent deficits in spatial information processing) in middle-aged long-term abstinent alcoholics (LTAA, abstinent for 6 months or more) compared to age and gender comparable non-alcoholic controls (NAC) Methods. In the current study, we examine cortical gray matter volumes in the same samples to determine whether gray matter volumes in LTAA are consistent with the cognitive results -i.e., exhibiting gray matter volumes comparable to NAC in most brain regions, except for possible indications of persistent shrinkage in the parietal lobe subserving spatial information processing. Results. We found gray matter shrinkage in LTAA in the parietal lobe consistent with the spatial processing deficits in this same sample. More compelling, in LTAA, the magnitude of parietal gray matter shrinkage was negatively associated with spatial processing domain performance and positively associated with alcohol dose. Gray matter volume deficits were present in the occipital and other cortical tissue, but poorer visuospatial test performance correlated significantly with smaller volumes in the parietal cortex only. Conclusions. Taken together, the cognitive and structural imaging data provide compelling evidence that chronic alcohol abuse results in shrinkage of the parietal cortex with associated deficits in spatial information processing

    Controlling for premorbid brain size in imaging studies: T1-derived cranium scaling factor vs. T2-derived intracranial vault volume. Psychiatry Res.

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    Abstract Intracranial vault (ICV) volume, obtained from T2-weighted magnetic resonance imaging (MRI), is generally used to estimate premorbid brain size in imaging studies. T1-weighted sequences lack the signal characteristics for ICV measurements [they have poor contrast at the outer boundary of sulcal cranium scaling factor (CSF)] but are valuable in imaging studies due to their excellent gray vs. white matter contrast. Smith et al. [NeuroImage 17 (2002) 479] suggested a T1-derived cranium scaling factor as an alternative control variable for premorbid brain size in cross-sectional studies. This index, which is computed using the SIENAX software, is a scaling factor comparing an individual's skull to a template skull derived from the Montreal Neurological Institute (MNI) average of 152 T1 studies (the MNI152). SIENAX computes coarsely defined estimates for the individual and MNI skulls rather than well-defined volumes. To test how well this approach would work as a control variable for premorbid brain size in cross-sectional studies, we compared the T1-derived cranium scaling factor to T2-derived ICV measurements in a sample of 92 individuals: 39 white males, 22 white females, and 31 African-American males, with an age range of 26 -78 years. The correlation between T1-and T2-derived variables was 0.94 and did not differ across subject groups. The T1-derived cranium scaling factor accounted for a statistically significant portion (87%) of the variance of the T2-derived ICV measure and thus is a good surrogate for ICV measurement of premorbid brain size as a reference measure in MRI atrophy studies. Furthermore, neither race, sex, nor age accounted for any additional variance in ICV, indicating that neither race-, gender-, nor age-associated cranial bone thickness effects were present in this data set

    Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer’s Disease Treated with Anti-Amyloid Beta Therapy

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    Amyloid-related imaging abnormalities (ARIA) are adverse events reported in Alzheimer’s disease trials of anti-amyloid beta (Aβ) therapies. This review summarizes the existing literature on ARIA, including bapineuzumab, gantenerumab, donanemab, lecanemab, and aducanumab studies, with regard to potential risk factors, detection, and management. The pathophysiology of ARIA is unclear, but it may be related to binding of antibodies to accumulated Aβ in both the cerebral parenchyma and vasculature, resulting in loss of vessel wall integrity and increased leakage into surrounding tissues. Radiographically, ARIA-E is identified as vasogenic edema in the brain parenchyma or sulcal effusions in the leptomeninges/ sulci, while ARIA-H is hemosiderin deposits presenting as microhemorrhages or superficial siderosis. ARIA tends to be transient and asymptomatic in most cases, typically occurring early in the course of treatment, with the risk decreasing later in treatment. Limited data are available on continued dosing following radiographic findings of ARIA; hence, in the event of ARIA, treatment should be continued with caution and regular monitoring. Clinical trials have implemented management approaches such as temporary suspension of treatment until symptoms or radiographic signs of ARIA have resolved or permanent discontinuation of treatment. ARIA largely resolves without concomitant treatment, and there are no systematic data on potential treatments for ARIA. Given the availability of an anti-Aβ therapy, ARIA monitoring will now be implemented in routine clinical practice. The simple magnetic resonance imaging sequences used in clinical trials are likely sufficient for effective detection of cases. Increased awareness and education of ARIA among clinicians and radiologists is vital

    ARIA in patients treated with lecanemab (BAN2401) in a phase 2 study in early Alzheimer\u27s disease

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    INTRODUCTION: Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at amyloid plaques. Amyloid-related imaging abnormalities (ARIA) profiles appear to differ for various anti-amyloid antibodies. Here, we present ARIA data from a large phase 2 lecanemab trial (Study 201) in early Alzheimer\u27s disease. METHODS: Study 201 trial was double-blind, placebo-controlled (core) with an open-label extension (OLE). Observed ARIA events were summarized and modeled via Kaplan-Meier graphs. An exposure response model was developed. RESULTS: In the phase 2 core and OLE, there was a low incidence of ARIA-E (\u3c10%), with \u3c3% symptomatic cases. ARIA-E was generally asymptomatic, mild-to-moderate in severity, and occurred early (\u3c3 months). ARIA-E was correlated with maximum lecanemab serum concentration and incidence was higher in apolipoprotein E4 (ApoE4) homozygous carriers. ARIA-H and ARIA-E occurred with similar frequency in core and OLE. DISCUSSION: Lecanemab can be administered without titration with modest incidence of ARIA

    Validation of 3‐ and 5‐point severity scales to assess ARIA‐E

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    Abstract INTRODUCTION Anti‐amyloid‐β (Aβ) monoclonal antibodies (mAbs) offer the promise of disease modification and are emerging treatment options in Alzheimer's disease. Anti‐Aβ mAbs require brain magnetic resonance imaging (MRI) examinations to detect anti‐amyloid‐induced amyloid‐related imaging abnormalities (ARIA), important adverse drug reactions associated with some anti‐Aβ mAbs currently available in the United States and in clinical development. We present a simple rating system for ARIA‐edema (ARIA‐E) that can assess severity on a 3‐ or 5‐point scale based upon a single linear measurement of the largest area of lesion, and dissemination in space, termed the 3‐point Severity Scale of ARIA‐E (SSAE‐3) and the 5‐point Severity Scale of ARIA‐E (SSAE‐5), respectively. METHODS MRI results were collected from 75 participants from the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) studies of gantenerumab. Three neuroradiologists experienced with the detection of ARIA‐E were selected to read all cases independently. One rater was then chosen for a second read to assess intra‐reader reproducibility. RESULTS The three raters had high agreement in identifying and grading ARIA‐E. The Cohen/Fleiss kappa (κ) scores (95% confidence interval [CI]) for the inter‐ and intra‐reader comparisons for SSAE‐3 and SSAE‐5 were 0.79 (0.70–1.00), 0.94 (0.94–1.00), 0.73 (0.66–1.00), and 0.90 (0.90–1.00), respectively. DISCUSSION Our study suggests that SSAE‐3 and SSAE‐5 are valid ARIA‐E rating scales for use in routine clinical practice by experienced radiologists in specialized settings. The application of these scales in everyday use in clinical practice will support the expansion of anti‐Aβ mAbs as a treatment option for people living with Alzheimer's disease. Highlights A simple rating scale is needed to rate severity of amyloid‐related imaging abnormalities–edema (ARIA‐E) in both research and clinical settings. The 3‐ and 5‐point Severity Scales of ARIA‐E (SSAE‐3/‐5) have good inter‐ and intra‐reader agreement. The SSAE‐3/‐5 have been used in most major Alzheimer's disease (AD) trials to date and are suitable for large‐scale use in routine clinical practice, which may help support the expansion of anti‐amyloid antibodies as treatment options for AD

    Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab: a historical, prospective secondary analysis

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    Background Amyloid-related imaging abnormalities due to haemosiderin deposition (ARIA-H) occur in patients with mild to moderate dementia due to Alzheimer's disease (AD) and have been reported with increased incidence in clinical trials of amyloid-lowering therapies under development for AD. Objective Our objective was to explore the relationship between the incidences of ARIA-H during treatment with placebo and different doses of bapineuzumab, a humanised monoclonal antibody directed against amyloid β. Methods Two neuroradiologists independently reviewed 2572 GRE/T2* MRI sequences from 262 participants in two phase two clinical trials of bapineuzumab and an open-label extension study. Readers were blinded to the participant's therapy, APOE ε4 genotype and medical history. Results Several risk factors for small ARIA-H <10 mm (microhaemorrhages) were identified: APOE ε4, bapineuzumab treatment, pre-existing small ARIA-H and use of antithrombotics. The HR (95%CI) for incident ARIA-H <10 mm associated with the number of APOE ε4 alleles was 11.9 (3.3 to 42.5) for 2 versus no alleles and 3.5 (1.0 to 12.0) for 1 versus no allele. The HR for bapineuzumab therapy was 3.5 (1.0 to 12.0); for the presence of baseline ARIA-H <10 mm, it was 3.5 (1.6 to 7.8), and for the use of antithrombotic agents it was 2.2 (1.0 to 4.8). The incidence rate for ARIA-H <10 mm was elevated only in the initial 6 months of active treatment and declined after this interval to a rate similar to that observed in the group treated with placebo. Conclusions ARIA-H represents a spectrum of MRI findings due to haemosiderin deposition that appears to be related to impaired vascular integrity. The increased risk for ARIA-H associated with APOE ε4 allele frequency, pre-existing ARIA-H, treatment with bapineuzumab and use of antithrombotic agents provides additional support for this hypothesis of loss of integrity of cerebral vessels due to amyloid burden

    Comparing ARIA-E severity scales and effects of treatment management thresholds

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    Introduction: Amyloid-related imaging abnormalities–edema (ARIA-E) is associated with anti-amyloid beta monoclonal antibody treatment. ARIA-E severity may be assessed using the Barkhof Grand Total Scale (BGTS) or the 3- or 5-point Severity Scales of ARIA-E (SSAE-3/SSAE-5). We assessed inter- and intra-reader correlations between SSAE-3/5 and BGTS. Methods: Magnetic resonance imaging scans were collected from 75 participants in the SCarlet RoAD and Marguerite RoAD studies. Three neuroradiologists reviewed scans at baseline and at follow-up. Concordance in dichotomized ARIA-E ratings was assessed for a range of BGTS thresholds. Results: SSAE-3/5 scores correlated with BGTS scores, with high inter-reader intraclass correlation coefficients across all scales. There was high agreement in dichotomized ratings for SSAE-3 > 1 versus BGTS > 3 for all readers (accuracy 0.85–0.93) and between pairs of readers. Discussion: SSAE-3/5 showed high degrees of correlation with BGTS, potentially allowing seamless transition from the BGTS to SSAE-3/5 for ARIA-E management
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