Citations

ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia in the elderly, marked by abnormal protein buildup (beta‐amyloid and tau) resulting in neuronal loss, especially in the medial temporal lobe and other limbic regions. The presence of transactive response DNA binding protein 43 (TDP‐43) immunoreactive inclusions in medial temporal lobe regions has also been associated with neuroimaging changes in limbic regions. It has been proposed that hypometabolism in limbic regions on [ 18 F] fluorodeoxyglucose positron emission tomography (FDG‐PET) in a patient with a slowly evolving amnestic syndrome may be a signature of the presence of TDP‐43. In this context, we observed an 86‐year‐old Caucasian female with dementia characterized by a slowly evolving amnestic syndrome, along with focal medial temporal atrophy evident on MRI and hypometabolism in limbic regions on FDG‐PET. The patient subsequently died and underwent an autopsy. We performed detailed neuroimaging and digital neuropathological analyses of the hippocampal subfields to better understand the relationship between clinico‐imaging findings and histopathology. In addition to TDP‐43, we identified three other pathological processes in the medial temporal lobe: sequestosome‐1/p62, argyrophilic grain disease (AGD), and primary age‐related tauopathy (PART). Hippocampal subfield volumes and rates of atrophy were no different from those of matched healthy controls, except for the atrophy rate in cornu ammonis 1 (CA1). Digital histopathology revealed the relative highest burden of pathology for p62, followed by TDP‐43, AGD, and PART in CA1. Multiple pathological processes appear to have contributed to the hippocampal atrophy and hypometabolism in our patient with a slowly progressive amnestic syndrome.

Purpose: These American Clinical Neurophysiology Society technical standards suggest best practices for electrical stimulation mapping (ESM) with subdural and stereotactic depth electrodes for seizure induction and mapping of brain function. Methods: A working group was convened from American Clinical Neurophysiology Society membership with expertise in ESM. PubMed searches were performed to identify pertinent peer-reviewed literature. Recurrent meetings reviewed progress, built consensus by discussion, and developed evidence-based recommendations to the extent possible. Recommendations: Stimulators used for ESM should have sufficient dynamic range, ability to interrupt a stimulus train, and ictal disrupt mechanism(s). Charge density should be calculated for the specific electrodes and ESM settings, the maximum safe limits being 52 to 57 μC/cm 2 /phase for subdural electrodes and not established for stereotactic depth electrodes. Subdural ESM for functional mapping is typically performed at 50-Hz pulse frequency, 200- to 300-µs pulse width, 2- to 8-s train duration, and 1- to 20-mA current strength. Stereo ESM is commonly performed using 2 different pulse frequencies: 1 Hz (300–500 µs pulse width, train duration up to 30 s, and often a constant current of 3–5 mA), and 50 Hz (100–500 µs pulse width, train duration 2-8 s, and 0.5–10 mA current intensity). Conclusions: This guideline provides technical standards for the performance of ESM, which will likely evolve over time with advances in technology and additional evidence (also see Graphical Abstract).

Abstract INTRODUCTION We investigated the association between alpha‐synuclein (α‐syn) pathology and brain glucose metabolism across the cognitive spectrum of Alzheimer's disease (AD) co‐pathologies. METHODS Fluorodeoxyglucose positron emission tomography (FDG‐PET) data from 829 Alzheimer's Disease Neuroimaging Initiative participants (648 cognitively impaired [CI], 181 unimpaired [CU]) were compared between α‐syn seed amplification assay (SAA) positive and negative groups. Interactions with cerebrospinal fluid (CSF) AD biomarkers were examined. RESULTS SAA+ was associated with widespread hypometabolism among CI individuals, particularly in posterior cortical regions, independent of CSF amyloid and tau levels in the occipital lobes. Regional hypometabolism mediated the effect of α‐syn SAA on disease severity in CI individuals, independent of CSF amyloid and tau levels. There were no influences of SAA on FDG‐PET in CU individuals. DISCUSSION This study supports a model in which α‐syn aggregation influences metabolic dysfunction, which then influences clinical disease severity, independent of AD. SAA+ could help optimize participant selection and outcome measures for clinical trials in AD. Highlights α‐synuclein seed amplification positivity (SAA+) was associated with hypometabolism in cognitively impaired individuals. Hypometabolism mediated the influence of α‐synuclein on disease severity. Occipital hypometabolism in SAA+ was independent of cerebrospinal fluid levels of Alzheimer's disease pathology. These findings can optimize future clinical trials targeting α‐synuclein pathology.

Abstract The design of clinical trials in Alzheimer's disease (AD) must consider the development of new plasma, cerebrospinal fluid (CSF), and imaging biomarkers. They must also define clinically meaningful outcomes for patients and set endpoints that measure these outcomes accurately. With the accelerated United States Food and Drug Administration (FDA) approval of the first anti‐amyloid, disease‐modifying treatment for AD, a monoclonal antibody called aducanumab, the landscape of clinical trial design is evolving. Enrolment in clinical trials may be impacted by the availability of this and other treatments, and trial design must take into consideration that patients may desire a disease‐modifying treatment rather than potentially being randomized to the placebo arm. The Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting discussed the consideration of well‐defined AD staging criteria in protocol design and how they influence more standardized inclusion/exclusion criteria for trials, as well as what constitutes meaningful differentiation between the stages. Discussion explored the current state of knowledge regarding biomarkers and how they can inform AD staging criteria, as many trials are now designed based on specific biomarker features, further underscoring the importance of coordinating AD staging criteria and biomarkers. The relationship between cognition and biomarkers has been studied and this must continue as trials move forward. Researchers, patients, clinicians, regulatory scientists, and payers discussed the state of the field as well as the future of symptomatic Alzheimer's disease clinical trials. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from academia and industry as well as patients, care partners, clinicians, regulators, and payers to discuss the topic of operationalizing selection criteria for clinical trials and the role of biomarkers. Well‐defined Alzheimer's disease (AD) staging criteria are an important consideration in study protocol design. Staging criteria and biomarkers must be coordinated to yield high‐quality clinical trial results that have meaning for patients with AD by selecting a population most likely to benefit from a specific treatment.

Background/Objectives: Stereotactic body radiation therapy (SBRT) for skull base reirradiation is particularly challenging, as patients have already received substantial radiation doses to the region, and nearby normal organs may have approached their tolerance limit from prior treatments. In this study, we reviewed the characteristics and capabilities of four advanced external beam radiation delivery systems and four modern treatment planning systems and evaluated the treatment plan quality of each technique using skull base reirradiation patient cases. Methods: SBRT plans were generated for sixteen skull base reirradiation patients using four modalities: the GK plan for the Elekta Leksell Gamma Knife Perfexion/ICON, the CyberKnife (CK) plan for the Accuray CyberKnife, the intensity-modulated proton therapy (IMPT) plan for the Hitachi ProBeat-FR proton therapy machine, and the volumetric-modulated arc therapy (VMAT) plan for the Varian TrueBeam STx. These plans were evaluated and compared using two novel gradient indices in addition to traditional dosimetry metrics for targets and organs at risk (OARs). The steepest border gradient quantified the percent prescription dose fall-off per millimeter at the boundary between the target and adjacent critical structures. This gradient index highlighted the system’s ability to spare nearby critical OARs. The volume gradient assessed the extent of dose spread outside the target toward the patient’s body. Results: All plans achieved comparable target coverage and conformity, while IMPT and VMAT demonstrated significantly better uniformity. The GK plans exhibited the highest border gradient, up to 20.9%/mm, followed by small-spot-size IMPT plans and CK plans. Additionally, IMPT plans showed the benefit of reduced dose spread in low-dose regions and the lowest maximum and mean doses to the brainstem and carotid artery. Conclusions: The advanced external beam radiotherapy modalities evaluated in this study are well-suited for SBRT in skull base reirradiation, which demands precise targeting of tumors with highly conformal doses and steep dose gradients to protect nearby normal structures.