Hippocampal Sparing Research Articles

Digital pathology analysis reveals TDP‐43 pathology as a strong predictor of glial activation in Alzheimer’s disease

AbstractBackgroundGlial activation plays a critical role in Alzheimer’s disease (AD) pathogenesis and is associated with amyloid‐β plaques and neurofibrillary tangles composed of phosphorylated tau (phospho‐tau). With approximately 40%‐60% of AD cases having limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), TDP‐43 pathology has become more the rule than the exception in AD brains. However, the effect of LATE‐NC in AD‐related glial activation is unknown.MethodWe analyzed the effect of TDP‐43 pathology on glial activation in three AD subtypes: hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. Twenty cases of each subtype (n = 60 total) were selected from the FLorida Autopsied Multi‐Ethnic (FLAME) cohort. Cases were immunohistochemically evaluated on serial sections of the hippocampus in the CA1 and subiculum subsectors, and superior temporal, inferior parietal, and mid‐frontal cortices with antibodies to CD68 (phagocytosis), GFAP (astrogliosis), GT‐38 (conformation‐specific AD‐type tau), 6F/3D (amyloid‐β), and phospho‐Serine 409/410 of TDP‐43 (pTDP‐43). Digital pathology was employed to quantify immunohistochemical staining. Multivariable regression modeling was utilized to understand the relationship between glial activation and AD pathologies.ResultThe level of glial activation, defined as % of immunoreactive surface area for CD68 and GFAP, was lowest in HpSp AD (0.54%, 13%), whereas typical AD (1.3%, 33%) and limbic predominant AD (1.3%, 30%) had similar levels suggesting a ceiling effect, or plateau, of gliosis levels (both p<0.001). HpSp AD was more often male (p<0.001) and younger at disease onset (p<0.001) compared to both typical AD and limbic predominant AD. Multivariable regression modeling of CD68 (subiculum R2 = 0.60) identified advanced tau to be a significant predictor of CD68 in all brain regions. LATE‐NC stage predicted increased CD68 levels in limbic brain regions. Multivariable regression modeling of GFAP (CA1 R2 = 0.60) showed that Aβ was the strongest predictor of astrogliosis in CA1 and subiculum (p<0.001). Advanced tau in CA1 and parietal cortex, LATE‐NC in subiculum and temporal cortex, and APOE4 genotype in CA1 predicted a significant increase in GFAP.ConclusionThese findings highlight the significant role TDP‐43 pathology plays in affecting the microenvironment and interplay between neuroinflammation and neurodegeneration and have important implications for therapeutic strategies in AD with co‐morbid LATE‐NC.

Relationship of Atrophy and Tau Imaging Subtypes in Prodromal and Clinical AD

AbstractBackgroundAmyloid‐positive MCI and AD participants show heterogeneity in patterns of atrophy and tau‐deposition. We sought to directly compare the previously‐defined subtypes (hippocampal sparing (HpSp), limbic predominate (LP), typical AD (tAD), and minimal atrophy) derived from [18F]flortaucipir PET (T) and structural MRI (N) in the context of positive amyloid (A). In addition, we examined assessed associations between demographic factors and subtype group for atrophy or tau.Methods243 amyloid‐positive participants from ADNI with MRI and tau PET scans at the same visit were included (160 MCI, 83 AD). Brain volumes were extracted using Freesurfer version 6 and tau PET SUVR values were extracted using standard techniques. Hippocampal to cortical ratios for grey matter volume and tau SUVR were calculated as previously described (Risacher et al. 2017 Neurology). Minimal pathology subjects showed similar levels of atrophy relative to cognitive normal participants. Relationships between atrophy‐ and tau‐based subtypes, as well as their relationship to sex and race/ethnicity were assessed using a Chi‐square test. An ANOVA model was used to compare age and education between atrophy‐ and tau‐based subtypes.ResultsA significant association between tau‐based and atrophy‐based subtypes was observed, driven by consistency in minimal atrophy, HpSp, and tAD groupsp = 0.024). In addition, differences by sex and race/ethnicity were also observed for atrophy but not tau subtypes with non‐Hispanic Whites most likely to be either minimal atrophy or tAD, while African Americans were more likely to be HpSp. Finally, significant differences in age and education were observed across the atrophy subtypes, with the HpSp group being younger and less educated, while the LP were older and more educated.ConclusionsOverall, we observed consistency between atrophy‐based and tau‐based subtypes, especially minimal pathology, tAD, and HpSp forms. Interesting associations between demographics and atrophy but not tau subtypes were also observed. Future studies in larger and more diverse samples are needed. These results underscore the importance of examining heterogeneity in amyloid‐positive MCI and AD across multiple modalities to better understand patterns of A/T/N pathophysiology that may have implications for risk of progression and personalized therapeutic strategies.

Distinct amyloid‐β deposits inversely correlate with glial activation and tangles in Alzheimer’s disease subtypes

AbstractBackgroundThe coarse‐grained plaque is a biochemically and morphologically distinct amyloid‐β (Aβ) deposit that was discovered in clinically‐defined atypical Alzheimer’s disease (AD). Unlike other Aβ deposits, this plaque is not observed in cognitively normal people. This study investigates the hypothesis that the coarse‐grained plaque is distinctly associated with AD neuropathologic change and glial activation within the context of AD subtypes.MethodSixty AD cases from the FLorida Autopsied Multi‐Ethnic (FLAME) cohort were assessed. We included 20 hippocampal sparing (HpSp) AD, 20 typical AD, and 20 limbic predominant AD. Immunohistochemistry was performed on the middle frontal, inferior temporal, and inferior parietal cortex for AD neuropathology (Aβ [6F/3D], phospho‐tau [AT8], tau [GT38]) and glial activation (CD68 [KP1] and GFAP). Digital pathology was used to quantify burden. Thioflavin‐S tangle counts were performed at time of neuropathologic diagnosis. Distinct deposit types, including classic cored plaques, coarse‐grained plaques, cerebral amyloid angiopathy (CAA)‐Type 1, and CAA‐Type 2, were semi‐quantitatively scored on Aβ (Fig. 1). Correlations between demographic, clinical, and neuropathologic characteristics were assessed using Spearman rho analysis and reported if p<0.05. An independent cohort of ∼100 HpSp AD cases will be assessed to validate initial findings.ResultIn the frontal cortex of HpSp AD, higher scores of classic cored plaques correlated with older age at onset and death, non‐APOE ε4 carriership, and less CAA‐Type 1 and Type 2 (Fig. 2). On the contrary, the severity of coarse‐grained plaques correlated with a younger age at onset and death, APOE ε4 carriership, higher scores for CAA‐Type 1, CAA‐Type 2, and increased burden of Aβ, GFAP, and CD68. Classic cored plaques correlated negatively with phospho‐tau and tau, whereas coarse‐grained plaques correlated positively with phospho‐tau, tau, and tangles. The two deposit types were negatively correlated with each other. Correlations were weaker but showed similar trends in other AD subtypes (Fig. 2) and regions.ConclusionWithin HpSp AD, classic cored and coarse‐grained plaques show distinct correlations with glial activation, (phospho‐)tau, and tangles. These results suggest opposite directions of association for these deposits on AD neuropathologic change that may impact clinical symptoms. These findings are relevant to therapies targeting overall Aβ pathology.

RADT-03. A CASE OF PARTIAL HIPPOCAMPAL-AVOIDANCE WHOLE BRAIN RADIOTHERAPY IN A PATIENT WITH METASTATIC INFILTRATION OF THE LEFT HIPPOCAMPUS

Abstract In addition to surgical resection and systemic therapy, whole brain radiotherapy (WBRT) is a crucial modality in the treatment of cancers that have metastasized to the brain. It has been shown to improve intracranial disease control and overall survival. However, WBRT also increases the risk of radiation-associated damage to sensitive structures like the hippocampus, often resulting in neurocognitive dysfunction and decline. Hippocampal avoidance WBRT (HAWBRT) has been shown to reduce neurocognitive sequalae without worsening survival outcomes or increasing the risk of metastasis to the spared region compared to conventional WBRT. In cases where both hippocampi cannot be completely spared, the effectiveness of partial hippocampal avoidance on neurocognitive function and tumor control have been poorly described. We present the case of a patient diagnosed with triple negative invasive ductal carcinoma of the breast and disease metastatic to the brain, lung, bones, adrenal glands, and liver. Brain imaging revealed multiple brain metastases, two of which were noted near the left hippocampus. The patient underwent partial HAWBRT with complete avoidance of the right hippocampus and partial avoidance of the left. At 1-year follow-up, there was no evidence of metastasis in or near the partially spared left hippocampus. The patient’s neurocognitive functional status remained consistent with the findings of prospective randomized trials in which total bilateral hippocampal sparing was performed. To our knowledge, no such case has been presented in the literature. Further studies assessing the role of partial hippocampal avoidance in WBRT are needed.

Longitudinal patterns of Alzheimer's disease subtypes: A follow-up magnetic resonance imaging and single-photon emission computed tomography study.

Alzheimer's disease (AD) is a biologically heterogenous disease. In a previous study, we classified 245 patients with probable AD into the typical AD (TAD), limbic-predominant (LP), hippocampal-sparing (HS) and minimal-change (MC) subtypes based on their medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission computed tomography, and described differences in clinical features among the patients with different AD subtypes. This study aimed to clarify the longitudinal patterns of changes in patients with the various AD subtypes by follow-up brain imaging analyses. Follow-up magnetic resonance imaging or single-photon emission computed tomography data obtained 12-48 months after the first brain imaging were investigated in 79 patients with probable AD, comprising 25 of the TAD subtype, 19 of the LP subtype, 17 of the HS subtype and 18 of the MC subtype. All patients of the TAD subtype remained as the same subtype at follow up. Approximately 37% of patients of the LP subtype and 29% of patients of the HS subtype progressed to the TAD subtype, and 17%, 33% and 6% of the MC subtype progressed to the TAD, LP and HS subtypes, respectively. The group of patients showing subtype progression was associated only with a longer follow-up duration. There might be different progression patterns and progression rates of changes among the atypical AD subtypes. Further longitudinal brain imaging studies might provide information regarding the pathophysiological association between the various AD subtypes, and might be helpful for determining appropriate therapies and management methods. Geriatr Gerontol Int 2023; 23: 919-924.

Prise en charge des cancers bronchiques à petites cellules de stade localisé, actualisation: Management of limited-stage small cell lung cancer, an update

Limited-stage small cell lung cancer (LS-SCLC) represents 15-20% of all lung cancers, and because of its rapid tumor kinetics, less than a third of SCLC are discovered at limited stage. The different steps and modalities of its management are well defined and codified. They involve a comprehensive staging assessment using CT scans of the chest, abdomen, and pelvis, PET-CT scans, and ideally brain imaging using MRI to avoid missing a more extensive stage of the disease, which would significantly alter the treatment strategy. The treatment consists of a combination of chemotherapy with platinum/ etoposide and radiotherapy, possibly delivered in a hyperfractionated schedule with two daily sessions. SCLC is particularly both chemosensitive and radiosensitive, so that the initial evaluation shows frequently a complete response, and prophylactic cranial irradiation (PCI) is then recommended. Relapses are unfortunately frequent, less responsive to second line treatments, and therapeutic options are limited. No targeted agents or immunotherapy have robustly demonstrated efficacy in the treatment of LS-SCLC. Even if hyperfractionated accelerated radiotherapy (HFART) at the dose of 45Gy in 30 fractions has given the best results, most clinicians use once-daily chemoradiation regimen (60-70Gy). Studies have evaluated dose escalation either with HFRAT or with conventional fractionation (66 to 70Gy). Several trials are currently investigating the addition of immunotherapy to chemoradiation, hippocampus sparing PCI or the omission of PCI. In rare cases of very early stage SCLC, surgery or stereotactic radiotherapy may be envisaged.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Hippocampal Sparing Whole Brain Radiation Therapy: 2 Arc Coplanar and 4 Arc Noncoplanar Planning Comparison

Whole brain radiation therapy (WBRT) has been shown to provide palliation but with negative neurocognitive effects associated with radiation-induced damage to the hippocampus. Sparing of the hippocampus has been shown to reduce the risk of neurocognitive deficit. Hippocampal sparing WBRT plan optimization is commonly done using 2 arc coplanar technique. The purpose of this work is to show that 4 arc noncoplanar plans will improve hippocampal sparing without compromising PTV coverage. Retrospective WBRT with hippocampal sparing using 2 arc coplanar and 4 arc noncoplanar VMAT technique were done on 10 patients previously treated for intracranial lesions. CT and MRI fused images were used to delineate the whole brain and hippocampus. Strictly following RTOG 0933 atlas guidelines, the hippocampus was manually delineated by a single Radiation Oncologist. Plans with prescription dose of 30 Gy in 10 fractions were generated using the 2 techniques. The 4 arc noncoplanar plan included 2 partial field arcs with couch angle at 90 degrees and 2 coplanar arcs. The 2 noncoplanar partial arcs consisted of a clockwise arc and a counterclockwise arc with gantry angles between 5 and 179 degrees. Lens were kept to < 7 Gy and pituitary gland to < 30 Gy. Dosimetric parameters from both techniques were compared by paired t-test. Radiation dose to the hippocampus was significantly reduced using 4 arc noncoplanar plan when compared to 2 arc coplanar plan. While hippocampus D100% were similar (7.25 Gy vs 7.32 Gy, p = 0.557), the mean dose (9.46 Gy vs 9.87 Gy, p = 0.003) and D0.03cc (12.48 Gy vs 12.94 Gy, p < 0.001) were significantly reduced with 4 arc noncoplanar plans. Whole brain PTV coverage remained at V100% = 95% for both techniques. However, the 4 arc noncoplanar plans showed significantly improved D2% (32.56 Gy vs 32.97 Gy, P = 0.003), D98% (28.11 Gy vs 27.91 Gy, P = 0.01), and homogeneity index (0.141 vs 0.159, P < 0.001). The 4 arc noncoplanar plans improved hippocampal sparing without compromising PTV coverage or compromise to other nearby organs at risk.

Identifying and Re-Planning Challenging Retrospective SRS Patients to Evaluate the Potential for a White Matter Tract Sparing Knowledge-Based Planning Model

Diffusion tensor imaging (DTI) with automated tractography, along with auto-parcellation of volumetric MRI (vMRI), allows for reliable parcellation of critical white matter (WM) and hippocampal structures in the brain. Knowledge-based planning (KBP) may facilitate the optimization of new brain SRS plans that highly prioritize WM tracts and hippocampal sparing, allowing for cognitive preservation. However, building a high-performing model is challenging as the geometry of WM tracts and their proximity to planning target volumes (PTVs) can vary substantially. In this work we propose an iterative step for creating a KBP model where we used a preliminary model to identify challenging plans and worked on improving their dosimetry to refine the model predictions. Tractography of eloquent deep WM was obtained from high resolution DTI, along with auto-segmentation of bilateral hippocampi from vMRI and an open-source software for processing and analyzing brain MRI images. These ROIs were imported to the treatment planning system as organs-at-risk (OARsDTI). A preliminary KBP model was built from an IRB-approved cohort of 30 consecutive patients (75 plans total) treated for brain metastasis with non-coplanar SRS with total dose from 20 to 30 Gy in one to five fractions using a LINAC. This preliminary model was used to identify the 7 plans with the highest doses to the OARsDTI. These plans were re-optimized with new objectives on the OARsDTI that were partially or totally overlapped with the isodose line representing 30% of the prescription dose (as a surrogate for proximity to the PTV). The OARsDTI that were overlapping with the PTV were excluded from this analysis. We evaluated the re-optimized plans (PlanNew) by comparing maximum and mean dose (Dmax and Dmean, respectively) of OARsDTI to the initial values from the preliminary plans (PlanPre). In order to verify that the PlanNew were not compromising other structures or treatment goals, we also evaluated conformity index (CI), PTV coverage and the dosimetry of OARs included in the PlanPre. Additionally, the PlanNew were normalized to our clinical standard used for the PlanPre (100% of prescription dose to 98% of the PTV). In the 7 plans, there were 30 OARsDTI overlapping with the 30% isodose line. Refining the dosimetric objectives for the OARsDTI decreased the Dmean on average 31% when comparing PlanNew to Planpre (p<0.05, Wilcoxon rank-sum test). The CI of the PlanNew were not statistically different from the PlanPre. Although Dmax of PlanNew was 12% lower than Dmax of Planpre, the difference was not statistically different. The addition of a plan refinement step was shown to improve dose to the OARsDTI in 7 challenging SRS plans. The generation of these plans are a necessary step to creating a refined KBP model capable of accounting for the high variability in WM tracts geometry and their proximity with PTV.

Hippocampal Avoidance Whole BRAIN Radiotherapy (HA-WBRT) with Simultaneous Integrated BOOST (SIB) vs. HA-WBRT in Multiple Brain Metastases: A Dosimetric Comparison

There has been a paradigm shift in managing multiple brain metastases. Various options include SRS, WBRT, and WBRT with Hippocampal avoidance (HA-WBRT). There is no consensus for the treatment of multiple brain metastases (>3 brain metastases). A new technique that has proven feasible is dose escalation in the form of simultaneous integrated boost. The aim of this study was to compare the dosimetry parameters of HA-WBRT plus simultaneous integrated boost versus HA-WBRT alone in multiple brain metastases. In a prospective trial,16 patients with multiple brain metastasis (≥ 3) from various primaries with good performance scores (ECOG PS ≤ 2) are recruited. All patients underwent CT simulation (1.5 mm slice thickness) and RT plans for HA-WBRT with (SIB) and HA-WBRT alone were made. A 5 mm margin was given to the bilateral hippocampus for Hippocampal Avoidance. In the HA-WBRT plan for the PTV i.e., whole brain plus 3 mm margin minus hippocampal avoidance region (H.A.), a dose of 30 Gy in 10 fractions is prescribed over two weeks. In HA-WBRT with SIB, a dose of 30 Gy in 10 fractions over two weeks is prescribed for the PTV, which is the clinical target volume, minus the hippocampal avoidance region (H.A.) minus the PTV Mets (1 mm margin to the GTV). A simultaneous Integrated Boost of 42.5 Gy in 10 # over two weeks is prescribed for PTVmets. Planning was done using a VMAT technique with 6MV F.F.F. beam energy in a treatment planning software. The mean B/L hippocampus volume is 3.47 cc. The mean dose of PTV D98% in HA-WBRT plans is 27.45 Gy, whereas in HA-WBRT with S.I.B. is 27.36 Gy (p = 0.90). V30 mean dose in HA-WBRT plans is 93.35%, and the mean dose in HA-WBRT SIB is 91.87% (p = 0.12). PTV D2% mean dose in HA-WBRT Is 36.06 Gy, and in HA-WBRT -S.I.B., it is 40.58 (p< 0.001). The mean bilateral hippocampus Dmax in HA-WBRT is 14.85 Gy, and in HA-WBRT-SIB is 14.25 Gy (p = 0.35). The mean Bilateral hippocampus D100% is 9.14 Gy in HA-WBRT and 9.01 Gy in HA-WBRT-SIB (p = 0.54). The mean brainstem Dmax in HA-WBRT is 36.82 Gy compared to 38.55 Gy in HA-WBRT-SIB (p = 0.02). In patients planned for a simultaneous boost along with hippocampal sparing whole brain radiotherapy, the mean dose to the hippocampal region did not increase. The Dmax of Brainstem, optic chiasma is significantly higher in HA-WBRT-). Our study, the mean dose to PTVmets is more than 45 Gy and more than 50 Gy to GTV with a BED of more than 65 Gy (α/ß = 10) to the metastases, which is equivalent to some ablative dose regimens. Simultaneous integrated boost along with hippocampal sparing radiotherapy thus helps in sparing the hippocampus and delivering higher doses to the metastases and intermediate doses to the rest of the brain, addressing the microscopic disease.

Hippocampal Avoidance Whole Brain Radiotherapy with Reduced Whole Brain Dose in Patients with Non-Small Cell Lung Cancer Brain Metastases

Hippocampal avoidance whole brain radiation (HA-WBRT) results in improved neurocognitive function (NCF) compared to standard WBRT, but > 50% of patients still experience NCF failure. We examined whether gentler fractionation of HA-WBRT with lower biologically effective dose (BED), typically delivering 30 Gy over 15 versus 10 fractions, may allow for better hippocampal sparing without impacting intracranial disease control in patients with non-small cell lung cancer (NSCLC). We conducted a retrospective study of patients with NSCLC receiving HA-WBRT between 2014-2022. Endpoints were distant brain failure free survival (DBFFS), local brain failure free survival (LBFFS), left and right hippocampal mean BED2 and BED21%. Kaplan-Meier survival analysis and Welch's t-test were performed. NCF outcomes were graded with CTCAEv5. The IRB approved this study. Sixty-nine consecutive patients treated with HA-WBRT were included, with median follow up of 51.2 weeks. Median age was 63 years and 29% had a targetable mutation. Thirty-six patients received standard HA-WBRT with median dose of 30 Gy (range 30-35 Gy) in 10 fractions (range 10-14). Thirty-three patients received reduced BED HA-WBRT, with median dose of 30 Gy (range 23-30) in 15 fractions (range 9-15) to the radiographically uninvolved brain. All patients in the reduced BED (RD) group had a simultaneous integrated boost (SIB) to gross disease (median 37.5 Gy (range 36-37.5 Gy)), while 18/36 in the standard dose (SD) group had an SIB (median 35 Gy (range 34-39 Gy)). There were no significant differences between SD and RD cohorts in age, systemic therapy use before WBRT or targetable mutations. There was no significant difference in median DBFFS of the SD [23.1 weeks (IQR 11.3-49.3)] and RD groups [40 weeks, (IQR 20.9-109.1)] (p = 0.27). There was also no difference in LBFFS of the SD (median 26.4 weeks, IQR 11.3-76.2) and RD groups (median 40 weeks, IQR (21-71.4) (p = 0.84). For the left and right hippocampi, both mean BED2 and D1% were significantly lower in the RD group (Table 1). Median cognitive disturbance was Grade (G) 0 (range 0-3) in both groups, with 4 G>2 events in the SD cohort vs. 3 in the RD cohort. In this single-institution cohort, HA-WBRT using a gentler fractionation with SIB was associated with improved hippocampal sparing without compromising intracranial control in patients with NSCLC. We suggest that further optimization of HA-WBRT dose and schedule may improve both intracranial control and NCF outcomes. This study is limited by its retrospective nature and potential selection bias. A phase II prospective study to test these concepts is ongoing.

Application of a Novel Methodology for Efficient Optimization of Hippocampal Avoidance Whole-Brain Radiotherapy

A growing awareness of the long-term neurocognitive toxicity associated with whole-brain radiotherapy (WBRT) has led to the development of newer delivery methods to achieve relative hippocampal sparing. In order to accomplish the required target coverage and dose constraints, however, hippocampal-avoidance WBRT (HA-WBRT) can prove labor intensive and time-consuming. We therefore developed a simplified and efficient planning model for generating optimized HA-WBRT treatment. Target volumes and organs at risk (OARs) were contoured per the NRG-CC001 protocol, including the whole-brain parenchyma, bilateral hippocampi, and optic apparatus. Treatment was planned using Eclipse 16.1 for a TrueBeam STx 2.7 LINAC, applying customizable optimization and clinical goals templates to rapidly generate uniform plans. An isocenter was placed at the point corresponding to the center of mass between the bilateral contoured 3-dimensional hippocampi. Volumetric modulated arc therapy (VMAT) using 6MV photons was designed using two sets of bi-directional full arcs, with collimator rotations of 85° and 95°. The two paired sets independently covered the superior and inferior portions of the treatment volume, respectively. Arcs shared a total 2cm overlap in the superior-inferior (X Jaws) direction. A total of 10 consecutive cases of HA-WBRT were retrospectively re-optimized using the described planning model. All plans were normalized to cover 95% of the treatment volume with prescription dose (V30Gy = 95%). The model achieved favorable dosimetry relative to NRG-CC001 per protocol constraints. Average maximal dose to the hottest 2% and minimal dose to 98% of the volume were 32.22 ± 0.26 Gy and 29.82 ± 1.46 Gy, well within protocol limits of 37.5 Gy and 25 Gy, respectively. The average maximal dose to 100% of the hippocampi (D100%) and to its hottest 0.03cc (Dmax) were 8.50 ± 0.34 Gy and 12.85 ± 0.70 Gy, compared to protocol limits of 9Gy and 16Gy, respectively. Mean Dmax to the total optic apparatus was 29.67 ± 0.52 Gy, with a maximum value within the cohort of 30 Gy, matching protocol constraints. The above presented methodology for optimizing HA-WBRT can consistently and efficiently generate plans with excellent target coverage and strict hippocampal avoidance per current collaborative group constraints. This method can be broadly applied to decrease the burden and heterogeneity across HA-WBRT planning.

Retrospective Evaluation of Neuropathologic Proxies of the Minimal Atrophy Subtype Compared With Corticolimbic Alzheimer Disease Subtypes.

Alzheimer disease (AD) is neuropathologically classified into 3 corticolimbic subtypes based on the neurofibrillary tangle distribution throughout the hippocampus and association cortices: limbic predominant, typical, and hippocampal sparing. In vivo, a fourth subtype, dubbed "minimal atrophy," was identified using structural MRI. The objective of this study was to identify a neuropathologic proxy for the neuroimaging-defined minimal atrophy subtype. We applied 2 strategies in the Florida Autopsied Multi-Ethnic (FLAME) cohort to evaluate a neuropathologic proxy for the minimal atrophy subtype. In the first strategy, we selected AD cases with a Braak tangle stage IV (Braak IV) because of the relative paucity of neocortical tangle involvement compared with Braak >IV. Braak IV cases were compared with the 3 AD subtypes. In the alternative strategy, typical AD was stratified by brain weight and cases having a relatively high brain weight (>75th percentile) were defined as minimal atrophy. Braak IV cases (n = 37) differed from AD subtypes (limbic predominant [n = 174], typical [n = 986], and hippocampal sparing [n = 187] AD) in having the least years of education (median 12 years, group-wise p < 0.001) and the highest brain weight (median 1,140 g, p = 0.002). Braak IV cases most resembled the limbic predominant cases owing to their high proportion of APOE ε4 carriers (75%, p < 0.001), an amnestic syndrome (100%, p < 0.001), as well as older age of cognitive symptom onset and death (median 79 and 85 years, respectively, p < 0.001). Only 5% of Braak IV cases had amygdala-predominant Lewy bodies (the lowest frequency observed, p = 0.017), whereas 32% had coexisting pathology of Lewy body disease, which was greater than the other subtypes (p = 0.005). Nearly half (47%) of the Braak IV samples had coexisting limbic predominant age-related TAR DNA-binding protein 43 encephalopathy neuropathologic change. Cases with a high brain weight (n = 201) were less likely to have amygdala-predominant Lewy bodies (14%, p = 0.006) and most likely to have Lewy body disease (31%, p = 0.042) compared with those with middle (n = 455) and low (n = 203) brain weight. The frequency of Lewy body disease was increased in both neuropathologic proxies of the minimal atrophy subtype. We hypothesize that Lewy body disease may underlie cognitive decline observed in minimal atrophy cases.

Distribution and failure patterns of primary central nervous system lymphoma related to the hippocampus: Implications for hippocampal sparing irradiation.

20 Background: Hippocampus (HC) injury by conventional whole brain radiotherapy (C-WBRT) contributes to the neurocognitive decline in primary central nervous system lymphoma (PCNSL). Hippocampal avoidance (HA–WBRT) could minimize neurocognitive impairment by reducing the radiation dose to HC. However, its feasibility in PCNSL has not been examined regarding the incidence of HC involvement and failures. In this retrospective study, we assessed the risk of hippocampal area involvement at diagnosis and after treatments in PCNSL patients. Methods: We identified 278 immunocompetent PCNSL patients diagnosed between 2000 and 2020. After high dose methotrexate-based induction chemotherapy followed by observation or consolidation including RT, cytarabine alone, or autologous stem cell transplantation (ASCT). HC was contoured on T1 MRI image and expanded with a 5mm margin, generating hippocampal avoidance region (HAR). The extent of initial and recurrent lesions was evaluated using pre-induction and post-consolidation T1 contrast-enhanced MRI images. HC failure was defined as recurrence or progression at HAR and those who progressed after induction were excluded. The median follow up was 38.7 months (3.1-239.4). Results: Of 278 patients diagnosed with PCNSL, 39.9% of them had initial lesions at HAR. After induction therapy, 212 evaluable patients received consolidation as follows: RT (n=145, 68.4%) consisting of C-WBRT (n=114), HA-WBRT (n=23), and focal RT (n=8), observation (n=38, 17.9%), cytarabine only (24, 11.3%), and ASCT (n=5, 2.4%). Intracranial failures occurred in 47.6% (n=101) of patients, with 33.7% (n=34) of them in HAR. The multivariate analysis identified multifocal disease (HR 3.86, 95% CI 1.15-9.73, p=0.004) as the only factor associated with the risk of HC failure. Those with unifocal lesion outside HAR showed the lowest HC failure rate, 7.0%, while the highest HC failure rate, 25.4% was observed in the subgroup with multifocal disease within HAR at diagnosis. In the lowest risk group (unifocal lesion outside HAR, n=66), C-WBRT was not significantly associated with HC failure (HR 0.57, CI 0.09-3.33, P=.572) or intracranial failure (HR 0.88, CI 0.40-1.91, P=.748). Conclusions: Our data suggest the HA-WBRT could be explored in patients whose lesion is unifocal and located outside HAR. WBRT, including the hippocampus, did not significantly change HC failure for patients without initial HAR involvement. Further prospective study will be warranted to assess the feasibility of HA-WBRT in the subgroup with low risk of HC failure.

Prevalence and clinical associations of atrophy subtypes using clinical routine image analysis software in MCI patients from a memory clinic population

AbstractBackgroundThree patterns of brain atrophy have been consistently identified in cases of Alzheimer’s dementia [1]: a limbic‐predominant (LP) phenotype, with atrophy of the hippocampus but relatively spared neocortex; a hippocampal sparing (HS) phenotype, with atrophy in the cortex (especially lateral temporal and parietal lobes) but sparing of the hippocampus; and a typical/diffuse (TD) phenotype that presents with atrophy in both. A recent study extended this concept to a less severely affected memory clinic population (the MEMENTO Study). Here, we assessed atrophy subtypes in that same population using an approach based on the output of QyScore® an FDA‐approved and CE‐marked image analysis software.Method1642 MCI participants from the MEMENTO cohort (Age 71±9, MMSE 27.8±2.0, CDR‐SB 0.6±0.7) had 3DT1 MRI scans analyzed with QyScore®. 678 (41%) had amyloid status from CSF or PET, of which 193 (28%) were amyloid‐positive (A+). Neurodegeneration‐positive (N+) atrophy subtypes were defined on individual scans using z‐scores from parietal cortex and hippocampus volumes referenced to 1290 cognitively normal individuals. LP and HS were defined by atrophy (z←1.64) of parietal lobe or hippocampus only, and TD by atrophy in both structures (otherwise N‐).ResultThe proportion of single‐domain amnestic (aMCIsd), multi‐domain amnestic (aMCImd), single‐domain non‐amnestic (naMCIsd) and multi‐domain non‐amnestic (naMCImd) individuals was 10%, 50%, 21% and 18% respectively. N+ subtypes were more prevalent in amnestic (aMCIsd 18%, aMCImd 17%) than non‐amnestic (naMCIsd 8%, naMCImd 10%) presentations. N+ subtypes were more common in A+ participants, especially the amnestic presentations (aMCIsd 42%, aMCImd 29%). Overall, the HS subtype was the most common (8% of all cases, 16% of A+ cases), followed by LP (4%/6%) and TD (2%/3%). The LP subtype was more prevalent in amnestic presentations.ConclusionThe relatively low prevalence of the TD subtype in this cohort is consistent with [2]. The overall prevalence of N+ subtypes in MEMENTO by this method is intermediate between those previously reported using a similar method for ADNI CN A+ and aMCI A+ cohorts [3].[1] Ferriera et al. (2020) Neurology 94:436 [2] Planche et al. (2021) Alz &amp; Dem 17(4):651 [3] Charil et al. (2018) AAIC

Four‐year cognitive decline in mild cognitive impairment patients with distinct baseline neuroanatomical atrophy profiles: A MEMENTO and QyScore® study

AbstractBackgroundNeuroanatomical atrophy profile is increasingly recognised as a valuable characterisation in mild cognitive impairment (MCI) individuals and may provide prognostic information about cognitive decline.Method1153 MCI participants from the MEMENTO memory clinic study with 48‐month longitudinal follow‐up were included (mean (sd) Age = 70.6 (8.2), 60% female, CDR‐SB = 0.63 (0.72)). QyScore® volumetric quantification was applied to baseline 3DT1 images and four recognized neuroanatomical subtypes defined based on regional atrophy with respect to an internal normative database (z←1.64) [1,2]: no/minimal atrophy [N‐] (n = 1,012), limbic predominant: LP (n = 37), hippocampal sparing: HS (n = 84) and combined hippocampal and cortical atrophy [typical/diffuse: TD] (n = 20). 145 participants were amyloid positive (A+) via CSF or PET (Age = 73.7 (5.9): 47% female: N‐ = 114, LP = 8, HS = 21 and TD = 2). All participants underwent cognitive and functional assessments at baseline and 48 months, including mini‐mental state examination (MMSE), clinical dementia rating (CDR), Free and Cued Selective Reminding Test (FCRST) and Instrumental Activities of Daily Living (IADL) scale. Linear regression analysis (correcting for age, sex and baseline performance) investigated the relationship between baseline neuroanatomical subtype and subsequent 4‐year cognitive decline. Bonferroni correction was applied.ResultAt month 48, all subtypes demonstrated significant decline across memory, orientation, and executive function. Severity of decline varied across subscales and subtype and was particularly marked in A+ LP individuals (Figure 1). IADL remained stable for the N‐ and TD subgroups. 143 participants converted to dementia [102 = N‐, 18 = LP, 15 = HS, and 8 = TD subtypes, representing 10%, 49%, 18% and 40% of the total N‐, LP, HS and TD atrophy subtypes respectively]. HS and N‐ individuals also demonstrated the least decline across all domains and did not significantly differ on any tests. LP atrophy subtype demonstrated the greatest decline across all cognitive domains as well as global CDR and IADL (p&lt;0.001 compared with N‐ and HS subtypes). Similarly, TD phenotypes showed significant decline across multiple cognitive subscales compared with N‐ and HS subtypes (p&lt;0.001) particularly for orientation and global CDR.ConclusionEarly atrophy profiles in MCI populations can provide insights into the domains and severity of future patient progression over 4 years.[1] Planche et al., (2020)[2] Schwarz et al., (AAIC2022)

WMH and biomarker heterogeneity of individuals on the amyloid pathway

AbstractBackgroundResearch studies of Alzheimer’s disease (AD) are increasingly using biomarker‐based criteria to define disease. One useful definition is amyloid positivity since it identifies those on a pathological pathway that likely results in AD. However, within amyloid positive individuals, there is substantial heterogeneity in terms of when biomarkers that measure different aspects of the disease become abnormal. Here we examine this heterogeneity amongst biomarkers that reflect various aspects of the disease process.MethodCSF Amyloid positive individuals’ data from Alzheimer’s Disease Neuroimaging Initiative (ADNIGO/2/3) were used (n = 376). Demographics were compared across diagnostic group using linear regression and Fisher’s exact tests where appropriate, table 1. CSF phosphorylated tau (ptau), whole‐brain and hippocampal volume, Logical memory (LM) and Trails A and B, and white matter hyperintensity (WMH) volumes were used to derive data‐driven subtypes using the z‐score version of the SuStaIn algorithm. The algorithm produced subtypes with differing patterns of biomarker orderings. SuStaIn calculated z‐scores using 86 CSF amyloid negative, APOE e4 non‐carrier healthy controls, selected from ADNIGO/2/3. Proportions of APOE e4 carriers, and clinical diagnosis were compared between subtypes using Fisher’s exact test.Result359 individuals were grouped into three subtypes (figure 1); determined using cross‐validation. Subtype one (n = 136) had an initial event of WMH, followed by LM, trails A and B, and whole‐brain volume (hippocampal sparing). Subtype two (n = 115) had initial events of ptau, followed by LM and hippocampal volume (tau‐led). Subtype three (n = 108) had initial events of LM total, followed by ptau and hippocampal volume (tau‐late). 17 individuals were not subtyped, as their biomarker data showed no significant abnormalities and would suggest that they are not on an AD pathway.There was a trend towards a higher proportion APOE e4 carriers in subtype one and three (p = .06). There was a significant difference in clinical diagnosis between subtypes (p &lt; .001), with subtype one having a lower proportion of CNs and a higher proportion of MCIs than subtypes two and three (figure 1).ConclusionWe found considerable heterogeneity in biomarker progression sequences in individuals with elevated amyloid.

Disentangling the heterogeneity of brain atrophy in Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia. In AD patients, structural MRI analyses have identified various brain atrophy patterns, which are likely the result of differences in regional pathology distribution and variable presence of co‐pathologies.MethodWe included 496 ADNI participants and applied our robust collaborative clustering approach (RCC) to the MRI scans of the Aβ+ participants. RCC removes noise while simultaneously clustering subjects and features. Group comparisons were performed applying Kruskal‐Wallis analyses for quantitative variables and chi‐square tests for categorical variables (Table 1). Power transformations were used to normalize the distribution of quantitative variable for linear regression analyses. APOE ε4 presence and white matter hyperintensity (WMH) volume were included as predictors. P‐values &lt;0.05 were considered statistically significant.ResultWe identified three distinct atrophy clusters among the Aβ+ participants (Table 1). A “limbic predominant” atrophy cluster showed greater cingulate and right hippocampus, inferior and middle temporal lobe atrophy than the cognitively unremarkable (CU) Aβ‐ reference group (Figure 1). The diffuse atrophy cluster showed greater parieto‐occipital‐temporal atrophy. The “hippocampus sparing” atrophy cluster showed a similar neocortical atrophy pattern except for less atrophy in the temporal lobe. The limbic predominant cluster participants had a higher APOE ε4 prevalence than the hippocampal sparing cluster participants (Table 1, 2). The three clusters had higher baseline ADAS‐Cog13 and flortaucipir SUVR binding in all the Braak staging‐defined areas than the CU Aβ‐ reference group (Table 3). The diffuse atrophy cluster had higher ADAS‐Cog13 scores, florbetapir composite scores, and flortaucipir SUVRs in all the Braak staging‐defined areas than the two other atrophy clusters. The hippocampal sparing atrophy cluster participants were older and had higher WMH volumes than the limbic predominant atrophy cluster and the CU Aβ‐ reference group participants.ConclusionOur clustering method discovered three reproducible atrophy patterns in AD, including typical and atypical presentations. This finding likely reflects different combinations of co‐pathology leading to the development of AD, some of which are captured with MRI. Mainly, WMH contributed to the heterogeneity of AD and the atypical neocortical variant.

CenTauRz: A standardized quantification of tau PET scans

AbstractBackgroundOver the past decade, several PET tracers were developed to visualise and quantify tau pathology in vivo. However, all these tracers have distinct off‐target binding, different dynamic ranges and likely different levels of non‐specific binding resulting in large variability in semiquantification. We propose to standardise the sampling and the quantification across all available tau tracers.Method549 participants underwent tau scans with either 18F‐FTP (Cognitively Unimpaired (CU) = 54/AD = 14), 18F‐MK6240 (CU = 186/AD = 89), 18F‐PI2620 (CU = 17/AD = 21), 18F‐PM‐PBB3 (CU = 30/AD = 28), 18F‐GTP1 (CU = 7/AD = 38) or 18F‐RO948 (CU = 35/AD = 30). All CU individuals were Aβ‐ and all AD were Aβ+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. We constructed a “universal” tau mask from the intersection of all the specific tau tracer masks, after subtracting AD from CU. All tau PET studies were sampled with a Mesial Temporal (MTL) and a Meta Temporal (MetaT) composites constrained by the universal mask. For each tracer and in composite, the mean and standard deviation of the Aβ‐ CU SUVR for each tau tracer were used to generate z‐scores (CenTauRz).ResultUsing a threshold of 2 CenTauRz in the MetaT regions, all tracers highly discriminated Aβ+ AD from Aβ‐ CU (ACC = [0.94‐1], sens = [0.84‐1], spec = [0.96‐1]) with mean CenTauRz for the different AD cohorts ranging from 8 to 14. Lower accuracy was observed in the MTL (ACC = [0.78‐1]) due to lower sensitivity in some cohorts [0.65‐1] however, the specificity was similar to that in the MetaT composite (spec = [0.94,1]).ConclusionAll tracers exhibited comparably high discriminative power to separate Aβ+ AD from Aβ‐ CU, where AD Aβ+ displayed a consistent range of CenTauRz across tracers. However, there were some differences between cohorts. For example, different PET scanners, with different sensitivities were used. For some cohorts, scans were selected as extreme representative cases, while for others the scans were more representative of clinical settings, with AD patients at early stages (with low or negative tau scans) or with suspected hippocampal sparing subtype that likely explains the lower accuracy in the MTL for some cohorts. Further studies with larger cohorts to validate the universal mask and CenTauRz scale are ongoing.

Neuropathological features of antemortem atrophy‐based subtypes of Alzheimer’s disease

AbstractBackgroundPure Alzheimer’s disease (AD), characterized by combined amyloid and tau pathology, is not the most prevalent form of the disease as non‐AD pathologies (e.g., alpha‐synuclein and TDP‐43) are commonly observed postmortem. The role of AD and non‐AD pathologies is unclear in relation to disease heterogeneity. Therefore, we investigated whether antemortem MRI‐based atrophy subtypes of AD differ in postmortem neuropathological features and comorbid non‐AD pathologies.MethodsWe selected individuals from the ADNI with antemortem MRI evaluating brain atrophy within 2 years before death; antemortem diagnosis of AD dementia/mild cognitive impairment; and a postmortem‐confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena using a recent conceptual framework: typicality (spanning limbic predominant AD to hippocampal sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathological evaluation included AD hallmarks (amyloid‐beta, tau), non‐AD pathologies (alpha‐synuclein, TDP‐43) and concomitant pathological burden. Partial correlations assessed the associations between antemortem atrophy subtype dimensions and postmortem neuropathological outcomes.ResultsIn 31 individuals (mean age = 80y, 26% females), antemortem typicality was significantly associated with neuropathological features: amyloid‐beta (rho = ‐0.39 overall), tau (rho = ‐0.38 regionally), neuritic plaque density (rho = ‐0.4 overall), alpha‐synuclein (rho = ‐0.39 regionally), TDP‐43 (rho = ‐0.49 overall), and concomitance pathological burden (rho = ‐0.59 regionally). This suggests that limbic predominant AD was associated with higher burden of these pathologies compared to hippocampal sparing AD. Antemortem severity was significantly associated with concomitant pathological burden (rho = ‐0.43 regionally), such that typical AD showed higher burden than minimal atrophy AD.ConclusionsBased on our direct antemortem‐to‐postmortem validation, we hypothesize that: (a) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non‐AD pathologies; (b) limbic predominant AD and typical AD subtypes may share similar biological pathways, making them more vulnerable to the investigated AD and non‐AD pathologies compared to hippocampal sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing prevailing knowledge of biological heterogeneity in AD.

Quality assurance and safety of hippocampal avoidance prophylactic cranial irradiation in the multicenter randomized phase III trial (NCT01780675)

ObjectiveNCT01780675, a multicenter randomized phase III trial of prophylactic cranial irradiation (PCI) versus PCI with hippocampal sparing in small cell lung cancer (SCLC) investigated neurocognitive decline and safety. As part of quality assurance, we evaluated if hippocampal avoidance (HA)-PCI was performed according to the NCT01780675 trial protocol instructions, and performed a safety analysis to study the incidence and location of brain metastases for patients treated with HA-PCI. MethodsThis retrospective analysis evaluated the quality of the irradiation given in the randomized controlled trial (RCT) comparing SCLC patients receiving PCI with or without hippocampal avoidance, using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). The dose distribution for each patient receiving HA-PCI was retrieved and analyzed to evaluate if the treatment dose constraints were met. A questionnaire was sent out to all participating sites, and data on radiotherapy technique, pre-treatment dummy runs, phantom measurements and treatment electronic portal imaging device (EPID) dosimetry were collected and analyzed. As part of the safety analysis, the follow-up magnetic resonance imaging (MRI) or computerized tomography (CT) scans on which cranial disease progression was first diagnosed were collected and matched to the radiotherapy planning dose distribution. The matched scans were reviewed to analyze the location of the brain metastases in relation to the prescribed dose. ResultsA total of 168 patients were randomized in the NCT01780675 trial in 10 centers in the Netherlands and Belgium from April 2013 until March 2018. Eighty two patients receiving HA-PCI without evidence of brain metastases were analyzed. All patients were treated with 25 Gy in 10 fractions. Dummy runs and phantom measurements were performed in all institutions prior to enrolling patients into the study. The radiotherapy (RT) plans showed a median mean bilateral hippocampal dose of 8.0 Gy, range 5.4–11.4 (constraint ≤ 8.5 Gy). In six patients (7.3%) there was a protocol violation of the mean dose in one or both hippocampi. In four of these six patients (4.9%) the mean dose to both hippocampi exceeded the constraint, in 1 patient (1.2%) only the left and in 1 patient (1.2%) only the right hippocampal mean dose was violated (average median dose left and right 8.9 Gy). All patients met the trial dose constraint of V115%PTV ≤ 1%; however the DmaxPTV constraint of ≤ 28.75 Gy was violated in 22.0% of the patients. The safety analysis showed that 14 patients (17.1%) developed cranial progression. No solitary brain metastases in the underdosed region were found. Two out of 11 patients with multiple brain metastasis developed metastasis in the underdosed region(s). ConclusionsThe radiotherapy quality within the HA-PCI trial is performed according to the protocol guidelines. The dose constraints to the hippocampi are met in the vast majority of cases. In all patients, the volume of the brain for which a higher dose was accepted, is according to the trial. However, within this volume there are small areas with higher doses than advised.