Neuropathological Findings Research Articles

Recent advances in benign adult familial myoclonus epilepsy

AbstractBenign adult familial myoclonus epilepsy (BAFME), also called familial cortical myoclonic tremor and epilepsy (FCMTE), autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME), and familial adult myoclonic epilepsy (FAME) is a disorder characterized by infrequent generalized seizures and tremulous myoclonus with an autosomal dominant mode of inheritance. The diagnosis of BAFME was previously based on clinical features and electrophysiological findings, but genetic analysis is now increasingly becoming important in the diagnosis after identification of repeat expansions; BAFME is caused by expansions of TTTCA and TTTTA repeats in SAMD12 (BAFME1), STARD7 (BAFME2), MARCHF6 (BAFME3), YEATS2 (BAFME4), TNRC6A (BAFME6), or RAPGEF2 (BAFME7). The findings strongly support a concept of “repeat motif–phenotype correlation” which we have proposed previously. Pathologically, BAFME1 patients carrying heterozygous expansions of TTTCA and TTTTA repeats do not show any obvious abnormal neuropathological findings in the central nervous system. These pathological findings, in addition to electrophysiological studies, suggest a dysfunctional neuronal circuit that causes enhanced excitability of the sensorimotor cortex. Autopsied brains of BAFME1 patients showed RNA foci consisting of UUUCA repeats in cortical neurons and cerebellar Purkinje cells. These findings suggest that RNA toxicity caused by UUUCA repeat expansions is involved in the pathogenesis of BAFME. Since our discovery of the causative gene for BAFME1, progress has been made in genetic studies of each type of BAFME, as well as in pathogenetic mechanisms of BAFME caused by TTTCA and TTTTA expansions. Here, we present a comprehensive review on recent advances focusing on expanded TTTCA and TTTTA repeats in BAFME.

Neuropathological Findings in Short-Chain enoyl-CoA Hydratase 1 Deficiency (ECHS1D): Case Report and Differential Diagnosis.

Short-chain enoyl-CoA hydratase 1 (ECHS1) is an enzyme that participates in the metabolism of valine, transforming methacrylyl-CoA in β-hydroxy-isobutyryl-CoA. There is an accumulation of intermediate acids and ammonium as a consequence of its deficit. This background generates a harmful environment for the brain causing neuronal death and severe brain lesions. We present a case of a 39 weeks newborn that died at 31 hours old. We found vacuolization in basal areas, brain stem, cerebellum and spinal cord white matter (spongiform myelinopathy). These vacuoles were periodic acid-Schiff stain negative, there were neither acompanion gliosis nor macrophagic reaction. These findings were suggestive of metabolism acid disorders. The final diagnosis was confirmed by genetic study by massive parallel sequencing, showing 2 previously described pathogenic variants (c.160C > T and c.394G > A) of short-chain enoyl-CoA hydratase 1 gene. To our knowledge, this is the first case reporting the histological changes in short-chain enoyl-CoA hydratase 1 deficiency. Histological study provides useful information to orientate the diagnostic and clarify the clinical manifestations, especially in hospitals where urine or blood samples are not taking routinely or where genetic studies may not be performed.Synopsis: The main neuropathological findings in Short-chain enoyl-CoA hydratase 1 deficiency are the presence of whitte matter vacuoles in basal areas, brain stem and spinal cord.

Tuberous sclerosis complex is associated with a novel human tauopathy.

Tuberous sclerosis complex (TSC) is a neurogenetic disorder leading to epilepsy, developmental delay, and neurobehavioral dysfunction. The syndrome is caused by pathogenic variants in TSC1 (coding for hamartin) or TSC2 (coding for tuberin). Recently, we reported a progressive frontotemporal dementia-like clinical syndrome in a patient with a mutation in TSC1, but the neuropathological changes seen in adults with TSC with or without dementia have yet to be systematically explored. Here, we examined neuropathological findings in adults with TSC (n = 11) aged 30-58years and compared them to age-matched patients with epilepsy unrelated to TSC (n = 9) and non-neurological controls (n = 10). In 3 of 11 subjects with TSC, we observed a neurofibrillary tangle-predominant "TSC tauopathy" not seen in epilepsy or non-neurological controls. This tauopathy was observed in the absence of pathological amyloid beta, TDP-43, or alpha-synuclein deposition. The neurofibrillary tangles in TSC tauopathy showed a unique pattern of post-translational modifications, with apparent differences between TSC1 and TSC2 mutation carriers. Tau acetylation (K274, K343) was prominent in both TSC1 and TSC2, whereas tau phosphorylation at a common phospho-epitope (S202) was observed only in TSC2. TSC tauopathy was observed in selected neocortical, limbic, subcortical, and brainstem sites and showed a 3-repeat greater than 4-repeat tau isoform pattern in both TSC1 and TSC2 mutation carriers, but no tangles were immunolabeled with MC1 or p62 antibodies. The findings suggest that individuals with TSC are at risk for a unique tauopathy in mid-life and that tauopathy pathogenesis may involve TSC1, TSC2, and related molecular pathways.

Neuropathological autopsy findings in an individual with Alzheimer’s disease who received long‐term treatment with lecanemab (BAN2401)

AbstractBackgroundAnti‐amyloid antibodies administered to patients with Alzheimer’s disease can result in marked reduction of brain amyloid as measured by neuroimaging with amyloid PET ligands. However, there is a lack of pathological data. Here we present neuropathological findings in a patient who received ∼173 weeks of (interrupted) treatment with lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated β‐amyloid species (protofibrils) and insoluble fibrils, in a Phase 2 study (NCT01767311, Alz Res Therapy 2021;13:80).MethodBrain autopsy was performed on an ∼85 year old whose lecanemab treatment history over 6 years was: 79 weeks 10mg/kg monthly in the double‐blind (DB) phase, then 98 weeks without treatment, then 94 weeks at 10mg/kg biweekly in the open‐label extension (OLE) phase, followed by ∼12 weeks of treatment discontinuation prior to death.ResultClinically, memory symptoms started age ∼77. Study entry was at age ∼80, with mild dementia, CDR 0.5, CDR‐SB 3, and MMSE 24. Florbetapir PET scan was positive at baseline, and negative after 53 weeks DB treatment and at start of OLE. These findings and clinical measures are shown in Table 1. ARIA was not observed during the study. Autopsy showed low brain weight (1052g) with diffuse atrophy, including hippocampi, consistent with atrophy seen on clinical MRI scans. Microscopic findings showed tau pathology including tangles and threads (by AT8 antibody and Bielschowsky staining) throughout neocortex (Braak NF stage VI; B3). Beta‐amyloid immunohistochemical stain (6E10) showed only modest amyloid load (Thal phase 2; A1), with near‐absence of diffuse amyloid deposits and only scattered clusters of neuritic plaques (CERAD stage B; C2).ConclusionIn this autopsy of an individual with Alzheimer’s disease treated with lecanemab, neuropathological changes showed tau and β‐amyloid deposits. However, the pattern of significant tau pathology, accompanied by only a mild degree of β‐amyloid deposits, (A1B3C2), is uncommon in typical (untreated) Alzheimer’s disease. For example, in the NACC neuropathology dataset, only 2% of brains with Braak B2 or B3 show Thal stage A0 or A1. This pattern suggests that lecanemab treatment resulted in a reduction in brain amyloid, consistent with the amyloid PET scanning results in this patient.

Divergent magnetic resonance imaging atrophy patterns in Alzheimer’s disease and primary age‐related tauopathy

AbstractBackgroundPrimary age‐related tauopathy (PART) is a pathological disorder characterized by the presence of tau‐positive neurofibrillary tangles (NFTs) and no amyloid‐beta (Aβ) deposition (“definite PART”). Currently, the diagnosis of PART is histologically assessed by the presence of tau positive NFT with Braak staging and a Consortium to Establish a Registry for Alzheimer’s disease (CERAD) Aβ stage of 0.MethodOur study compared brain magnetic resonance imaging (MRI) with neuropathological findings in patients with PART and AD, while assessing the relationship between brain atrophy and clinical impairment. We analysed 233 participants: 32 with no plaques (“definite” PART ‐ CERAD 0), and 201 cases within the AD spectrum, with 25 with sparse (CERAD 1), 76 with moderate (CERAD 2) and 100 with severe (CERAD 3) degree of neuritic plaques.ResultUpon correcting for age, sex and age difference at MRI and death, there were significantly higher levels of atrophy in CERAD 3 compared to CERAD 1‐2 and a trend compared to CERAD 0. In the anterior temporal region, there was a trend for higher levels of atrophy in CERAD 0 compared to CERAD 1. We then assessed the correlation between regional brain atrophy and CDR‐sum‐of‐boxes score for PART and AD, and found that overall cognition deficits are directly correlated with regional atrophy in the AD continuum, but not in definite PART. We further observed correlation between regional brain atrophy with multiple neuropsychological metrics in AD, while PART showed only specific correlations between language deficits and anterior temporal atrophy.ConclusionOverall, these findings support PART as an independent pathologic process from AD.

Impact of α‐synuclein RNA interference on Neuropathological and Clinical Phenotypes in a mouse model of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by the pathologic accumulation of beta amyloid (Aβ), Tau and α‐synuclein (α‐syn). The role of α‐synuclein has been extensively studied in Parkinson’s disease, but less so in AD. Recent studies have shown that α‐syn may also play a role in AD and its downregulation could be protective against the toxic effects of Aβ accumulation. First, we hypothesized that selectively knocking down α‐syn improves the neuropathological, biochemical, and cognitive findings in AD. Second, we tested whether α‐syn ablation could enhance AD treatments with donepezil (pro‐cholinergic) and memantine (glutamate antagonist), which are currently ineffective at slowing progression of disease.MethodPSAPP transgenic mice were used to model AD and knockdown of a‐syn was performed by RNA interference. 43 non‐transgenic and 33 PSAPP mice were used in this study. We have selectively knocked‐down α‐syn by two differentmethodsa) first, by stereotaxic bilateral injection of either LV‐shRNA (pan) α‐syn or LV‐shRNA‐luc (control) into the hippocampus and striatum; b) second, by intraperitoneal injection of a complex of ApoB11 and shRNA‐α‐syn, which was previously shown to cross the BBB. Water maze and open field testing were used to measure cognitive deficits. Biochemistry and immunohistochemistry were performed on each hemibrain.ResultWe have successfully utilized these two strategies to down‐regulate α‐syn as shown by lower levels of α‐syn through biochemistry and immunohistochemistry. Importantly, this correlates with a significant reduction in the number of Aβ plaques and tau peptides, suggesting the overlap between Aβ, tau and α‐syn in pathology. Other findings include a reduction in Iba1 staining in mice injected with LV‐shRNA‐α‐syn suggesting involvement of microglia in pathology. Open field testing indicates that α‐synuclein reduction could restore context dependent memory. Moreover, injection of LV‐shRNA‐α‐syn into the hippocampus of mice treated with memantine rescues cognitive deficits to a non‐disease level, as shown by all variables analyzed during water maze trials with an invisible platform (time, entrances and passes in correct zone).ConclusionOverall, this study provides evidence that α‐synuclein knock‐down improves some of the neuropathological and cognitive deficits and could be of therapeutic value in AD, especially when combined with a glutamate antagonist.

Quantifying Extent, the Spatial Distribution of Flortaucipir PET Uptake, in an Autopsy Cohort and its Correspondence to Post‐Mortem Staining of Alzheimer’s Disease Biomarkers

AbstractBackgroundIn Alzheimer’s disease, neurofibrillary tangle (NFT) burden can be characterized in postmortem staining and in vivo NFT‐specific flortaucipir PET by increases in intensity and spatial distribution. Previous work compared intensity based standard uptake value ratios (SUVRs) from Early Tau and MUBADA volumes of interest (VOIs) in detecting Braak stage pathology. We propose a measure called Extent to quantify the spatial distribution of NFT‐specific uptake in flortaucipir PET from the Phase III study AV‐1451‐A16 and compare against Early Tau and MUBADA SUVRs in detecting Braak stage pathology and post‐mortem amyloid burden.MethodsThis retrospective analysis of the AV‐1451‐A16 study included 60 subjects that underwent ante‐mortem flortaucipir imaging and post‐mortem assignment of Braak stages and Thal/CERAD scoring for amyloid burden. The processing of the flortaucipir scans and the recording of neuropathological findings were performed as previously described except cerebellum crustaneous was used as a reference region. Extent was calculated by 1) creating a Z‐score image using 16 young cognitively normal controls, 2) retaining voxel clusters with Z‐scores smaller than a false discovery corrected p‐value of 0.01, and 3) calculating the ratio of the number of surviving voxels against the total number of voxels in the mask. Flortaucipir positivity was defined as greater than 2.5 SD of the mean of young controls for Early Tau and MUBADA SUVRs and as non‐zero for Extent. Amyloid positivity was defined by a Thal/CERAD scoring of 2 or higher and compared to flortaucipir positivity using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).ResultsExtent detected subjects with flortaucipir positivity comparably to Early Tau in Braak stages I, II, and III while detecting more subjects with flortaucipir positivity in Braak stages V and VI than Early Tau and MUBADA (Table 1 and Figure 1). For amyloid positivity, Extent had the highest sensitivity (79.62%) and NPV (29.42%) while MUBADA had the highest specificity (87.50%) and PPV (97.06%) (Table 2).ConclusionBased on the Correspondence to post‐mortem staining, the Extent measure of flortaucipir spatial distribution may provide benefit over intensity based SUVRs in detecting flortaucipir and amyloid positive subjects for inclusion in future studies.

Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation

Mutations in the gene encoding the ubiquitously expressed free radical scavenging enzyme superoxide dismutase-1 (SOD1) are found in 2–6% of amyotrophic lateral sclerosis patients. The most frequent SOD1 mutation worldwide is D90A. Amyotrophic lateral sclerosis caused by this mutation has some unusual features: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement. Furthermore, the mutant protein resembles the wild type, with normal content and enzymatic activity in the central nervous system. Here, we report neuropathological findings in nine patients homozygous for the D90A mutation. All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem. In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns. We also found intense gliosis in circumscribed cortical areas of the frontal and temporal lobes and in the insula. In these areas and in adjacent white matter, there were SOD1 staining neuropil threads. A few SOD1-immunopositive cytoplasmic neuronal inclusions were observed in cortical areas, as were glial nuclear inclusions. As suggested by the symptoms and signs and earlier neurophysiological and imaging investigations, the histopathology in patients homozygous for the D90A SOD1 extends beyond the motor system to include cognitive and sensory cortical areas. However, even in the patients that had a symptomatic disease duration of more than 2 or 3 decades and lived into their 70s or 80s, there were no SOD1-inclusion pathology and no typical dysfunction (apart from the musculature) in non-nervous organs. Thus, only specific parts of the CNS seem to be vulnerable to toxicity provoked by homozygously expressed mutant SOD1.

Sporadic Creutzfeldt–Jakob Disease in the young (50 and below): 10-year review of United Kingdom surveillance

IntroductionSporadic Creutzfeldt–Jakob Disease (sCJD) is the commonest human prion disease, with a median age of onset of 68 years. We characterise the clinical, investigation, and neuropathological features in young individuals with sCJD using data from UK national CJD surveillance.MethodsReferrals between 2011 and 2021 were examined, with definite (post-mortem confirmed) or probable sCJD cases included. Clinical features, MRI, EEG, CSF RT-QuIC, 14-3-3, PRNP sequencing and neuropathological findings were examined. We compared younger (≤ 50 years age of onset) with older individuals. Records of Non-sCJD referrals were also reviewed.Results46 (4%) young individuals were identified (age at onset 25–50) from 1178 cases. 15 (33%) were autopsy confirmed. Psychiatric disturbance (37% vs 22%, p = 0.02) and headache (11% vs 3%, p = 0.01) at presentation, and longer disease duration (by 1.45 months, 95% CI 0.43–2.79, logrank p = 0.007) were commoner. CSF RT-QuIC showed lower sensitivity (82% vs 93%, p = 0.02). There was no difference in sensitivity of MR brain or CSF 14-3-3. There were no significant co-pathologies in autopsy-confirmed cases. For non-sCJD referrals, 41 cases were of other CJD subtypes, and 7 non-prion diagnoses.ConclusionsYoung-onset sCJD is more likely to present with neuropsychiatric symptoms and headache, longer disease duration, and lower sensitivity of RT-QuIC. These findings may be driven by the underlying molecular subtypes. Our results guide the evaluation of younger individuals presenting with rapidly progressive cognitive, neuropsychiatric, and motor decline, and emphasise the need for additional vigilance for atypical features by clinicians and CJD surveillance programmes worldwide.

Peripheral neuropathy and MOG-IgG: A clinical and neuropathological retrospective study

BackgroundMyelin oligodendrocyte glycoprotein antibodies (MOG-Abs) may rarely be associated with peripheral nervous system involvement. We aimed to test MOG-Abs in patients with undetermined peripheral neuropathy (PN). MethodsConsecutive patients with available sural nerve biopsy and paired serum sample were retrospectively identified (January, 1st 2016-November, 1st 2021) and tested for MOG-Abs with live cell-based assay (CBA). Patients with antibody titre ≥1:160 (secondary H + L antibody) and selective MOG-IgG presence (IgG-Fc predominance) were considered MOG-IgG positive. All positive samples were analysed with immunohistochemistry and CBAs for antibodies against Neurofascin-155 and Contactin-1. Clinical and neuropathological data were collected through clinical reports. ResultsAmong 163 patients, 5 (3%) resulted positive for predominantly IgG MOG-Abs (median titer 1:320, range 1:160–1:5120), none showed other concomitant antibodies. Median age was 74 years-old (range 55–81), median disease duration was 60 months (range 1–167), 60% of patients were female. Of these, 4/5 cases had clinical features suggestive of acute (n = 1) or chronic (n = 3) inflammatory demyelinating neuropathy, 2/5 fulfilled the criteria of combined central and peripheral demyelination (CCPD) whilst 3/5 had isolated PNS involvement. Neuropathological findings showed mixed axonal-demyelinating features in 2/5, predominant demyelination in 3/5 cases. Other neuropathological hallmarks included paranodal demyelination (n = 3), myelin outfoldings (n = 4), slight inflammatory infiltrates (n = 3), onion bulbs (n = 3), and clusters of regeneration (n = 4). DiscussionMOG-IgG can be detected in patients with isolated PN or CCPD. Clinical and neuropathological features are suggestive for demyelination and slight inflammation. Further studies should include larger cohorts of patients to elucidate the utility of MOG-Abs testing in PN.

Is intracranial electroencephalography mandatory for MRI-negative neocortical epilepsy surgery?

MRI-negative focal epilepsy is one of the most challenging cases in surgical epilepsy treatment. Many epilepsy centers recommend intracranial electroencephalography (EEG) for MRI-negative cases, especially neocortical epilepsy. This retrospective study aimed to explore whether intracranial monitoring is mandatory in MRI-negative neocortical epilepsy surgery and the factors that significantly influence the decision on whether to perform intracranial recording. In this study, consecutive surgical patients with focal MRI-negative neocortical epilepsy were recruited. All patients underwent routine preoperative evaluation according to the dedicated protocol of the authors' epilepsy center to determine the treatment strategy. Patients were divided into two groups according to the surgical strategy, i.e., a direct group and a stereo-EEG (SEEG)-guided group. History of epilepsy, seizure frequency, interictal and ictal EEG data, PET data, PET/MRI coregistration data, neuropathological findings, and surgical outcomes were compared between the two groups. Multivariate analysis was performed to identify factors influencing the decision to perform SEEG monitoring. Sixty-four patients were included in this study, 19 and 45 of whom underwent direct and SEEG-guided cortical resection, respectively. At an average follow-up of 3.9 years postoperatively, 56 patients (87.5%) had Engel class I results without permanent neurological deficits. Surgical outcomes were not significantly different between the direct and SEEG-guided groups (94.7% vs 84.4%). PET hypometabolic abnormalities were detected in all patients. There were significant differences between the two groups in the extent of hypometabolism (focal vs nonfocal, p < 0.01) and pathological subtype (focal cortical dysplasia type II vs others, p = 0.03). Multivariate analysis revealed that the extent of hypometabolism (OR 0.01, 95% CI 0.00-0.15; p = 0.001) was the only independent factor affecting the treatment strategy. Careful selection of patients with MRI-negative neocortical epilepsy may yield favorable outcomes after direct cortical resection without intracranial monitoring. PET/MRI coregistration plays an essential role in the preoperative evaluation and subsequent resection of these patients. Intracranial monitoring is not a mandatory requirement for surgery if the focal hypometabolic areas are consistent with the findings of semiology and scalp EEG.

Epilepsy-associated death in the Southwestern Ontario: A clinicopathological correlation study.

Patients with epilepsy are at elevated risk for premature mortality, of which sudden unexpected death in epilepsy (SUDEP) is one of the leading causes. SUDEP incidence varies significantly depending on the population and the methods used to document the cause of death. We performed retrospective case review at the London Health Sciences Centre for the period of 2000 to 2018. Clinical information, scene investigations, general pathology findings, toxicology, and neuropathology findings were obtained, examined, and confirmed by two neuropathologists and one epileptologist. The characteristics were compared and summarized. We also evaluated the impact of 2010 revision of Ontario Coroner Act Regulation, which significantly limited whole brain examination. Among the 12,206 cases reviewed, we identified 152 cases with a known history of epilepsy. Ninety-seven cases (64%) were classified as SUDEP. There were significantly more SUDEP decedents found dead unwitnessed at night in prone position, than non-SUDEP. Generalized seizures were strongly associated with SUDEP. A male predominance was observed in SUDEP group between 15 and 35 years old. Near half of the brains examined were "unremarkable." There was no difference in neuropathology findings between SUDEP and non-SUDEP groups. After implementation of the 2010 revision of Ontario Coroner Act Regulation, fixed whole brain examination was reduced from 88% to 7% of the epilepsy-related death investigation. Except a lower diagnosis rate of "inflammatory/infectious changes," there were no significant differences in neuropathology findings. This is the first detailed clinical-pathological study on epilepsy-related death based on a Canadian cohort. This study reinforces the previously reported findings in SUDEP and highlights the importance of clinicopathological correlation for accurate classification of epilepsy-related death.

Sleep architecture and sleep-disordered breathing in fatal insomnia

Study objectivesFatal insomnia (FI) is a rare prion disease severely affecting sleep architecture. Breathing during sleep has not been systematically assessed. Our aim was to characterize the sleep architecture, respiratory patterns, and neuropathologic findings in FI. MethodsEleven consecutive FI patients (ten familial, one sporadic) were examined with video-polysomnography (vPSG) between 2002 and 2017. Wake/sleep stages and respiration were evaluated using a modified scoring system. Postmortem neuropathology was assessed in seven patients. ResultsMedian age at onset was 48 years and survival after vPSG was 1 year. All patients had different combinations of breathing disturbances including increased respiratory rate variability (RRV; n = 7), stridor (n = 9), central sleep apnea (CSA) (n = 5), hiccup (n = 6), catathrenia (n = 7), and other expiratory sounds (n = 10). RRV in NREM sleep correlated with ambiguous and solitary nuclei degeneration (r = 0.9, p = 0.008) and reduced survival (r = −0.7, p = 0.037). Two new stages, Subwake1 and Subwake2, present in all patients, were characterized. NREM sleep (conventional or undifferentiated) was identifiable in ten patients but reduced in duration in eight. REM sleep occurred in short segments in nine patients, and their reduced duration correlated with medullary raphe nuclei degeneration (r = −0.9, p = 0.005). Seven patients had REM without atonia. Three vPSG patterns were identified: agitated, with aperiodic, manipulative, and finalistic movements (n = 4); quiet-apneic, with CSA (n = 4); and quiet-non-apneic (n = 3). ConclusionsFI patients show frequent breathing alterations, associated with respiratory nuclei damage, and, in addition to NREM sleep distortion, have severe impairment of REM sleep, related with raphe nuclei degeneration. Brainstem impairment is crucial in FI.

Longitudinal Patterns of Cortical Atrophy on MRI in Patients With Alzheimer Disease With and Without Lewy Body Pathology.

Although Alzheimer disease (AD) and dementia with Lewy bodies (DLBs) represent 2 different pathologies, they have clinical overlap, and there is a significant degree of co-occurrence of their neuropathologic findings. Many studies have examined imaging characteristics in clinically diagnosed patients; however, there is a relative lack of longitudinal studies that have studied patients with pathologic confirmation. We examined whether there were differences in longitudinal patterns of cortical atrophy between patients with both AD and DLB (AD/DLB) vs those with AD alone. We collected and analyzed clinical and neuroimaging data from the AD Neuroimaging Initiative (ADNI) database for patients who underwent autopsy. The rates of change in various neuropsychological assessments were not significantly different between patients with AD/DLB and AD, and each group had neuropsychological outcomes consistent with disease progression. For our neuroimaging analysis, we used a linear mixed-effects model to examine whether there were longitudinal differences in cortical rates of atrophy between patients with AD/DLB and AD. Autopsies and serial neuroimaging were available on 48 patients (24 AD and 24 AD/DLB). Patients with AD alone had significantly higher atrophy rates in the left cuneus, lateral occipital, and parahippocampal regions over time when compared with patients with concomitant DLB, after covarying for interval from imaging to autopsy, sex, and total estimated intracranial volume. Site ID was included as a random effect to account for site differences. For these regions, the rate of decline over time in the AD/DLB group was less steep by a difference of 0.1887, 0.395, and 0.0989, respectively (p = 0.022, 0.006, and 0.006). The lattermost left cuneus volume measurement and Braak Lewy score had a Pearson product-moment correlation of 0.37, p = 0.009, while the lattermost left parahippocampal volume measurement and Braak neurofibrillary tangle score had a Pearson product-moment correlation of -0.327, p = 0.02. Patients with AD had more significant atrophy in the left cuneus, lateral occipital, and parahippocampal regions when compared with patients with AD/DLB. These regions are known to distinguish DLB and AD pathology cross-sectionally but here are shown to distinguish longitudinal disease progression.

Biochemical and Neuropathological Findings in a Creutzfeldt-Jakob Disease Patient with the Rare Val180Ile-129Val Haplotype in the Prion Protein Gene.

Genetic Creutzfeldt–Jakob disease (gCJD) associated with the V180I mutation in the prion protein (PrP) gene (PRNP) in phase with residue 129M is the most frequent cause of gCJD in East Asia, whereas it is quite uncommon in Caucasians. We report on a gCJD patient with the rare V180I-129V haplotype, showing an unusually long duration of the disease and a characteristic pathological PrP (PrPSc) glycotype. Family members carrying the mutation were fully asymptomatic, as commonly observed with this mutation. Neuropathological examination showed a lesion pattern corresponding to that commonly reported in Japanese V180I cases with vacuolization and gliosis of the cerebral cortexes, olfactory areas, hippocampus and amygdala. PrP was deposited with a punctate, synaptic-like pattern in the cerebral cortex, amygdala and olfactory tract. Western blot analyses of proteinase-K-resistant PrP showed the characteristic two-banding pattern of V180I gCJD, composed of mono- and un-glycosylated isoforms. In line with reports on other V180I cases in the literature, Real-Time Quaking Induced Conversion (RT-QuIC) analyses did not demonstrate the presence of seeding activity in the cerebrospinal fluid and olfactory mucosa, suggesting that this haplotype also may result in a reduced seeding efficiency of the pathological PrP. Further studies are required to understand the origin, penetrance, disease phenotype and transmissibility of 180I-129V haplotype in Caucasians.

P11.34.A Pseudoprogression in cases of brain metastases and its neurooncological pitfalls under PD-1 inhibitor therapy in the era of personalized medicine

Abstract Background Immunotherapy plays an increasing role in combating malignant cancers. Recently, there has been a noticeable uptick of pseudoprogression mimicking true tumor growth or even intracranial abscess. PD-1 inhibitors especially have come under scrutiny for imitating progressive diseases. Here, we summarize our departmental findings to this regard. Material and Methods We analyzed the clinical, intraoperative and neuropathological findings as well as perioperative radiological imaging in four cases. Results Four patients (three males and one female, ranged 52-74 years) underwent resection for brain metastases and were subsequently treated with radiotherapy and with PD-1 inhibitors. Within one-year post-surgery, cranial MRI-imaging showed space-occupying, contrast enhanced lesions in all four patients. In two cases FET-PETs were performed pre-operatively. They showed a significant increase in aminoacid uptake. In two cases, 5-aminolevulineacid (5-ALA) was applied pre-operatively. In one case, there was considerable 5-ALA uptake. The fourth patient presented radiological signs of an abscess and underwent emergency surgery. The neuropathological workup of all tissues in question depicted highly increased activity of lymphocytes and microglia, accompanied by necrosis. All cases were classified as pseudoprogression, which, on top, had developed supramarginally in previously healthy tissue. Conclusion Neurooncologists face crescent challenges in the increasing cases of pseudoprogression under/after immunotherapy. Radiological imaging doesn’t seem to be able to clearly differentiate between true and pseudoprogression. Even FET-PETs, in general a valid diagnostic tool, seem to be fooled by checkpoint inhibitors. Furthermore, pseudoprogressive tissue after PD-1 inhibitor therapy might mimic tumor tissue intra-operatively by increased 5-ALA uptake. All these characteristics increase the risk of overly aggressive resection of the suspected cancerous or infectious, but in the end pseudo-progressive tissue. Brain edema and clinical symptoms spurred by pseudoprogression may be an indication for surgery, but the risk of performing possibly unnecessary surgery based on radiological findings fooled by PD-1 inhibitors should be taken into consideration. At this point, there does not seem to be a foolproof diagnostic method to differentiate pseudo- from true progression. And there is the possibility that the pseudoprogression is happening in tissue adjacent to the previously resected lesion. Neurooncologists need to acknowledge that pseudoprogression under/after immunotherapy will become only more prevalent in the future and take this message to their patients.

Neuropathology of major psychiatric disorders: A systematic review

Objective: The purpose of this paper is to review literature on the neuropathology of major psychiatric disorders. Methods: Systematic reviews of neuropathology of psychiatric disorders were identified from 1972 to 2022 through the use of the PubMed database, using the keywords: ‘neuropathology’ AND ‘schizophrenia’ OR ‘bipolar’ OR ‘major depression’. The search was then narrowed to systematic reviews. Results: Ten systematic reviews were selected in this review. The neuropathological findings were identified and detailed for schizophrenia, bipolar disorder, and major depression, at the macroscopic and microscopic levels. Conclusion: Most of the Psychiatric disorders showed cortical damage in certain areas of the brain especially the cingulate cortex, temporal lobe, and the amygdala. The main limitation of interpreting neuropathological findings in major psychiatric disorders is simply identifying and analyzing brain samples of sufficient quantity and quality for research.

Frontal intradiploic encephalocele in a 44-year-old male patient: illustrative case.

Encephaloceles are protrusions of the cerebral tissue through a skull defect. They occur mostly in children and very rarely in adults. The authors present a case of a 44-year-old man presenting with a first-time generalized seizure. Computed tomography of the head showed bone destruction associated with a right frontal lesion. Magnetic resonance imaging scans demonstrated a largely isointense lesion in the intradiploic space that contained small, hyperintense nodular components and showed a low to moderate contrast agent enhancement. The patient underwent resection, during which the histological examination found the lesion to be an intradiploic encephalocele. The patient had an uneventful postoperative course with a cessation of seizures. The imaging and neuropathological findings as well as a literature review, together with a discussion on the etiology of intradiploic encephaloceles, are contained in this report.

Toxic leukoencephalopathy with axonal spheroids caused by chemotherapeutic drugs other than methotrexate

BackgroundThe objective of this report is to share the clinicopathological features of chemotherapy-induced toxic leukoencephalopathy, which is a rare and under-recognized disease, clinically characterized by rapidly progressive cognitive loss that often leads to sudden death.Case presentationA 64-year-old woman and a 63-year-old man, who had both suffered from a rapid deterioration of consciousness, were autopsied under the clinical impressions of either the central nervous system graft versus host disease (CNS-GVHD), infectious encephalitis, or autoimmune encephalitis. Both patients had been treated with multiple chemotherapy regimens, including adriamycin, cytarabine arabinoside, daunorubicin, fludarabine, azacitidine, and allogeneic peripheral blood stem cell transplantation to treat hematological malignancies (acute myelogenous leukemia and myelodysplastic syndrome). Neuropathological findings at autopsy revealed rarefaction and vacuolar changes of the white matter with axonal spheroids, reactive gliosis, and foamy macrophage infiltration, predominantly in the visual pathways of the occipital and temporal lobes. Damaged axons exhibited immunoreactivity to beta-amyloid, consistent with axonopathy. However, there was no lymphocyte infiltration that suggested CNS-GVHD or any type of encephalitis.ConclusionThe neuropathology found in the presented cases had the characteristic features of toxic leukoencephalopathy (chemobrain). Our cases showed that toxic leukoencephalopathy can also be caused by chemotherapy drugs other than methotrexate.

Preclinical Alzheimer's disease biomarkers accurately predict cognitive and neuropathological outcomes.

Alzheimer's disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer's disease biomarkers predict Alzheimer's neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer's disease neuropathological findings. This study included 720 participants, 42-91 years of age, who were enrolled in longitudinal studies of memory and aging in the Washington University Knight Alzheimer Disease Research Center and were cognitively normal at baseline, underwent amyloid PET imaging and/or CSF collection within 1 year of baseline clinical assessment, and had subsequent clinical follow-up. Cognitive status was assessed longitudinally by Clinical Dementia Rating®. Biomarker status was assessed using predefined cut-offs for amyloid PET imaging or CSF p-tau181/amyloid-β42. Subsequently, 57 participants died and underwent neuropathologic examination. Alzheimer's disease neuropathological changes were assessed using standard criteria. We assessed the predictive value of Alzheimer's disease biomarker status on progression to cognitive impairment and for presence of Alzheimer's disease neuropathological changes. Among cognitively normal participants with positive biomarkers, 34.4% developed cognitive impairment (Clinical Dementia Rating > 0) as compared to 8.4% of those with negative biomarkers. Cox proportional hazards modelling indicated that preclinical Alzheimer's disease biomarker status, APOE ɛ4 carrier status, polygenic risk score and centred age influenced risk of developing cognitive impairment. Among autopsied participants, 90.9% of biomarker-positive participants and 8.6% of biomarker-negative participants had Alzheimer's disease neuropathological changes. Sensitivity was 87.0%, specificity 94.1%, positive predictive value 90.9% and negative predictive value 91.4% for detection of Alzheimer's disease neuropathological changes by preclinical biomarkers. Single CSF and amyloid PET baseline biomarkers were also predictive of Alzheimer's disease neuropathological changes, as well as Thal phase and Braak stage of pathology at autopsy. Biomarker-negative participants who developed cognitive impairment were more likely to exhibit non-Alzheimer's disease pathology at autopsy. The detection of preclinical Alzheimer's disease biomarkers is strongly predictive of future cognitive impairment and accurately predicts presence of Alzheimer's disease neuropathology at autopsy.