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Purpose

To compare intravoxel incoherent motion (IVIM) imaging to dynamic susceptibility-weighted contrast (DSC) perfusion MRI in differentiating tumor recurrence from treatment-induced changes.

Methods

Our prospective study included patients previously treated with radiotherapy for intracranial tumors who later developed a new or increasing contrast-enhancing lesion. The final diagnosis was based on neuropathology or 6-month follow-up. MR examinations were performed for calculation of the perfusion fraction (f) using the IVIM technique and relative blood volume (rCBV) using DSC perfusion. Measurements of f and rCBV were made by two independent readers in hotspots when possible, but otherwise in the whole enhancing region. Measures of rCBV were normalized to the contralateral region. Receiver operating characteristics (ROC) analysis was performed.

Results

Sixty patients (35 men, median age 49, range 20–77) were evaluated. Forty-four patients had tumor recurrence and 16 had treatment-induced changes. Mean f was 0.090 for tumors and 0.058 for treatment-induced changes (p = 0.002). Mean rCBV was 3.52 and 1.79, respectively (p = 0.002). The area under the curve (AUC) in the ROC analysis was 0.72 for f and 0.77 for rCBV. Cutoff values of 0.073 for f and 2.26 for rCBV yielded equal values for sensitivity (73%), specificity (75%), and accuracy (73%). The 90th percentile value of rCBV was 4.77 for tumors and 2.53 for treatment-induced changes (p = 0.0004) and yielded the highest AUC (0.79) and a sensitivity/specificity/accuracy of 80%/75%/78% at cutoff value 3.25.

Conclusion

The accuracy of the IVIM parameter f is similar to that of rCBV in differentiating tumor recurrence from treatment-induced changes.

Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to the morgue of Uppsala University Hospital during a 15-year-long period. Among the 1630 subjects, 1610 were ≥ 41 years of age (range 41 to 102 years). Overall, hyperphosphorylated (HP) τ was observed in the brains of 98% of the 1610 subjects, and amyloid β-protein (Aβ) in the brains of 64%. The most common alteration observed was Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) in 26% of the subjects. In 16% of the subjects, HPτ was limited to the locus coeruleus. In 14 subjects (<1%), no altered proteins were observed. In 3 subjects, only Aβ was observed, and in 17, HPτ was observed in a distribution other than that seen in ADNC/PART. The transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant age-related TDP encephalopathy (LATE) was observed in 565 (35%) subjects and α-synuclein (αS) pathology, i.e., Lewy body disease (LBD) or multi system atrophy (MSA) was observed in the brains of 21% of the subjects. A total of 39% of subjects with ADNC, 59% of subjects with PART, and 81% of subjects with HPτ limited to the locus coeruleus lacked concomitant pathologies, i.e., LATE-NC or LBD-NC. Of the 293 (18% of the 1610 subjects) subjects with dementia, 81% exhibited a high or intermediate level of ADNC. In 84% of all individuals with dementia, various degrees of concomitant alterations were observed; i.e., MIXED-NC was a common cause of dementia. A high or intermediate level of PART was observed in 10 subjects with dementia (3%), i.e., tangle-predominant dementia. No subjects exhibited only vascular NC (VNC), but in 17 subjects, severe VNC might have contributed to cognitive decline. Age-related tau astrogliopathy (ARTAG) was observed in 37% of the 1610 subjects and in 53% of those with dementia.

It has been suggested that alcohol consumption protects against Parkinson's disease (PD). Here we assessed postmortem tissue samples from the brains and livers of 100 subjects with ages at death ranging from 51 to 93. Twenty percent of these subjects were demented. We used standardized assessment strategies to assess both the brain and liver pathologies (LP). Our cohort included subjects with none, mild, moderate, and severe LP caused by alcohol consumption. We noted a significant negative correlation of categorical data between liver steatosis and alpha-synuclein (alpha S) in the brain and a significant negative correlation between the extent of liver steatosis and fibrosis and the extent of alpha S in the brain. There was a significant negative association between the observation of Alzheimer's type II astrocytes and alpha S pathology in the brain. No association was noted between LP and hyperphosphorylated tau (HP tau). No significant correlation could be seen between the extent of LP and the extent of HP tau, amyloid beta protein (A beta) or transactive DNA binding protein 43 (TDP43) in the brain. There were significant correlations observed between the extent of HP tau, A beta, alpha S, and TDP43 in the brain and between liver steatosis, inflammation, and fibrosis. Subjects with severe LP displayed a higher frequency of Alzheimer's type II astrocytes compared to those with no, or mild, LP. The assessed protein alterations were not more prevalent or severe in subjects with Alzheimer's type II astrocytes in the brain. In all cases, dementia was attributed to a combination of altered proteins, i.e., mixed dementia and dementia was observed in 30% of those with mild LP when compared with 13% of those with severe LP. In summary, our results are in line with the outcome obtained by the two recent meta-analyses suggesting that subjects with a history of alcohol consumption seldom develop an alpha-synucleinopathy.

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD. 

Background: Amyloid-beta (A beta) is one of the hallmark lesions of Alzheimer's disease (AD). During the disease process, A beta undergoes biochemical changes, producing toxic beta variants, proposed to be detected within the neurons. Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive impairment, gait, and urinary symptoms in elderly, that can be reversed by a ventriculo-peritoneal shunt. Majority of iNPH subjects display different A beta variants in their brain biopsies, obtained during shunting. Objective: To study the cellular compartmentalization of different A beta variants in brain biopsies from iNPH subjects. Methods: We studied the cellular localization of different proteoforms of A beta using antibodies towards different amino acid sequences or post-translational modifications of A beta, including clones 4G8, 6F/3D, unmodified- (7H3D6), pyroglutamylated-(N3pE), phosphorylated-(1E4E11) A beta and A beta protein precursor (A beta PP), in brain biopsies from 3 iNPH subjects, using immunohistochemistry and light microscopy (LM), light microscopy on semi-thin sections (LMst), and electron microscopy (EM). Results: In LM all A beta variants were detected. In LMst and EM, the A beta 4G8, 6F/3D, and the pyroglutamylated A beta were detected. The A beta PP was visualized by all methods. The A beta labelling was located extracellularly with no specific signal within the intracellular compartment, whereas the A beta PP was seen both intra- and extracellularly. Conclusions: TheA beta markers displayed extracellular localization when visualized by three assessment techniques, reflecting the pathological extracellular accumulation of A beta in the human brain. No intracellular A beta pathology was seen. A beta PP was visualized in intra- and extracellularly, which corresponds to the localization of the protein in the membranes of cells and organelles.

Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

Aims This study aims to study the association between pancreatic islet amyloid polypeptide (IAPP) and Alzheimer's disease neuropathological change (ADNC) in brain biopsies obtained from subjects with idiopathic normal pressure hydrocephalus (iNPH) and in post-mortem (PM) brain samples obtained from aged individuals.

Methods For the immunohistochemical (IHC) analyses, two IAPP antibodies (Abs), monoclonal and polyclonal, and Abs directed towards ADNC were applied.

Results The iNPH cohort included 113 subjects. Amyloid-& beta; (A & beta;) was detected in 50% and hyperphosphorylated & tau; (HP & tau;) in 47% of the cases. Concomitant pathology was seen in 32%. The PM cohort included 77 subjects. A & beta; was detected in 69% and HP & tau; in 91% of the cases. Combined A & beta;/HP & tau; pathology was seen in 62%. Reactivity for the monoclonal IAPP was not detected in the brain tissue in either of the cohorts. Reactivity for the polyclonal IAPP was observed in all 77 PM brain samples.

Conclusions There was no specific expression of IAPP in human brain tissue; hence, an association between IAPP and ADNC is not assessable. Of note, the observed reactivity of the polyclonal IAPP Ab was not reproduced with a specific monoclonal Ab; thus, we considered the observed staining with the polyclonal Ab to be unreliable. When using IHC, several pitfalls, especially the choice of an Ab, always need to be considered. Polyclonal Abs cross-react with other epitopes and proteins, thus leading to false-positive results. This seems to be the case for the polyclonal IAPP Abs in the human brain.

Stroke caused by dissection of arteries of the vertebrobasilar system in children is still poorly investigated in terms of etiology, means of treatment, course of disease, and prognosis. The aim of this report was to describe the unusual course of a spontaneous dissection of the basilar artery (BA) in a child treated with endovascular techniques and to point out that the plasticity of the brain stem can fully compensate for structural damage caused by stroke. We report the case of a 15-year-old boy who suffered a wake-up stroke with BA occlusion caused by spontaneous dissection. A blood clot was aspirated from the false lumen and the true lumen re-opened, but the patient deteriorated a few hours later, and repeated angiography revealed that the intimal flap was detached, occluding the BA again. The lumen of BA was then reconstructed by a stent. Despite a large pons infarction, the patient was completely recovered 11 months after the onset. The case was analyzed with angiograms and magnetic resonance imaging, macroscopic and microscopic pathological analysis, computed tomographic angiography, magnetic resonance-based angiography, and diffusion tensor imaging. This case illustrates that applied endovascular techniques and intensive care measures can alter the course of potentially fatal brain stem infarction. Our multimodal analysis gives new insight into the anatomical basis for the plasticity mechanism of the brain stem.

Background: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed.

Objective: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer's disease (sAD).

Methods: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations.

Results: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations.

Conclusion: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness.

Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b⁺ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.