1. Chalif EJ, Murray RD, Mozaffari K, et al. Malignant pineal parenchymal tumors in adults: a National Cancer Database analysis. Neurosurgery 2022;90:807–15
Pineal parenchymal tumors (PPTs) are rare tumors of the pineal gland that account for <1% of primary central nervous system tumors in adults. Although these tumors are heterogeneous and display a wide degree of morphological variation, the World Health Organization (WHO) Classification of Tumors separates these into 5 distinct histological entities: pineocytoma (WHO grade I), PPT of intermediate differentiation (PPTID, WHO grade II/III), pineoblastoma (PB, grade IV), papillary tumor of the pineal region (PTPR, WHO grade II/III), and the recently characterized desmoplastic myxoid SMARCB1-mutant.
The National Cancer Database was queried for histologically confirmed PPT diagnosed from 2007 to 2016. Univariate and multivariate Cox regressions were used to evaluate the prognostic impact of covariates. Kaplan–Meier survival curves were generated for comparative subanalyses.
Of the 251 patients who met inclusion criteria, 172 had PPTs of intermediate differentiation (PPTID) and 79 had pineoblastoma. A plurality of patients with pineoblastomas were treated with trimodal therapy (39.1%), whereas patients with PPTID were commonly treated with either surgery alone or surgery and radiation (33.7% each). Factors independently associated with improved overall survival include younger patient age, female sex, lower comorbidity score, lower tumor grade, and treatment with surgery or radiation. Subanalyses confirm the effect of radiation on survival in patients with grade III PPTID with subtotal resection; however, no survival benefit of adjuvant radiation is demonstrated in patients with grade II PPTID with subtotal resection.
The authors conclude that although radiotherapy and surgery were found to increase survival in all patients with PPT, there was no demonstrable survival benefit of adjuvant radiation in surgically treated patients with grade II PPTID.
6 figures, 2 tables with no imaging
2. Hannan CJ, Hammerbeck-Ward C, Pathmanaban ON, et al. Multiple meningiomas as a criterion for the diagnosis of neurofibromatosis type 2 and other tumor predisposition syndromes. Neurosurgery 2022;90:793–99
Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome, with affected individuals developing schwannomas, meningiomas, and spinal ependymomas. Although the presence of bilateral vestibular schwannomas has long been accepted to be pathognomonic of the condition, there are additional clinical criteria that can lead to the diagnosis of NF2, in the absence of bilateral vestibular schwannomas. A previous study of more than 1300 patients with NF2 demonstrated that the most common of these additional criteria are the presence of a unilateral vestibular schwannomas (UVS) in combination with multiple meningiomas (MM) or with ≥2 nonintradermal schwannomas (NIDS), as well as those presenting with MM in conjunction with a positive family history or the presence of other NF2-associated tumors.
However, it is way more complicated:
Schwannoma tumors from patients with schwannomatosis have been found to harbor somatic mutations in SMARCB1 or the neurofibromin-2 gene (schwannomatosis-1).
Loss of leucine zipper-like transcriptional regulator 1 (LZTR1) function can predispose to the development of autosomal dominant multiple schwannomas (schwannomatosis-2).
A significant minority of patients meeting NF2 diagnostic criterion the basis of the presence of unilateral vestibular schwannoma and other schwannomas actually have an underlying diagnosis of LZTR1-associated schwannomatosis. Similarly, patients suspected of having NF2 presenting with MM may in fact be afflicted by SMARCB1-associated schwannomatosis or clear cell meningiomatosis in association with a pathogenic variant (PV) in SMARCE1.
A total of 31 of 131 patients presenting with a unilateral vestibular schwannoma and MM had a non-refuted diagnosis of NF2 after molecular studies, in comparison with 85 of 96 patients presenting with unilateral vestibular schwannoma and ≥2 nonintradermal schwannomas. Fifty percent of patients presenting with a UVS and ≥2 nonintradermal schwannomas with NF2 developed bilateral VS, compared with only 26% of those who presented with a UVS and MM. In total, 11 of 152 patients presenting with MM without fulfilling NF2 criteria were found to have a pathogenic variant in SMARCE1, and 7 of 152 were confirmed to have mosaic NF2.
The authors demonstrate for the first time that there is a significant difference in the proportion of patients with a nonrefuted diagnosis of NF2 in those who present with UVS and MM, as compared with those who present with UVS and ≥2 NIDS; 100% of those presenting with UVS and MM had a nonrefuted NF2 diagnosis, in comparison with 89% of those presenting with UVS and ≥2 NIDS. This work confirms the previous observation regarding the specificity of UVS with ≥2 NIDS as a diagnostic criterion for NF2; at least 11% of patients presenting in this manner will not have NF2, and this further highlights the need for testing for pathogenic variant in LZTR1 in this population.
3 figures, no imaging
3. Kimura K, Kubo Y, Dobashi K, et al. Angiographic, cerebral hemodynamic, and cognitive outcomes of indirect revascularization surgery alone for adult patients with misery perfusion due to ischemic Moyamoya disease. Neurosurgery 2022;90:676–83
The objectives were to determine angiographic, cerebral hemodynamic, and cognitive outcomes of indirect revascularization surgery alone for adult patients with misery perfusion due to ischemic MMD (indirect revascularization group -IDR group) and to test the superiority of indirect revascularization surgery for cognitive improvement by conducting comparisons with historical control patients who had undergone direct revascularization surgery (DR group) through prospective cohort study with historical controls. As a reminder, misery perfusion is defined as cerebral autoregulatory capacity is exhausted, and cerebral blood supply in insufficient to meet metabolic demand.
Twenty adult patients with cerebral misery perfusion underwent encephaloduro-myo-arterio-pericranial-synangiosis alone. Cerebral angiography through arterial catheterization, brain perfusion single-photon emission computed tomography, and neuropsychological testing were performed preoperatively and at 6 months postoperatively.
In 17 patients of the IDR group, collateral flows that were newly formed after surgery on angiograms fed more than one-third of the middle cerebral artery (MCA) cortical territory. In the IDR group, perfusion in the MCA territory was significantly increased after surgery, and the difference in MCA perfusion between before and after surgery was significantly greater compared with the DR group. Improved cognition was significantly more frequent in the IDR group (65%) than in the DR group (31%).
They conclude that indirect revascularization surgery alone forms sufficient collateral circulation, improves cerebral hemodynamics, and recovers cognitive function in adult patients with misery perfusion due to ischemic MMD. The latter 2 beneficial effects may be higher when compared with patients undergoing direct revascularization surgery.
2 tables, 4 figures with catheter angio, with PET and SPECT
4. Bonney PA, Briggs RG, Wu K, et al. Pathophysiological mechanisms underlying idiopathic normal pressure hydrocephalus: a review of recent insights. Front Aging Neurosci 2022;14(April):1–10. Available from: https://www.frontiersin.org/articles/10.3389/fnagi.2022.866313/full
iNPH classically presents with the clinical triad of gait disturbance, urinary incontinence, and dementia, with gait disturbance typically presenting first and cognitive manifestations arising later. The hallmark of the disease is an enlarged ventricular system without an increase in intracranial pressure (ICP). Despite progress in characterizing iNPH and its natural history, its pathophysiology has not been clearly defined.
Diagnostic radiographic features include ventricular enlargement with an Evans index of 0.3 or greater. Other common findings on brain imaging include a callosal angle of 90 degrees or less, periventricular hyperintensities, and enlargement of the temporal horns. A trial of CSF drainage is often undertaken to aid in the diagnosis, commonly via the lumbar subarachnoid space. Clinical benefit after temporary CSF drainage is strongly predictive of improvement in at least one symptom after shunting. In patients unable or unwilling to receive a shunt, serial lumbar punctures may be a treatment option.
That iNPH may fundamentally represent a vascular disorder is intriguing, given the high incidence of vascular risk factors including hypertension and diabetes in iNPH patients. Supporting this notion is the near-ubiquitous finding of deep white matter and periventricular lesions in iNPH, hallmarks of small vessel disease. Variations in regional hypoperfusion and degree of hypoxic changes may help explain the clinical heterogeneity of iNPH and poor responses to shunting. The author’s view is that iNPH is fundamentally a cerebrovasculature disorder. Impaired compliance triggers a cascade of events culminating in the development of hydrocephalus, which subsequently begins a cycle that unchecked eventually progresses to irreversible dementia and neurologic injury. Shunting reverses some of the clinical manifestations, although even with treatment the disease is associated with progressive morbidity, which suggests a component of irreversible small vessel disease.
4 figures with CT images
5. Hermann P, Zerr I. Rapidly progressive dementias — aetiologies, diagnosis and management. Nat Rev Neurol 2022;18:363–76. Available from: https://www.nature.com/articles/s41582-022-00659-0
The term ‘rapidly progressive dementia’ (RPD) is commonly used to describe a cognitive disorder with fast progression leading to the clinical syndrome of dementia, as defined by the Diagnostic and Statistical Manual of Mental Disorders fourth edition, within a relatively brief time period, which is commonly considered to be less than either 1 or 2 years. This rather vague definition encompasses a large group of heterogeneous disorders, including immune- mediated, infectious and metabolic encephalopathies, as well as prion diseases and atypically rapid presentations of other neurodegenerative diseases. As RPD is one of the typical clinical characteristics of Creutzfeldt–Jakob disease (CJD) and has long been part of the diagnostic criteria for this condition, prion diseases have been considered to be prototypical RPDs. However, the growing recognition of immune- mediated encephalitis, rapidly progressive subtypes of classic dementias such as Alzheimer disease (AD) and various other mimics of prion diseases demands a thorough consideration of differential diagnoses, especially potentially reversible conditions.
The clinical diagnosis of a prion disease can be supported by CSF analysis, MRI and EEG. Although EEG might provide important information, classic periodic sharp and slow wave complexes are a late feature of prion disease. By contrast, MRI sequences such as FLAIR and DWI can detect signal hyperintensities very early in the disease course and have become a valuable part of the commonly applied diagnostic criteria. MRI might also help to define the clinicopathological disease subtype on the basis of specific patterns of alterations. A diagnosis of sCJD is further supported by the detection of biomarkers in blood or CSF, including 14-3-3 protein and the phosphorylated tau (p- tau) to tau ratio as markers of neuronal damage. In the differential diagnosis of neurodegenerative disorders, elevated levels of 14-3-3 and/or tau support a diagnosis of sCJD with a sensitivity of 85–94% and a specificity of 80%. Another class of assay based on initial amplification of abnormal prion protein (PrPSc) shows considerable promise for specific and sensitive pre- mortem testing for CJD. Real- time quaking- induced conversion (RT- QuIC) is an amplification system that mimics the conversion process from physiological PrP to PrPSc. This technique allows the amplification and detection of femtogram amounts of PrPSc from the CSF. Given its high sensitivity and specificity, it has recently become part of the clinical diagnostic criteria and could improve early diagnosis and surveillance of CJD.
2 tables, 3 figures including MRI
6. Garcia-Hernandez R, Cerdán Cerdá A, Trouve Carpena A, et al. Mapping microglia and astrocyte activation in vivo using diffusion MRI. Sci Adv 2022;8:eabq2923. Available from: https://www.science.org/doi/10.1126/sciadv.abq2923?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
A few recent studies, establishing the groundwork for this work, showed that conventional MRI signal can be sensitive to various alterations in microglia, but none so far showed specificity to microglia and astrocyte activation, or inflammation in the presence of neurodegeneration. Achieving specificity is of key importance as neurodegenerative diseases manifest through different mechanisms, involving specific cell populations, all playing potentially different roles in disease causation and progression. By combining advanced dw-MRI sequences with mathematical models based on neurobiological knowledge of brain parenchyma morphology, the diffusion characteristics within specific tissue compartments, and even cell types, could be measured. With this idea in mind, the authors developed an innovative strategy to image microglia and astrocyte activation in gray matter using dw-MRI, by building a microstructural multicompartment tissue model informed by knowledge of microglia and astrocyte morphology.
By taking advantage of the different activation windows of glia in an LPS-driven immunological challenge in rats, and by using pharmacological tools to deplete microglia in the brain, they were able to dissect the MRI signatures of specific glial responses. They identified three MRI parameters, namely, the stick fraction, the stick dispersion, and the small sphere size, which, combined, provide sensitivity to, and only to, microglia activation. Similarly, the large sphere size is sensitive to astrocyte activation. In addition, using injections of ibotenic acid, they demonstrate that the framework can distinguish between glia activation and proliferation, independently of an underlying neurodegenerative process.
They also tested the robustness of the developed biomarker set for inflammation in a condition of demyelination. They found that, even in a condition of severe demyelination only comparable to multiple sclerosis, microglia-associated MRI parameters such as the stick dispersion parameter and the small sphere size, and the astrocyte-associated big sphere size, were not confounded.
6 figures
7. Wang C, Martins-Bach AB, Alfaro-Almagro F, et al. Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging. Nat Neurosci 2022;25:818–31. Available from: https://www.nature.com/articles/s41593-022-01074-w
The UK Biobank study is collecting brain images in 100,000 participants who are largely healthy when scanned. Participants have been deeply phenotyped and genotyped and consented to long-term access to their health records. UK Biobank has identified relationships between brain imaging markers and phenotypes, including obesity, vascular disease and aging. It has also enabled major new insights into the genetic correlates of imaging phenotypes, identifying genes with known links to psychiatric illness, vascular disease and neurodegeneration.
The authors developed a quantitative susceptibility mapping (QSM) pipeline for UK Biobank that was run on the current release of 35,273 participants (with repeat imaging in 1,368 participants) and produced imaging-derived phenotypes (IDPs) of magnetic susceptibility (χ) in various brain structures. These data constitute an enhancement to the UK Biobank neuroimaging resource through the provision of QSM-derived χ estimates. To demonstrate the scientific value of this resource, they present phenotypic and genetic associations, focusing on examples that demonstrate the new information contributed by QSM.
The authors identify statistically significant associations of 251 phenotypes with magnetic susceptibility that include body iron, disease, diet and alcohol consumption. Genome-wide associations relate magnetic susceptibility to 76 replicating clusters of genetic variants with biological functions involving iron, calcium, myelin and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* signal decay time measures.
6 figures, 2 tables
8a. Iram T, Kern F, Kaur A, et al. Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17. Nature 2022;605:509–15
8b. Zawadzki M, Lehtinen MK. Young cerebrospinal fluid is a tonic for memory. Nature 2022;428–29
The authors infused CSF from young adult mice (10 weeks old) into the brains of aged mice (18 months old) over 7 days. This treatment improved the memory recall of the old animals in a fear-conditioning task, in which they learnt to associate a small electric shock with a tone and flashing light. Iram and colleagues then used RNA sequencing to determine how CSF treatment altered gene expression in the hippocampus — a key memory center in the brain that is often the focus of studies of age-associated cognitive decline. Previous work has demonstrated that successful fear-conditioning in mice requires oligodendrocyte proliferation and myelin formation, and that disruption of this process impairs memory. The authors therefore examined whether treatment with the young CSF affected the proliferation and maturation of oligodendrocyte precursor cells (OPCs). They found that young CSF more than doubled the percentage of OPCs actively proliferating in the hippocampus of old animals. This cellular change was followed three weeks later by an increase in myelin production. The findings strongly suggest that young CSF improves the cognitive abilities of aged mice by modulating oligodendrocytes.
The authors took a deeper dive into the pathways activated by young CSF using an established line of rat oligodendrocyte precursor cells grown in cell culture. Gene transcription involves the formation of chains of various nucleoside molecules to make RNA, so Iram et al. added a labelled nucleoside to the culture medium in which the oligodendrocyte precursor cells were grown — this enabled the authors to isolate and sequence newly made RNA transcripts, which had incorporated the labelled nucleoside. The greatest increase in gene expression in response to young CSF treatment was in serum response factor (Srf).
CSF contains a rich cocktail of signaling molecules and growth factors, many of which could induce the SRF signaling pathways seen in the oligodendrocyte precursor cells. Iram et al. identified candidate factors capable of inducing Srf expression in published protein databases from large-scale studies of CSF. Fibroblast growth factor 17 (FGF17) emerged as a compelling candidate.
Not only does the study imply that FGF17 has potential as a therapeutic target, but it also suggests that routes of drug administration that allow therapeutics to directly access the CSF could be beneficial in treating dementia.
4 figures in the Iram article
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