Diagnostic Value of Brain Calcifications in Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia

Konno, Tetsuo; Broderick, Daniel F.; Mezaki, Naomi; Isami, Aiko; Kaneda, Daita; Tashiro, Yuichi; Tokutake, Takayoshi; Keegan, B. Mark; Woodruff, Bryan K.; Miura, Takeshi; Nozaki, Hiroaki; Nishizawa, Masatoyo; Onodera, Osamu; Wszołek, Zbigniew K.; Ikeuchi, Takeshi

doi:10.3174/ajnr.a4938

Cited by 49 publications

(52 citation statements)

References 20 publications

(41 reference statements)

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“…Fluid-attenuated inversion recovery sagittal imaging is recommended to evaluate changes in the corpus callosum. Abnormal signaling in the pyramidal tracts and diffusion-restricted lesions are observed in some cases [5,11]. None of the ALSP cases showed middle cerebellar peduncle lesions, which are known as a characteristic finding of some leukoencephalopathies On brain CT scans, calcifications are often observed bilaterally in the frontal white matter adjacent to the anterior horn of the lateral ventricle and the subcortical region of the parietal lobe.…”

Section: Discussionmentioning

confidence: 99%

“…Calcifications can be very small. Thus, thin-slice CT (1 mm) is recommended to detect them [5,11]. Characteristic 'stepping stone appearance' can be seen on sagittal view [10] …”

Section: Discussionmentioning

confidence: 99%

“…Frontal and parietal lobe predominance is observed with involvement of the periventricular deep white matter and dilation of the lateral ventricles. Thinning of the corpus callosum with signal abnormalities is observed even in the early stages of the disease [9,11]. Fluid-attenuated inversion recovery sagittal imaging is recommended to evaluate changes in the corpus callosum.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation

Konno

Yoshida

Mizuta

et al. 2017

Euro J of Neurology

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Background and purpose To establish and validate diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony‐stimulating factor 1 receptor (CSF1R) mutation. Methods We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation‐negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results Among the CSF1R mutation‐positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation‐negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

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Section: Discussionmentioning

confidence: 99%

“…Calcifications can be very small. Thus, thin-slice CT (1 mm) is recommended to detect them [5,11]. Characteristic 'stepping stone appearance' can be seen on sagittal view [10] …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation

Konno

Yoshida

Mizuta

et al. 2017

Euro J of Neurology

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“…Several lines of evidence indicate that cell-autonomous defects in microglia lead to brain disease and cerebral calcification 31, 32, 37, 38, 40 . Microglia have also emerged as a disease modifier in a wide range of neurodegenerative diseases (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, patients with mutations in other genes implicated in microglial development and function (e.g. IRF8 , CSF1R ) develop intracerebral calcifications 38–40 . Thus, cell-autonomous defects in microglia lead to the formation of brain calcifications.…”

Section: Introductionmentioning

confidence: 99%

Microglia control small vessel calcification via TREM2

Zarb

Nassiri

Utz

et al. 2019

Preprint

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23Microglia participate in CNS development and homeostasis and are often implicated in 24 modulating disease processes in the CNS. However, less is known about the role of microglia 25 in the biology of the neurovascular unit (NVU). In particular, data are scant on whether 26 microglia are involved in CNS vascular pathology. In this study, we use a mouse model of 27 primary familial brain calcification (PFBC) -Pdgfb ret/ret to investigate the role of microglia in 28 calcification of the NVU. We report that microglia enclosing vessel-calcifications, coined 29 calcification-associated microglia (CAM), display a distinct activation signature. 30Pharmacological ablation of microglia with the CSF1R inhibitor -PLX5622 leads to aggravated 31 vessel calcification. Additionally, depletion of microglia in wild-type and Pdgfb ret/ret mice 32 causes the development of bone protein (osteocalcin, osteopontin) containing axonal spheroids 33 in the white matter. Mechanistically, we show that microglia require functional TREM2 for 34 controlling vessel-associated calcification. In conclusion, our results demonstrate that 35 microglial activity in the setting of pathological vascular calcification is beneficial. In addition, 36we identify a new, previously unrecognized function of microglia in halting the expansion of 37 ectopic calcification. 38 39 2 injury results in microglial activation with the rapid development of processes that shield a 57 lesioned blood vessel section and phagocytose debris 2 . These findings support the important 58 role of microglia in vascular repair. 59Optimal functioning of the NVU, which mediates hyperaemia, is crucial for cerebral 60 perfusion 4 . Blood vessels play an integral role in brain development and provide a niche for 61 brain stem cells. In addition, cerebral vasculature senses the environment and communicates 62 changes to neural tissue, participates in glymphatic clearance, and controls immune quiescence 63 in the CNS [11][12][13][14][15] . Accordingly, dysfunction of the NVU accompanies or may even represent a 64 primary cause of many neurodegenerative diseases 4,16 . In the case of the primary familial brain 65 calcification (PFBC), bilateral basal ganglia calcification of blood vessels is a key diagnostic 66 criterion. The pathogenic mechanism points to a compromised NVU 17-20 . PFBC is a clinically 67 and genetically heterogenous disease caused by mutations in at least in five genes -MYORG, 68 PDGFB, PDGFRB, SLC20A2 and XPR1 21-25 . Of note, recent studies have estimated the 69 minimal prevalence of PFBC ranges from 4-6 p. 10,000, depending of the causative gene 70 mutation, thus suggesting that PFBC is not a rare disorder and is likely underdiagnosed 26,27 . In 71 addition, basal ganglia calcification is a common radiological finding, estimated in up to 20% 72 3 of patients undergoing CT imaging 28,29 . Although the effect of cerebral calcification on the 73 NVU and brain parenchyma is unknown, peripheral vascular calcification can lead to 74 cardiovascular morbidity and mortality...

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Brain Calcifications in Adult-Onset Genetic Leukoencephalopathies

et al. 2017

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IMPORTANCE Adult-onset genetic leukoencephalopathies and leukodystrophies are increasingly recognized as a heterogeneous group of disorders with new diagnostic approaches and potential treatments. In the new era of genomics, the challenging interpretation of individual genetic variations requires an accurate phenotypic description and classification. Clinical and magnetic resonance imaging (MRI)-based approaches have been proposed to improve the diagnostic process of adult-onset leukoencephalopathies. Cerebral calcifications, when associated with white matter hyperintensities, are of major importance in the decision-making process to focus the diagnosis among the diversity of rare causes.OBSERVATIONS This literature review demonstrated that the morphologic features and topography of the calcifications observed in a careful combined analysis of computed tomographic and MRI scans may help indicate the diagnosis of adult-onset genetic leukoencephalopathies. Vascular genetic leukoencephalopathies are an important cause of leukoencephalopathy with calcifications. Among them, COL4A1-related disorders are frequently associated with spotlike calcifications in the basal ganglia. Adult-onset leukoencephalopathy with axonal spheroids, a probably underestimated disorder, is associated with a specific pattern of calcifications: small, symmetric, sparing the basal ganglia, and a stepping stone appearance in the frontal pericallosal region. Moreover, disorders primarily associated with basal ganglia calcifications, such as primary familial brain calcifications, can be associated with marked leukoencephalopathy. CONCLUSIONS AND RELEVANCEThe number of identified causes of adult-onset genetic leukoencephalopathies has recently increased. A diagnostic algorithm should take into account the pattern of calcifications to better target the genetic analyses.

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Diagnostic Value of Brain Calcifications in Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia

Cited by 49 publications

References 20 publications

Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation

Diagnostic criteria for adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation

Microglia control small vessel calcification via TREM2

Brain Calcifications in Adult-Onset Genetic Leukoencephalopathies

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