Association between Body Mass Index and Medication-Overuse Headache among Individuals with Migraine: A Cross-Sectional Study.

INTRODUCTION: Medication-overuse headache (MOH) is a secondary chronic headache disorder that occurs in individuals with a pre-existing primary headache disorder, particularly migraine disorder. Obesity is often combined with chronic daily headaches and is considered a risk factor for the transformation of episodic headaches into chronic headaches. However, the association between obesity and MOH among individuals with migraine has rarely been studied. The present study explored the association between body mass index (BMI) and MOH in people living with migraine. METHODS: This cross-sectional study is a secondary analysis of data from the Survey of Fibromyalgia Comorbidity with Headache study. Migraine and MOH were diagnosed using the criteria of the International Classification of Headache Disorders, 3rd Edition. BMI (kg/m2) is calculated by dividing the weight (kg) by the square of the height (m). Multivariable logistic regression analysis was used to evaluate the association between BMI and MOH. RESULTS: A total of 2,251 individuals with migraine were included, of whom 8.7% (195/2,251) had a concomitant MOH. Multivariable logistic regression analysis, adjusted for age, sex, education level, headache duration, pain intensity, headache family history, chronic migraine, depression, anxiety, insomnia, and fibromyalgia, demonstrated there was an association between BMI (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.11; p = 0.031) and MOH. The results remained when the BMI was transformed into a category. Compared to individuals with Q2 (18.5 kg/m2 ≤ BMI ≤23.9 kg/m2), those with Q4 (BMI ≥28 kg/m2) had an adjusted OR for MOH of 1.81 (95% CI, 1.04-3.17; p = 0.037). In the subgroup analyses, BMI was associated with MOH among aged more than 50 years (OR, 1.13; 95%, 1.03-1.24), less than high school (OR, 1.08; 95%, 1.01-1.15), without depression (OR, 1.06; 95%, 1.01-1.12), and without anxiety (OR, 1.06; 95%, 1.01-1.12). An association between BMI and MOH was found in a sensitivity analysis that BMI was classified into four categories according to the World Health Organization guidelines. CONCLUSION: In this cross-sectional study, BMI was associated with MOH in Chinese individuals with migraine.

Headache attributed to giant cell arteritis complicated with rheumatic polymyalgia diagnosed with F18-fluorodeoxyglucose positron emission tomography and computed tomography: a case report.

Giant cell arteritis (GCA) is a kind of systemic vasculitis affecting individuals over 50 years old and is often the cause of new-onset headaches in older adults. Patients with GCA sometimes have rheumatic polymyalgia (PMR). The diagnosis of GCA generally depends on clinical manifestation, elevated erythrocyte sedimentation rate (ESR) or C-reactive protein, and positive imaging findings commonly obtained by ultrasound or temporal artery biopsy. In this study, we report a case of an 83-year-old woman with a new-onset headache and an elevated ESR. The result of the temporal artery ultrasound did not distinguish between vasculitis and atherosclerosis. The F18-fluorodeoxyglucose positron emission tomography and computed tomography (18F FDG PET-CT) were performed and suggested large vessel vasculitis with temporal artery involvement. In addition, polyarticular synovitis and bursitis were also revealed. Finally, the diagnosis of secondary headache attributed to CGA complicated with PMR was established. The patient experienced remission of symptoms after glucocorticoid therapy. PET can become a powerful tool for diagnosis and differential diagnosis when the ultrasound result is ambiguous and a biopsy is not obtained.

Status of diagnosis and preventative treatment for primary headache disorders: real-world data of unmet needs in China.

BACKGROUND: Headache disorders are widely prevalent and pose a considerable economic burden on individuals and society. Globally, misdiagnosis and inadequate treatment of primary headache disorders remain significant challenges, impeding the effective management of such conditions. Despite advancements in headache management over the last decade, a need for comprehensive evaluations of the status of primary headache disorders in China regarding diagnosis and preventative treatments persists. METHODS: In the present study, we analyzed the established queries in the Survey of Fibromyalgia Comorbidity with Headache (SEARCH), focusing on previous diagnoses and preventative treatment regimens for primary headache disorders. This cross-sectional study encompassed adults diagnosed with primary headache disorders who sought treatment at 23 hospitals across China between September 2020 to May 2021. RESULTS: The study comprised 2,868 participants who were systematically examined. Migraine and tension-type headaches (TTH) constituted a majority of the primary headache disorders, accounting for 74.1% (2,124/2,868) and 23.3% (668/2,868) of the participants, respectively. Medication overuse headache (MOH) affected 8.1% (231/2,868) of individuals with primary headache disorders. Over half of the individuals with primary headache disorders (56.6%, 1,624/2,868) remained undiagnosed. The previously correct diagnosis rates for migraine, TTH, TACs, and MOH were 27.3% (580/2,124), 8.1% (54/668), 23.2% (13/56), and 3.5% (8/231), respectively. The misdiagnosis of "Nervous headache" was found to be the most prevalent among individuals with migraine (9.9%, 211/2,124), TTH (10.0%, 67/668), trigeminal autonomic cephalalgias (TACs) (17.9%, 10/56), and other primary headache disorders (10.0%, 2/20) respectively. Only a minor proportion of individuals with migraine (16.5%, 77/468) and TTH (4.7%, 2/43) had received preventive medication before participating in the study. CONCLUSIONS: While there has been progress made in the rate of correct diagnosis of primary headache disorders in China compared to a decade ago, the prevalence of misdiagnosis and inadequate treatment of primary headaches remains a veritable issue. As such, focused efforts are essential to augment the diagnosis and preventive treatment measures related to primary headache disorders in the future.

The prevalence and clinical features of fibromyalgia in Chinese hospital patients with primary headache: The survey of fibromyalgia comorbid with headache.

OBJECTIVE: The aims were to explore the prevalence and clinical features of fibromyalgia in Chinese hospital patients with primary headache. BACKGROUND: Studies done in non-Chinese populations suggest that around one-third of patients with primary headache have fibromyalgia, but data from mainland China are limited. Investigations into the prevalence and clinical features of fibromyalgia in Chinese patients with primary headache would improve our understanding of these two complex disease areas and help guide future clinical practice. METHODS: This cross-sectional study included adults with primary headache treated at 23 Chinese hospitals from September 2020 to May 2021. Fibromyalgia was diagnosed using the modified 2010 American College of Rheumatology criteria. Mood and insomnia were evaluated employing the Hospital Anxiety and Depression Scale and the Insomnia Severity Index. RESULTS: A total of 2782 participants were analyzed. The fibromyalgia prevalence was 6.0% (166/2782; 95% confidence interval: 5.1%, 6.8%). Compared to primary headache patients without combined fibromyalgia, patients with primary headache combined with fibromyalgia were more likely to be older (47.8 vs. 41.7 years), women (83.7% [139/166] vs. 72.8% [1904/2616]), less educated (65.1% [108/166] vs. 45.2% [1183/2616]), and with longer-duration headache (10.0 vs. 8.0 years). Such patients were more likely to exhibit comorbid depression (34.3% [57/166] vs. 9.9% [260/2616]), anxiety (16.3% [27/166] vs. 2.7% [70/2612]), and insomnia (58.4% [97/166] vs. 17.1% [447/2616]). Fibromyalgia was more prevalent in those with chronic (rather than episodic) migraine (11.1% [46/414] vs. 4.4% [72/1653], p < 0.001) and chronic (rather than episodic) tension-type headache (11.5% [27/235] vs. 4.6% [19/409], p = 0.001). Most fibromyalgia pain was in the shoulders, neck, and upper back. CONCLUSIONS: The prevalence of fibromyalgia in mainland Chinese patients with primary headache was 6.0%. Fibromyalgia was more common in those with chronic rather than episodic headache. The most common sites of fibromyalgia pain were the neck, shoulders, and back.

Cognitive Impairments and blood-brain Barrier Damage in a Mouse Model of Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is commonly involved in various brain diseases. Tight junction proteins (TJs) are key components constituting the anatomical substrate of the blood-brain barrier (BBB). Changes in cognitive function and BBB after CCH and their relationship need further exploration. To investigate the effect of CCH on cognition and BBB, we developed a bilateral common carotid artery stenosis (BCAS) model in Tie2-GFP mice. Mice manifested cognitive impairments accompanied with increased microglia after the BCAS operation. BCAS mice also exhibited increased BBB permeability at all time points set from D1 to D42. Furthermore, BCAS mice showed reduced expression of TJs 42 d after the operation. In addition, correct entrances of mice in radial arm maze test had a moderate negative correlation with EB extravasation. Our data suggested that BCAS could lead to cognitive deficits, microglia increase and BBB dysfunction characterized by increased BBB permeability and reduced TJs expression level. BBB permeability may be involved in the cognitive impairments induced by CCH.

A Preliminary Study on Change of Serum Immunoglobulin G Glycosylation in Patients With Migraine.

Background and Objective: Migraine is a common neurological disease, but its pathogenesis is still unclear. Previous studies suggested that migraine was related to immunoglobulin G (IgG). We intended to analyze the immune characteristics of migraine from the perspective of IgG glycosylation and provide theoretical assistance for exploring its pathogenesis. Methods: The differences in the serum level of IgG glycosylation and glycopeptides between patients with episodic migraine and healthy controls were analyzed by applying the poly(glycerol methacrylate)@chitosan (PGMA@CS) nanomaterial in combination with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). We constructed a binary classification model with a feedforward neural network using PyTorch 1.6.0 in Python 3.8.3 to classify the episodic migraine and healthy control groups. Results: Twenty patients with migraine and 20 healthy controls were enrolled and the blood samples and clinical information were collected. Forty-nine IgG N-glycopeptides were detected in the serum of the subjects. The serum level of N-glycopeptide IgG1 G0-NF (p = 0.012) was increased in patients with migraine. The serum level of N-glycopeptide IgG3/4 G2FS (p = 0.041) was decreased in patients with migraine with family history of headache. It was found that the serum level of the IgG1 G1 (p = 0.004) and IgG2 G0 (p = 0.045) was increased in patients with migraine with aura, while the serum level of IgG2 G0N (p = 0.043) in patients with migraine with aura was significantly lower than that in patients with migraine without aura. In addition, a linear feedforward neural network (FFNN) was used to construct a binary classification model by detected IgG N-glycopeptides. The area under the curve (AUC) value of the binary classification model, which was constructed with 7 IgG N-glycopeptides, was 0.857, suggesting a good prediction performance. Among these IgG N-glycopeptides that were constructed the model, IgG1 G0-NF was overlapped with the differential IgG N-glycopeptide between patients with migraine and healthy controls detected with MALDI-TOF-MS. Conclusion: Our results indicated that the serum level of N-glycopeptides IgG1 G0-NF might be one of the important biomarkers for the diagnosis of migraine. To the best of our knowledge, this is the first study about the changes of IgG N-glycosylation in patients with migraine by the method of MALDI-TOF-MS. The results indicated a relationship between the migraine and immune response.

Total Cerebral Small Vessel Disease Burden on MRI Correlates With Cognitive Impairment in Outpatients With Amnestic Disorders.

Objectives: The main markers of cerebral small vessel disease (cSVD) on MRI may be entered into a scoring system, with the total score representing the overall burden of cSVD. An association between total cSVD score and cognitive dysfunction has been reported in several cohorts. The present study aimed to investigate this association in outpatients with amnestic disorders. Materials and Methods: Outpatients with amnestic complaints in a memory clinic (n = 289) were recruited retrospectively. All the patients had undergone clinical and cognitive evaluation at first presentation. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) scale. The total cSVD score was based on the following markers on MRI: lacune; white matter hyperintensities, microbleed, and enlarged perivascular spaces. The association between total cSVD score and MoCA score was tested via Spearman's analysis and a linear regression model. Results: Among the 289 patients, rates for 0-4 cSVD markers respectively ranged from 30.4 to 2.8%. A multiple linear regression model revealed an inverse correlation between the total cSVD score and MoCA score. The association remained significant after adjusting for gender, age, education, levels of medial temporal lobe atrophy, and classical vascular risk factors [ß = -0.729, 95% CI (-1.244, -0.213); P = 0.006]. When individual markers were individually analyzed after adjusting for the same factors, only microbleed associated with MoCA score [ß = -3.007, 95% CI (-4.533, -1.480), P < 0.001]. Conclusions: A significant association was demonstrated between total cSVD score and cognitive performance in the outpatients with amnestic disorders.

Elevated Resting State Gamma Oscillatory Activities in Electroencephalogram of Patients With Post-herpetic Neuralgia.

In acute and ongoing pain, the spontaneous oscillatory activity of electroencephalogram (EEG) has been characterized by suppression of alpha band oscillations and enhancement of gamma band oscillations. In pathological chronic pain which is more severe and common in clinic practice, it is of great interest to investigate the oscillatory activity especially at the broad gamma frequency bands. Our present study explored the resting state oscillatory activities of EEG in patients with post-herpetic neuralgia (PHN) over 3 months which is a typical neuropathic pain model in clinical researches. It was found that the PHN patients showed anxiety and depression revealed by Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) examinations. Power spectrum analysis revealed that the power at gamma frequency band (from 40 to 70 Hz) of EEG was significantly higher in the PHN patients, and positively correlated with pain intensity, anxiety, and depression indexes. Further, increased gamma activity derived from the prefrontal cortex and the cerebellum were revealed by cluster-based sensor level and the beamforming source level analyses. These results suggest the enhanced gamma oscillatory activity in the prefrontal cortex and cerebellum is a characteristic marker in chronic neuropathic pain patients.

Histidine Alleviates Impairments Induced by Chronic Cerebral Hypoperfusion in Mice.

Chronic cerebral hypoperfusion is one of the fundamental pathological causes of brain disease such as vascular dementia. Exploration of effective treatments for this is of great interest. Histidine has been reported to be effective in anti-apoptosis, antioxidant, and against excitotoxicity. In the present study, we aim to investigate whether histidine could have a therapeutic effect on the impairments induced by chronic cerebral hypoperfusion. Cerebral hypoperfusion model was established through bilateral common carotid arteries stenosis (BCAS) operation in Tie2-GFP mice. Radial arm maze and Morris water maze revealed that histidine showed potential improvement of the tendency of cognitive impairments induced by hypoperfusion. The possible mechanisms were further investigated. After administration of histidine in hypoperfusion mice, immunofluorescent BrdU staining revealed more new-born nerve cells. In vivo observation through a cranial window under two-photon laser-scanning microscopy demonstrated that the blood flow velocity in capillary was improved, the distance between the astrocytes and the penetrating artery was shortened. Histidine administration also significantly increased the protein expression level of zonula occludens protein 1, an indicator of the integrity of blood-brain barrier (BBB). These results suggest that histidine could alleviate the impairments induced by chronic cerebral hypoperfusion in mice, and this effect may be related to the neurogenesis, astrocytes, and the integrity of the BBB.

Extracting Neural Oscillation Signatures of Laser-Induced Nociception in Pain-Related Regions in Rats.

Previous studies have shown that multiple brain regions are involved in pain perception and pain-related neural processes by forming a functionally connected pain network. It is still unclear how these pain-related brain areas actively work together to generate the experience of pain. To get a better insight into the pain network, we implanted electrodes in four pain-related areas of rats including the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), primary somatosensory cortex (S1) and periaqueductal gray (PAG). We analyzed the pattern of local field potential (LFP) oscillations under noxious laser stimulations and innoxious laser stimulations. A high-dimensional feature matrix was built based on the LFP characters for both experimental conditions. Generalized linear models (GLMs) were trained to classify recorded LFPs under noxious vs. innoxious condition. We found a general power decrease in α and ß bands and power increase in γ band in the recorded areas under noxious condition. After noxious laser stimulation, there was a consistent change in LFP power and correlation in all four brain areas among all 13 rats. With GLM classifiers, noxious laser trials were distinguished from innoxious laser trials with high accuracy (86%) using high-dimensional LFP features. This work provides a basis for further research to examine which aspects (e.g., sensory, motor or affective processes) of noxious stimulation should drive distinct neural activity across the pain network.

Astrocyte activation and capillary remodeling in modified bilateral common carotid artery occlusion mice.

OBJECTIVE: The cerebral ischemia leads to brain dysfunction with neuron degeneration and responses from astrocytes and vessels. The aim of this study was to study the changes of astrocyte and microvessel in modified BCCAO mice. METHODS: Adult transgenic Tie2-GFP mice were subjected to modified BCCAO operation and cranial window implantation. CBF and neurological injury were examined after ischemia. Astrocytes and vessels were investigated by two-photon laser-scanning microscope and confocal laser-scanning microscope in vivo. RESULTS: The CBF decreased to approximately 40% of the baseline in the ischemic mice (P<.05). The neuron damage was explicit after the cerebral ischemia (P<.05), while no significant impairment of the motor and cognitive function was detected (P>.05). The density of astrocyte and volume of the astrocyte soma was increased significantly after ischemia (P<.01). Meanwhile, the mean distance between the penetrating artery and the nearest astrocyte soma decreased significantly (P<.01). Besides, the increased diameter of capillary and change of vessel arrangement were observed. CONCLUSION: The cerebral ischemia was successfully induced by this modified BCCAO model. Astrocyte activation and the capillary remodeling, including dilution of capillary and tortuosity, were observed in this model.

131I-MIBG myocardial scintigraphy for differentiation of Parkinson's disease from multiple system atrophy or essential tremor in Chinese population.

OBJECTIVE: Clinical distinction of Parkinson's disease (PD) from multiple system atrophy (MSA) or essential tremor (ET) is sometimes difficult. The purpose of this study was to assess changes in cardiac sympathetic nerve function in PD, MSA, and ET by 131I-MIBG myocardial scintigraphy METHODS: Patients with PD (25), MSA (18), or ET (11) and 10 healthy controls (HC) were enrolled. 131I-MIBG myocardial scintigraphy was performed for each subject, and heart/mediastinum (H/M) ratios were calculated at two sample times (15min and 4h after the injection of 131I-MIBG), representing the 131I-MIBG myocardial uptake ratios. The washout ratio (WOR) of MIBG which indicates the activity tone of the presynaptic sympathetic nerves was calculated for each subject. RESULTS: The H/M ratios at the two sample times (15min and 4h) were 1.65±0.36 and 1.50±0.43 in the PD group, 1.97±0.36 and 2.08±0.57 in the MSA group, 2.34±0.34 and 2.46±0.51 in the ET group, and 2.41±0.26 and 2.66±0.47 in the HC group. The H/M ratios at the two sample times were lower in the PD group than in the MSA, ET, or HC groups, with statistical significance (all P<0.05). The H/M ratios at the two sample times were significantly lower in the MSA group than in the HC group (all P<0.05). There was no significant difference in H/M ratios at either sample time between the ET and HC group (all P>0.05). The washout ratios (WORs) of MIBG were significantly increased in PD group compared with those in MSA, ET and HC groups. In subgroup analysis, The H/M ratios at the two sample times were decreased in early PD group compared with those in early MSA and early ET groups, with statistical significance (all P<0.05). CONCLUSIONS: Cardiac sympathetic dysfunction can occur in both PD and MSA patients, especially in PD patients, whereas it remains normal in ET patients. 131I-MIBG myocardial scintigraphy can help distinguish patients with PD from those with MSA or ET with good sensitivity and specificity.

Superior sagittal sinus thrombus secondary to occult meningioma: a case report.

A 58-year-old man presented with intermittent white flashes in both eyes during the past year. Six years earlier (2004), the patients received a diagnosis of superior sagittal sinus (SSS) thrombosis on the basis of elevated intracranial pressure and imaging findings, for example, computed tomography, magnetic resonance imaging, magnetic resonance venography, and cerebral angiography, and was treated with urokinase and anticoagulatants. Symptoms resolved and the patient remained well until March 2009, when intermittent white flashes started to occur in both the eyes. The patient did not seek medical help until 1 year later (March 2010). Cerebral angiography (digital subtraction arteriography) revealed SSS thrombosis and a network of collateral venous circulation. Computed tomography and magnetic resonance imaging demonstrated a mass in the parietooccipital lobe that surrounded the SSS. Pathologic examination of the specimen removed during surgery revealed meningioma.

Capillary remodeling and collateral growth without angiogenesis after unilateral common carotid artery occlusion in mice.

OBJECTIVE: To clarify the mechanisms of blood flow restoration after major artery occlusion, we presented first dynamic changes in cortical vessel morphology observed through a cranial window in mice after unilateral common carotid artery (CCA) occlusion. METHODS: The density and diameter of capillaries, as well as diameters of pial arteries, were measured by confocal laser-scanning microscopy and fluorescent microscopy, respectively. Possible angiogenesis was evaluated by detecting any outgrowth of endothelial cells from pre-existing vessels or intussusception in Tie2-GFP mice. RESULTS: Immediately after unilateral CCA occlusion, cerebral blood flow (CBF) index, the reciprocal of mean transit time, reduced significantly and returned to the previous level after 14 days. Repeated observation of the cortical vessels did not reveal any angiogenesis, whereas the cortical capillary diameter increased by 74% after 14 days. The anterior cerebral artery (ACA) and collateral vessels connecting ACA and middle cerebral artery also dilated significantly. The capillary dilatation to the size of arteriole in the settings of collateral growth and CBF restoration suggested capillary remodeling. CONCLUSIONS: Our results indicate that capillary remodeling, pial artery dilatation and collateral growth without angiogenesis are sufficient mechanisms to restore normal cerebral blood flow after unilateral CCA occlusion.

Dominant expression of angiogenin in NeuN positive cells in the focal ischemic rat brain.

Angiogenin (ANG) is a potent angiogenic factor. The purposes of this study were to observe the change of the expression level of ANG and to identify the cell types that express ANG in the focal ischemic rat brain. The rat brain ischemia-reperfusion model was produced by a 2 h occlusion of the left middle cerebral artery with a nylon thread followed by reperfusion for 1 day, 3 days, 7 days or 14 days. The expression levels of ANG in the rat brain at each time points were determined by western blotting. The co-staining of ANG with NeuN was observed using double immunofluorescent labeling combined with confocal laser scanning microscope. We found that the expression level of ANG increased significantly in the rat brain 1 day, 3 days, and 7 days after ischemia (P<0.05), and peaked 3 days after ischemia. Double immunofluorescent labeling showed that ANG positive cells were mostly co-stained with NeuN. Our observations suggest that the level of ANG increased significantly in the rat brain after ischemia. The upregulated ANG was mostly expressed by neurons.

The kinetic change of the serum angiogenin level in patients with acute cerebral infarction.

Serum angiogenin (ANG) levels were measured with ELISA in 30 cerebral infarction patients at different time points (within 48 h and on days 3, 7 and 14 after onset of cerebral infarction) and in 20 control subjects. Serum ANG levels in patients were 415.1 +/- 76.8, 410.6 +/- 82.1, 443.6 +/- 91.1 and 395.3 +/- 83.9 ng/ml within 48 h and on days 3, 7 and 14 after cerebral infarction, respectively. Serum ANG level in control group was 334.9 +/- 93.9 ng/ml. Serum ANG levels were significantly higher in patients with cerebral infarction within 48 h and on days 3 and 7 than in the control group (p < 0.05). Serum ANG level decreased on day 14. Serum ANG levels were significantly higher in patients with large infarction than in those with moderate and small infarction at each time point (p < 0.05). Our observations that serum ANG levels increase significantly in patients with cerebral infarction and the increase in ANG levels correlates with the infarct size suggest that ANG might be involved in the pathophysiologic process of ischemic brain damage.

Serial measurement of serum basic fibroblast growth factor in patients with acute cerebral infarction.

Basic fibroblast growth factor (bFGF) has been reported to be involved in the pathophysiological changes following cerebral infarction. Basic fibroblast growth factor is upregulated in the brain and conduces to neuroprotection and angiogenesis in experimental brain ischemia, but the change of serum bFGF in cerebral infarction patients has not been reported. In the present study, we investigated the dynamic changes of serum bFGF in 30 patients with acute cerebral infarction and found that serum bFGF increased significantly after cerebral infarction compared with the control group (p<0.05). Serum bFGF peaked on day 3 (15.46 +/- 5.58 pg/ml; p<0.01) and remained significantly elevated on day 14 following cerebral infarction. In this study, it was also found that the levels of bFGF with large infarction were higher at each time point than those with moderate or small infarction (p<0.05). There was a positive correlation between the peak level of bFGF and improvement of clinical neurological deficits scored by Scandinavian Stroke Scale (SSS) (r=0.596; p<0.05). These results suggest that the serum bFGF level increased significantly after cerebral infarction and the level of serum bFGF could be of value to estimate the infarction size and clinical prognosis.

Beta1-integrins are critical for cerebellar granule cell precursor proliferation.

We have previously shown that mice with a CNS restricted knock-out of the integrin beta1 subunit gene (Itgb1-CNSko mice) have defects in the formation of lamina and folia in the cerebral and cerebellar cortices that are caused by disruption of the cortical marginal zones. Cortical structures in postnatal and adult Itgb1-CNSko animals are also reduced in size, but the mechanism that causes the size defect has remained unclear. We now demonstrate that proliferation of granule cell precursors (GCPs) is severely affected in the developing cerebellum of Itgb1-CNSko mice. In the absence of beta1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely. In vitro studies provide evidence that beta1 integrins act at least in part cell autonomously in GCPs to regulate their proliferation. Previous studies have shown that sonic hedgehog (Shh)-induced GCP proliferation is potentiated by the integrin ligand laminin. We show that Shh directly binds to laminin and that laminin-Shh induced cell proliferation is dependent on beta1 integrin expression in GCPs. Taken together, these data are consistent with a model in which beta1 integrin expression in GCPs is required to recruit a laminin-Shh complex to the surface of GCPs and to subsequently modulate the activity of signaling pathways that regulate proliferation.