Leptomeningeal Vessels Research Articles

Alpha4 beta7 integrin controls Th17 cell trafficking in the spinal cord leptomeninges during experimental autoimmune encephalomyelitis.

Th1 and Th17 cell migration into the central nervous system (CNS) is a fundamental process in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Particularly, leptomeningeal vessels of the subarachnoid space (SAS) constitute a central route for T cell entry into the CNS during EAE. Once migrated into the SAS, T cells show an active motility behavior, which is a prerequisite for cell-cell communication, in situ reactivation and neuroinflammation. However, the molecular mechanisms selectively controlling Th1 and Th17 cell trafficking in the inflamed leptomeninges are not well understood. By using epifluorescence intravital microscopy, we obtained results showing that myelin-specific Th1 and Th17 cells have different intravascular adhesion capacity depending on the disease phase, with Th17 cells being more adhesive at disease peak. Inhibition of αLβ2 integrin selectively blocked Th1 cell adhesion, but had no effect on Th17 rolling and arrest capacity during all disease phases, suggesting that distinct adhesion mechanisms control the migration of key T cell populations involved in EAE induction. Blockade of α4 integrins affected myelin-specific Th1 cell rolling and arrest, but only selectively altered intravascular arrest of Th17 cells. Notably, selective α4β7 integrin blockade inhibited Th17 cell arrest without interfering with intravascular Th1 cell adhesion, suggesting that α4β7 integrin is predominantly involved in Th17 cell migration into the inflamed leptomeninges in EAE mice. Two-photon microscopy experiments showed that blockade of α4 integrin chain or α4β7 integrin selectively inhibited the locomotion of extravasated antigen-specific Th17 cells in the SAS, but had no effect on Th1 cell intratissue dynamics, further pointing to α4β7 integrin as key molecule in Th17 cell trafficking during EAE development. Finally, therapeutic inhibition of α4β7 integrin at disease onset by intrathecal injection of a blocking antibody attenuated clinical severity and reduced neuroinflammation, further demonstrating a crucial role for α4β7 integrin in driving Th17 cell-mediated disease pathogenesis. Altogether, our data suggest that a better knowledge of the molecular mechanisms controlling myelin-specific Th1 and Th17 cell trafficking during EAE delevopment may help to identify new therapeutic strategies for CNS inflammatory and demyelinating diseases.

Comparison of post contrast fluid attenuated inversion recovery, 3D T1-SPACE, and T1W MRI sequences with fat suppression in the diagnosis of infectious meningitis.

To assess the usefulness of post contrast Fluid attenuated inversion recovery (FLAIR), 3D T1-SPACE, and T1W magnetic resonance imaging (MRI) sequences with fat suppression in diagnosis of infectious meningitis. 75 patients with clinical suspicion of meningitis were evaluated with post contrast FLAIR (PC-FLAIR), post contrast T1-SPACE (PC-T1-SPACE), and post contrast T1WI (PC-T1WI). Sensitivity, specificity, positive predictive value, and negative predictive value of individual sequences were assessed. The sensitivity of PC-FLAIR (88.4%) was greater than PC-T1-SPACE (85.5%) and PC-T1WI (82.6%), considering cerebrospinal fluid (CSF) analysis as gold standard (p < 0.05). Kappa inter-rater agreement between two radiologists was 0.921 for PC-T1-SPACE, 0.921 for PC-T1WI, and 1.0 for PC-FLAIR with a p value <0.05. Both PC-T1-SPACE and PC-FLAIR performed equally in sulcal space enhancement. PC-T1-SPACE and PC-T1WI performed better in evaluation of pachymeningeal enhancement, ependymal enhancement in cases of ventriculitis, whereas PC-FLAIR was more sensitive in assessment of basal cistern enhancement and enhancement along the cerebellar folia. Meningeal enhancement could be better appreciated in PC-FLAIR image than PC-T1WI and PC-T1-SPACE. Enhancement in PC-T1-SPACE was comparable to that of PC-T1WI. Being a T1 based spin echo sequence, PC-T1-SPACE has all the advantages of PC-T1WI in addition to its ability to differentiate meningeal enhancement from leptomeningeal vessels. Hence, PC-T1WI can be replaced by PC-T1-SPACE and PC-FLAIR can be added to routine MRI protocol in suspected case of meningitis.

Abstract Number ‐ 70: Combined Trans‐arterial Flow Diversion and Trans‐venous Embolization Management of High‐Flow Traumatic Cavernous‐Carotid Fistula (CCF)

Introduction Carotid‐Cavernous fistulas (CCF) are abnormal vascular shunts between the internal carotid artery (ICA) and the cavernous sinus. Most commonly due to trauma (75%), CCF occurs in 4%(1) of skull‐base fracture patients. Visual impairment, diplopia, and headache are typical presenting symptoms (88%). Proptosis, chemosis, ophthalmoparesis, and orbital bruits are notable exam findings. Cerebral angiography is the gold standard for diagnosis, showing cavernous sinus enlargement and ophthalmic vein or leptomeningeal vessel dilatation. CCF is typically treated endovascularly andballoon embolization has achieved cure rates of 88–99%(2). Successful obliteration using stents, however, has been reported(3, 4). While both trans‐arterial and the trans‐venous approach embolization are feasible depending on local vascular anatomy and accessibility of fistula points, the combination of trans‐arterial and trans‐venous approach is rarely employed.We present a case of traumatic, high‐flow CCF treated with combined trans‐arterial and trans‐venous coiling embolization and telescoped flow‐diverting stents. Methods A case report of successful treatment of traumatic high‐flow CCF with a combined trans‐arterial and trans‐venous coiling embolization with telescoped flow‐diverting stents. Results A 26‐year‐old woman presented with right eye proptosis, periorbital ecchymosis, and chemosistwo weeks after severe closed head injury treated with decompressive hemicraniectomy and subdural hematoma evacuation. Examination was notable for right eye blindness without light perception and right‐sided third, fourth, and sixth cranial nerve palsies and elevated intraocular pressure. CT head showed a skull base fracture involving the right carotid canal and angiography of ICA confirmed a high‐flow multi‐channel right CCF with diminished intracranial arterial flow and engorged bilateral ophthalmic veins. After unsuccessful attempts to catheterize the fistula via arterial approach, superior‐segment coil embolization was performed using an inferior petrosal venous approach; but further embolization of the cavernous sinus was unsuccessful. Using the cavernous‐petrous segment of the right ICA, a flow‐diversion stent was placed that significantly decreased cross‐fistula blood flow, improved intracranial arterial flow, and reduced bilateral ophthalmic vein congestion. After two months, intraocular pressure normalized and right eye vision returned, though moderate exophthalmos persisted. Angiography showed decreased but persistent residual CCF flow. Another flow‐diversion stent was successfully placed via trans‐arterial approach, covering the previous pipeline stent through petrous‐to‐ophthalmic right ICA. Three‐month follow‐up angiogram showed closure of the CCF with complete restoration of right eye vision. She ultimately underwent right cranioplasty and was able to return to work. Conclusions A combined trans‐venous coiling embolization and trans‐arterial flow‐diversion stenting may be effectively employed in the treatment of CCF with reversal of clinical symptoms and restoration of visual loss. Larger studies are needed to explore the role of this combined approach in the management of CCF.

Spontaneous intracerebral haemorrhage associated with early-onset cerebral amyloid angiopathy and Alzheimer’s disease neuropathological changes five decades after cadaveric dura mater graft

Cerebral amyloid angiopathy (CAA) is a small vessel disease, causing spontaneous intracerebral hemorrhage (ICH) in the elderly. It is strongly associated with Alzheimer disease (AD), as most CAA patients show deposition of Aβ—i.e. the basic component of parenchymal Alzheimer amyloid deposits—in the cerebral vessels. Iatrogenic early-onset CAA has been recently identified in patients with a history of traumatic brain injury or other cerebral as well as extra-cerebral lesions that led to neurosurgery or other medical procedures as intravascular embolization by cadaveric dura mater extracts many years before the first ICH event. In those patients, a transmission of Aβ seeds from neurosurgical instruments or from cadaveric dura mater exposure was suggested. We report a 51-year-old woman with unremarkable family history who presented abruptly with aphasia and right hemiparesis. A cerebral left lobar haemorrhagic stroke was documented by neuroimaging. Accurate anamnesis revealed a neurosurgical procedure with cadaveric dura mater graft at the age of 2 years for an arachnoid cyst. The neuropathological examination of the cerebral parietal biopsy showed severe amyloid angiopathy in many leptomeningeal and cortical vessels, as well as abundant parenchymal Aβ deposits, neurofibrillary tangles and neuropil threads. The mechanism involved in the human-to-human transmission of the Aβ proteinopathy remains to be clarified. In our patient the cadaver derived dura used for grafting is a very strong candidate as the source of the transmission. A systematic monitoring of individuals who have had neurosurgical procedures in early life, especially those involving cadaveric dural grafts, is required to determine the ratio of those affected by CAA many years later and unaffected. Moreover, our report confirms that in addition to vascular and parenchymal Aβ pathology, neurofibrillary changes indistinguishable from AD may develop in specific conditions with long latency period from the neurosurgical or embolization procedure.

Cerebrospinal Fluid Biomarkers and Amyloid-β Elimination from the Brain in Cerebral Amyloid Angiopathy-Related Inflammation.

Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results. We investigated the relationship between CSF amyloid-β protein (Aβ) and vascular pathological findings to elucidate the mechanisms of Aβ elimination from the brain in CAA-ri. We examined Aβ 40 and Aβ 42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer's disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aβ 40 and Aβ 42 depositions on the leptomeningeal blood vessels (arteries, arterioles, and veins) using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri. The median Aβ40 and Aβ42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aβ40, 6837 pg/ml; Aβ42, 324 pg/ml) and AD-CAA (Aβ40, 7669 pg/ml, p = 0.345; Aβ42, 355 pg/ml, p = 0.760). Aβ40 and Aβ42 levels in patients with post-treatment CAA-ri (Aβ40, 1770 pg/ml, p = 0.056; Aβ42, 167 pg/ml, p = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aβ40 and Aβ42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aβ-deposited blood vessels than postmortem CAA-ri cases (Aβ40, 20.8% versus 3.9%, p = 0.0714; Aβ42, 27.4% versus 2.0%, p = 0.0714, respectively). Lower levels of CSF Aβ40 and Aβ42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function.

Rapidly progressive diffuse leptomeningeal glioneuronal tumor in an adult female: illustrative case.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare brain tumor only recently classified by the World Health Organization in 2016 and has few reports on its incidence in adults. The authors describe a case of DLGNT presenting in a 47-year-old female with seizures, cranial neuropathies, and communicating hydrocephalus with rapid clinical progression. Workup demonstrated progressive leptomeningeal enhancement of the skull base, cranial nerves, and spine, and communicating hydrocephalus. Elevated serum rheumatological markers and early response to systemic corticosteroids and immunosuppressant therapy complicated the diagnosis. Multiple biopsy attempts were required to obtain diagnostic tissue. Pathology demonstrated hypercellularity surrounding leptomeningeal vessels with nuclear atypia, staining positive for GFAP, Olig2, S100, and synaptophysin. Molecular pathology demonstrated loss of chromosome 1p, BRAF overexpression but no rearrangement, and H3K27 mutation. Repeat cerebrospinal fluid (CSF) diversion procedures were required for hydrocephalus management due to high CSF protein content. This report describes a rare, aggressive, adult presentation of DLGNT. Leptomeningeal enhancement and communicating hydrocephalus should raise suspicion for this disease process. Biopsy at early stages of disease progression is essential for early diagnosis and prompt treatment. Further study into the variable clinical presentation, histological and molecular pathology, and optimal means of diagnosis and management is needed.

Cortical Superficial Siderosis and Transient Focal Neurological Episode Preceding Lobar Hemorrhage in Cerebral Amyloid Angiopathy.

Cortical Superficial Siderosis and Transient Focal Neurological Episode Preceding Lobar Hemorrhage in Cerebral Amyloid Angiopathy.

Fatal thrombolysis-related intracerebral haemorrhage associated with amyloid-β-related angiitis in a middle-aged patient – case report and literature review

BackgroundAmyloid-β-related angiitis (ABRA) is a rare complication of cerebral amyloid angiopathy, characterized by amyloid-β deposition in the leptomeningeal and cortical vessels with associated angiodestructive granulomatous inflammation. The clinical presentation is variable, including subacute cognitive decline, behavioural changes, headaches, seizures and focal neurological deficits, which may mimic other conditions. Here, we present a case with fatal thrombolysis-related haemorrhage associated with ABRA in a middle-aged patient.Case presentationA 55-year-old man was admitted to hospital with sudden onset left-sided cheek, arm and hand sensory loss, blurred vision, and worsening headache, with a National Institutes of Health Stroke Scale (NIHSS) score of 3. An acute CT head scan showed no contraindications, and therefore the decision was made to give intravenous thrombolysis. Post-thrombolysis, he showed rapid deterioration with visual disturbances, headache and confusion, and a repeat CT head scan confirmed several areas of intracerebral haemorrhage. No benefit from surgical intervention was expected, and the patient died four days after the first presentation. Neuropathological examination found acute ischemic infarcts of three to five days duration in the basal ganglia, insular cortex and occipital lobe, correlating with the initial clinical symptoms. There were also extensive recent intracerebral haemorrhages most likely secondary to thrombolysis. Furthermore, the histological examination revealed severe cerebral amyloid angiopathy associated with granulomatous inflammatory reaction, consistent with ABRA.ConclusionsPresentation of ABRA in a middle-aged patient highlighted the difficulties in recognition and management of this rare condition. There is emerging evidence that patients with CAA may have increased risk of fatal intracerebral haemorrhages following thrombolysis. This may be further increased by a coexisting CAA-related inflammatory vasculopathy which is potentially treatable with steroid therapy if early diagnosis is made.

Positive association of Cerebral Amyloid Angiopathy (CAA) with R2 Relaxation rate: A study of ex‐vivo MRI and pathology

AbstractBackgroundCerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid‐β in the walls of cortical and leptomeningeal small vessels. CAA is common in older adults and has been associated with cognitive decline and dementia. In this work, the association of CAA with the transverse relaxation rate R2 values in a large community‐based cohort of older adults was investigated.MethodCerebral hemispheres from 797 participants of three cohort studies of aging, the Rush Memory and Aging Project, the Minority Aging Research Study, and the Religious Orders Study (Figure 1) were included in this work. All hemispheres were imaged ex‐vivo at approximately 30 days postmortem using 3T clinical MRI scanners. Each scan included a multi‐echo spin‐echo sequence, and in each voxel, the signals from the different echoes were used to fit a mono‐exponential T2 decay equation (R2 is the reciprocal of T2). The resulting R2 maps were registered to an ex‐vivo brain hemisphere template using ANTS. Following the MRI scan, each hemisphere underwent thorough neuropathologic evaluation (Figure 2). The assessed pathologies were: CAA, Alzheimer’s pathology, LATE‐NC, hippocampal sclerosis (HS), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts.Voxel‐wise linear regression was conducted to test the association of R2 with CAA, controlling for all other neuropathologies listed above, demographics (age at death, sex, education), and other variables (postmortem interval to immersion in fixative, postmortem interval to ex‐vivo MRI, scanners). Statistical analysis was done using PALM with tail‐accelerated 1000 permutations, threshold‐free cluster enhancement, and family‐wise error rate correction. Statistical significance was set at p&lt;0.05.ResultThe voxel‐wise analysis revealed a spatial pattern of higher R2 values for higher CAA burden (Figure 3). The pattern included subcortical structures such as the caudate, putamen, nucleus accumbens, hippocampus, regions in the insula, anterior cingulate cortex, orbitofrontal cortex, and superior frontal cortex (Figure 3). No voxel showed a negative association between R2 values and CAA burden.ConclusionOur work showed that CAA is associated with higher R2 among older adults, independent of other neuropathologies and demographic factors. The spatial pattern for this association derived from the voxel‐wise analysis included subcortical and frontal lobe structures.

Diagnosis, treatment, and follow-up of patients with cerebral amyloid angiopathy-related inflammation

PurposeCerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare potentially reversible encephalopathy associated with an autoimmune process against proteins deposited in the walls of cortical and leptomeningeal brain vessels. Definite diagnosis requires histopathological features of vascular inflammation and amyloid deposition from brain biopsy. Clinical-neuroradiological criteria have been recently introduced and validated to reduce the need for biopsy. The purpose of this paper is to report a historical retrospective review of clinical-neuroradiological follow-up of two patients with probable CAA-ri and five patients with a reasonably probable suspect of CAA-ri (4 females, 3 males, patient’s age at admission: 66–79 years) seen at our institution between 2007 and 2021, focusing on clinical and neuroradiological awareness to this entity and variable response to immunotherapy.Materials and methodsClinical features at presentation included subacute to acute confusion (6/7), seizures (4/7), cognitive impairment (5/7), and focal neurological signs (3/7). Neuroradiology included braincomputed tomography followed by magnetic resonance imaging. Infectious diseases and autoimmune workups were then performed.ResultsCSF analysis was performed in two patients. Cerebral angiography was performed in two patients, to rule out vascular malformations. Hemorrhagic posterior reversible encephalopathy syndrome has been suspected in two patients. Four patients underwent immunotherapy with corticosteroids followed by reduction of brain dysfunctions. Three patients did not undergo immunotherapy but underwent clinical and/or neuroradiological remission.ConclusionsPatients with CAA-ri present a rare steroid-responsive acute to subacute brain dysfunction. Thus, it has to be known and recognized both clinically and neuroradiologically. Spontaneous clinical and/or neuroradiological improvement is possible in patients with mild symptoms.

Phosphorylated-S6 Expression in Sturge-Weber Syndrome Brain Tissue

Background: Sturge-Weber Syndrome (SWS) is a rare neurovascular disorder associated with port-wine birthmarks, glaucoma, and abnormal leptomeningeal blood vessels. It is most commonly caused by a R183Q somatic mutation in GNAQ predicted to result in impaired deactivation of the protein Gαq, and downstream pathways such as the Ras-Raf-MEK-ERK and mTOR pathways. The GNAQ mutation is reportedly enriched in endothelial cells. Methods: Using a phosphorylated-S6 (p-S6) antibody, a marker for mTOR pathway activity, we analyzed p-S6 protein expression in human brain tissue samples from SWS subjects and epilepsy controls. Results: SWS brain tissue was more likely to have leptomeningeal endothelial p-S6 antibody staining, compared with epilepsy controls, while the percentage of samples with p-S6 staining in perivascular cells and cortex were not significantly different. Conclusions: Leptomeningeal endothelial mTOR activity may contribute to abnormal endothelial cell morphology and function. This finding implicates mTOR as a potential treatment target for Sturge-Weber Syndrome.

Distinct roles of the meningeal layers in CNS autoimmunity

The meninges, comprising the leptomeninges (pia and arachnoid layers) and the pachymeninx (dura layer), participate in central nervous system (CNS) autoimmunity, but their relative contributions remain unclear. Here we report on findings in animal models of CNS autoimmunity and in patients with multiple sclerosis, where, in acute and chronic disease, the leptomeninges were highly inflamed and showed structural changes, while the dura mater was only marginally affected. Although dural vessels were leakier than leptomeningeal vessels, effector T cells adhered more weakly to the dural endothelium. Furthermore, local antigen-presenting cells presented myelin and neuronal autoantigens less efficiently, and the activation of autoreactive T cells was lower in dural than leptomeningeal layers, preventing local inflammatory processes. Direct antigen application was required to evoke a local inflammatory response in the dura. Together, our data demonstrate an uneven involvement of the meningeal layers in CNS autoimmunity, in which effector T cell trafficking and activation are functionally confined to the leptomeninges, while the dura remains largely excluded from CNS autoimmune processes.

Maximizing Brain Health After Hemorrhagic Stroke: Bugher Foundation Centers of Excellence.

Maximizing Brain Health After Hemorrhagic Stroke: Bugher Foundation Centers of Excellence.

Main features of hereditary cerebral amyloid angiopathies: A systematic review

The term Cerebral Amyloid Angiopathy (CAA) refers to a group of neurovascular disorders characterized by amyloid deposition within the walls of leptomeningeal and cortical blood vessels of the brain, with specific predilection for arterioles, and (less often) capillaries and veins. Most CAA cases in the general population are sporadic in nature, and represent primarily an age-related condition affecting individuals in the fifth decade of life and beyond. Sporadic CAA is caused by deposition of amyloid-β (Aβ), originating from proteolytic cleavage of the Amyloid Precursor Protein (APP), within the walls of cerebral small caliber vessels. However, hereditary forms of CAA have also been described, generally presenting as rare familial disorder with monogenic (predominantly autosomal dominant) inheritance patterns. Hereditary CAA forms tend to affect younger individuals, and their course and clinical progression is more severe. Studies to date primarily focused on the vascular manifestations of sporadic and hereditary CAA, chiefly symptomatic lobar Intracerebral Hemorrhage (ICH). However, in the past decade sporadic CAA has also been consistently linked to progressive neurocognitive, neurobehavioral, and neuropsychiatric symptoms. This systematic review focuses on the genetics, pathogenesis, neuroimaging, neuropathology, and clinical manifestations of hereditary CAA with specific emphasis on previously overlooked cognitive, behavioral, and psychiatric symptoms.

Aspectos clínicos e patológicos de um surto de infecção por Streptococcus suis sorotipo 9 em suínos

ABSTRACT: Streptococcus suis is a Gram-positive pathogen that inhabits the upper respiratory tract and can cause severe systemic inflammatory disease in pigs, mainly during the nursery phase. Streptococcus suis is a reemergent pathogen, and outbreaks of its inducing disease represent significant economic losses for the pig industry worldwide. In this study, we described the clinical, pathological, and molecular aspects of an outbreak of S. suis infection with atypically high mortality. The outbreak occurred in nursery farms integrated into a cooperative in the state of Paraná, Brazil. Of the 30 nurseries, 10 were severely affected by the pathogen and had high economic losses. Clinical signs usually started approximately 10 days after weaning and were mainly characterized by acute nervous and locomotor disorders. The mortality of the affected batches usually ranged between 8% and 10%, but in some cases, it reached 18%. Nine piglets were submitted to post mortem examination. Macroscopically, the synovial joints were enlarged and contained fibrinous exudates. In the central nervous system, there was hyperemia of the leptomeningeal vessels associated with deposition of fibrin and purulent exudate in the leptomeninges. In three piglets, there was thickening of the choroid plexus associated with dilation of the lateral ventricles. Microscopic lesions were characterized mainly by fibrinosuppurative inflammation, which involved the synovial membranes, leptomeninges of the brain, and spinal cord. Furthermore, it also affects the choroid plexus, ependyma, nerve roots, and central canal of the spinal cord. S. suis was isolated from the cerebrospinal fluid, meningeal swabs, and/or synovial fluid of 8/9 piglets, and typified as serotype 9 by multiplex PCR.

CAA and related co‐morbidities in Down syndrome and Alzheimer disease

AbstractBackgroundCerebral amyloid angiopathy (CAA) is a form of cerebrovascular pathology characterized by the deposition of beta‐amyloid in the leptomeningeal and cortical blood vessels of the brain. CAA is a critical factor contributing to dementia in sporadic Alzheimer’s disease (AD). Many individuals with Down syndrome (DS) develop CAA due to the overexpression of the amyloid precursor protein (APP) gene and the subsequent increase of beta‐amyloid in the brain. However, little is known about the role of co‐morbidities like seizures in the presence and severity of CAA, or the effect that CAA has on the course of AD in individuals with DS.MethodClinical and neuropathology data for 48 individuals were included in the study. The clinical data, including the presence or absence of seizures and APOE genotype, was collected prospectively as part of a longitudinal research protocol for AD in DS at UCI as well as through a retrospective chart review of the medical records of patients at the AD in DS Memory Care Clinic at UCI. The neuropathology data, including the presence and severity of CAA, was recorded using the guidelines of the National Alzheimer’s Coordinating Committee (NACC).ResultA greater percentage of individuals with seizures have CAA as compared to those who did not have seizures, although the presence of seizures does not appear to impact the severity of CAA. Regarding those individuals with the APOE e4 allele, the majority of these individuals experienced moderate or severe CAA, with relatively few individuals with mild CAA or none. The duration of AD course appeared to decrease as CAA severity increased, but the results were not conclusive.ConclusionOverall, we did not find a significant correlation between seizures and the presence or absence of CAA, or between the severity of CAA and the duration of AD course. Some limitations to our study included a limited number of individuals without CAA or seizures compared to those who presented these conditions. Continuing studies will reinforce the role of CAA in the development of AD and contribute to our understanding of the role of clinical co‐morbidities in AD progression.

Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease.

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre‐codon 200 (n = 10), PSEN1 post‐codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid‐beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub‐group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post‐codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post‐codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD.

Decreased Basal Ganglia Volume in Cerebral Amyloid Angiopathy.

Background and PurposeCerebral amyloid angiopathy (CAA) is a common pathology of the leptomeningeal and cortical small vessels associated with hemorrhagic and non-hemorrhagic brain injury. Given previous evidence for CAA-related loss of cortical thickness and white matter volume, we hypothesized that CAA might also cause tissue loss in the basal ganglia. MethodsWe compared basal ganglia volumes expressed as a percentage of total intracranial volume (pBGV) of non-demented patients with sporadic and hereditary CAA to age-matched healthy control (HC) and Alzheimer’s disease (AD) cohorts. ResultsPatients with sporadic CAA had lower pBGV (n=80, 1.16%±0.14%) compared to HC (n=80, 1.30%±0.13%, P<0.0001) and AD patients (n=80, 1.23%±0.11%, P=0.001). Similarly, patients with hereditary CAA demonstrated lower pBGV (n=25, 1.26%±0.17%) compared to their matched HC (n=25, 1.36%±0.15%, P=0.036). Using a measurement of normalized basal ganglia width developed for analysis of clinical-grade magnetic resonance images, we found smaller basal ganglia width in patients with CAA-related lobar intracerebral hemorrhage (ICH; n=93, 12.35±1.47) compared to age-matched patients with hypertension-related deep ICH (n=93, 13.46±1.51, P<0.0001) or HC (n=93, 15.45±1.22, P<0.0001). Within the sporadic CAA research cohort, decreased basal ganglia volume was independently correlated with greater cortical gray matter atrophy (r=0.45, P<0.0001), increased basal ganglia fractional anisotropy (r=–0.36, P=0.001), and worse performance on language processing (r=0.35, P=0.003), but not with cognitive tests of executive function or processing speed. ConclusionsThese findings suggest an independent effect of CAA on basal ganglia tissue loss, indicating a novel mechanism for CAA-related brain injury and neurologic dysfunction.

Cerebral Amyloid Angiopathy-Related Inflammation/Vasculitis

Cerebral amyloid angiopathy (CAA) is a disorder characterized by the deposition of amyloid in the leptomeningeal and cortical blood vessels. Sporadic amyloid β (Aβ)-type CAA is the most common form of CAA. Although CAA is a well-known cause for recurrent cerebral lobar hemorrhage, inflammation, and vasculitis, CAA-related inflammation/vasculitis (CAA-ri/vasculitis) induced by Aβ deposition on vessel walls is emerging as a treatable condition. The estimated total number of cases of and prevalence of CAA-ri/vasculitis in Japan were 170 and 0.13 per 100 000 population, respectively. Patients with CAA-ri/vasculitis show acute or subacute-onset of cognitive impairment, behavioral changes, and headache. Brain magnetic resonance imaging, showing asymmetrical white matter abnormalities and occasional meningeal enhancement, is a useful tool for the diagnosis of CAA-ri/vasculitis. Moreover, elevation of anti-Aβ antibodies and inflammatory markers in the cerebrospinal fluid can help in clinical diagnosis. Although several clinical diagnostic criteria have been proposed, neuropathological examination of a brain biopsy remains the gold standard for detecting severe Aβ deposition and vasculopathic changes with lymphocytic infiltrations and/or granulomatous vasculitis. No validated treatment regimen has been established to date. Nearly 80% patients with CAA-ri/vasculitis improved after immunosuppressant therapy with corticosteroid and/or cyclophosphamide. Early treatment is essential to prevent irreversible sequelae in the brain.

Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.