[Analysis of the prevalence of anticoagulant therapy in patients with cognitive disorders and cerebral amyloid angiopathy (CAA)]. / Analyse zur Häufigkeit einer gerinnungshemmenden Medikation bei Patientinnen mit kognitiven Störungen und zerebraler Amyloidangiopathie (CAA).

OBJECTIVES: To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as the relationship between the presence of oral anticoagulation and CAA-specific lesion load. MATERIALS AND METHODS: Patients with subjective cognitive decline (SCD), amnestic and non-amnestic mild cognitive impairment (aMCI/naMCI), Alzheimer's disease (AD), mixed dementia (MD) and vascular dementia (VD) who presented to our outpatient dementia clinic between February 2016 and October 2020 were included in this retrospective analysis. Patients underwent cranial magnetic resonance imaging (MRI). MRI data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. Presence of anticoagulant therapy was determined by chart review. RESULTS: Within the study period, 458 patients (209 male, 249 female, mean age 73.2 ± 9.9 years) with SCD (n = 44), naMCI (n = 40), aMCI (n = 182), AD (n = 120), MD (n = 68) and VD (n = 4) were analyzed. A total of 109 patients (23.8%) were diagnosed with possible or probable CAA. CAA prevalence was highest in aMCI (39.4%) and MD (28.4%). Of patients with possible or probable CAA, 30.3% were under platelet aggregation inhibition, 12.8% were treated with novel oral anticoagulants and 3.7% received phenprocoumon treatment. Regarding the whole study cohort, patients under oral anticoagulation showed more cerebral microbleeds (p = 0.047). There was no relationship between oral anticoagulation therapy and the frequency of cortical superficial siderosis (p = 0.634). CONCLUSION: CAA is a frequent phenomenon in older patients with cognitive disorders. Almost half of CAA patients receive anticoagulant therapy. Oral anticoagulation is associated with a higher number of cortical and subcortical microbleeds.

Post-Ischemic Permeability of the Blood-Brain Barrier to Amyloid and Platelets as a Factor in the Maturation of Alzheimer's Disease-Type Brain Neurodegeneration.

The aim of this review is to present evidence of the impact of ischemic changes in the blood-brain barrier on the maturation of post-ischemic brain neurodegeneration with features of Alzheimer's disease. Understanding the processes involved in the permeability of the post-ischemic blood-brain barrier during recirculation will provide clinically relevant knowledge regarding the neuropathological changes that ultimately lead to dementia of the Alzheimer's disease type. In this review, we try to distinguish between primary and secondary neuropathological processes during and after ischemia. Therefore, we can observe two hit stages that contribute to Alzheimer's disease development. The onset of ischemic brain pathology includes primary ischemic neuronal damage and death followed by the ischemic injury of the blood-brain barrier with serum leakage of amyloid into the brain tissue, leading to increased ischemic neuronal susceptibility to amyloid neurotoxicity, culminating in the formation of amyloid plaques and ending in full-blown dementia of the Alzheimer's disease type.

Effect of cerebral microhemorrhages on neurocognitive functions in patients with end-stage renal disease.

BACKGROUND: Death is the most serious complication of intracerebral hemorrhage. Microbleeding can be a precursor of intracerebral hemorrhage. Susceptibility weighted imaging (SWI) should be included in imaging protocols for some specific groups such diabetic hemodialysis patients in terms of prediction of macrohemorrhages. PURPOSE: To investigate intracerebral microbleeding in hemodialysis patients and the correlation between microbleeding and neurocognitive impairment. MATERIAL AND METHODS: Forty-nine hemodialysis cases were involved in the study. Locations of microbleeding, correlation between microbleeding and hypertension, diabetes mellitus (DM), age, and duration of dialysis were analyzed. Standardized mini-mental test was performed. The tested cases were divided into two groups: intracerebral microbleeding (group 1, n = 26) and without intracerebral microbleeding (group 2, n = 17). RESULTS: Incidence of microbleeding and macrohemorrhage was noted as 59% and 14%, respectively, in all cases. All macrohemorrhagic cases also have microbleeding. In group 1, neurocognitive impairment was detected in 10 (38.4%) cases: six and four cases with moderate and mild impairment, respectively. In group 2, neurocognitive impairment was detected in 2 (11.7%) cases, both with mild impairment. A significant positive correlation was detected between microbleeding and neurocognitive impairment (P = 0.031). Although there was no correlation between attention disorder and microbleeding, a positive correlation was detected between close memory impairment and microbleeding (P = 0.027). A positive correlation was detected between DM and microbleeding (P = 0.027). CONCLUSION: In hemodialysis patients, microbleeding can be a cause of neurocognitive impairment which will be important for guide to treatment protocols. SWI should be included in the imaging protocol of diabetic hemodialysis patients with neurocognitive deterioration.

[Facial linear scleroderma associated with neurological abnormalities relating to microangiopathy]. / Sclérodermie linéaire de la face associée à des anomalies neurologiques par microangiopathie.

BACKGROUND: Linear scleroderma is a fibrotic disease affecting the skin and sometimes the deeper tissues. We describe a case of scleroderma associated with neurological anomalies not previously reported in the literature. PATIENTS AND METHODS: A 16-year-old male patient presented in 2009 for hemifacial linear scleroderma. Treatment with methotrexate for 14 months resulted in stabilization of the disease. In 2013, we noted worsening of the patient's skin lesions as well as homolateral ptosis. Head MRI revealed unilateral hemispherical signal abnormalities with T2 hypersignal in the basal gangliaand punctate foci of T2* hyposignal corresponding to microbleeds. In 2014 and 2015, the patient presented three brief episodes of right hemicorpus paresthesia (with temporary aphasia followed by headache during the first episode). The head MRI showed worsening of the anomalies, suggesting progressing cerebral microangiopathy. DISCUSSION: Clinicians may not always be familiar with the neurological abnormalities associated with localized facial scleroderma even if such abnormalities are not uncommon (their exact prevalence is unknown). Clinical signs vary but, in most cases, the radiological features are calcifications and hyperintense foci of white matter lesions in T2. As far as we are aware, there have been no reports to date of microbleeding as observed in our patient. The worsening with time of these neurological anomalies of unknown origin does not appear to be correlated with the dermatological lesions. It is important for dermatologists be aware of these complications of facial linear scleroderma.

[Cerebral amyloid angiopathy and dementia]. / Zerebrale Amyloidangiopathie und Demenz.

Cerebral amyloid angiopathy (CAA) is one of the most frequent causes of intracerebral hemorrhage (ICH). The deposition of beta amyloid leads to vascular fragility due to degeneration of vessel walls, formation of microaneurysms particularly in cortical blood vessels and fibrinoid vessel wall necrosis. The Congo red positive amyloid deposits are biochemically similar to the material comprising senile plaques in Alzheimer's disease. Recurrent or multiple simultaneous hemorrhages particularly in older patients should raise the suspicion of CAA. Gradient echo magnetic resonance imaging (MRI) is a sensitive, non-invasive technique for identifying even very small hemorrhages and superficial siderosis, which may cause transient symptoms in CAA. There is also a correlation between CAA, microbleeding and cognitive decline. Inflammatory variants of CAA must be suspected whenever patients present with progressive dementia, headache and multifocal symptoms in association with CAA findings in MRI. Histopathologically, a distinction is made between CAA-related inflammation (CAA-ri) with perivascular inflammatory infiltrates and amyloid beta-related angiitis (ABRA) with histological detection of transmural vasculitis. Inflammatory variants should be treated with corticosteroids and immunosuppressants.

HTRA1-related cerebral small-vessel disease causes cerebral microbleeds on the brainstem surface.

BACKGROUND AND OBJECTIVES: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) has recently been known as HTRA1-related cerebral small-vessel disease (CSVD), it is caused by variants in HTRA1. Recently, it has been reported to develop in heterozygotes with some variants of the gene. Multiple prospective studies have reported that the frequency of heterozygous HTRA1 variants developing CSVD is 2 - 6.5 % in CARASIL. Heterozygous variant cases lack unique clinical features, have an older age of onset, and are difficult to detect. Characteristic findings are required to identify such cases. METHOD: Magnetic resonance imaging (MRI) images of cases that experienced cerebral infarction and carried heterozygous variants in HTRA1 were reviewed. RESULTS: Four cases of heterozygous HTRA1-related CSVD in two families (Family 1: c.754G > A, p.A252T; three males. Family 2: c.497G > T, p.R166L, one female). In all cases, white matter lesions with lacunar infarcts were observed in the periventricular and basal ganglia, external capsule, and brainstem. Moreover, T2 star weighted image (T2*WI) low presented dot-like lesions were present along the surface of the brainstem, which have only been reported in one homozygous case. Susceptibility-weighted imaging (SWI) was performed in two cases, and the dot-like lesions on T2*WI resembled a pearly tiara along the surface of the brainstem. CONCLUSION: Brainstem surface on T2*WI low showed dot-like lesions, which are not generally observed in patients with stroke and can be characteristic of HTRA1-CSVD associated with heterozygous variant. The pathology requires further investigation for diagnosis.

[Amyloid ß-related angiitis presenting extensive brain involvement without detection of hemorrhagic lesions: A case report].

In amyloid ß-related angiitis, cortical or subcortical microbleeding or cortical superficial siderosis supports clinical diagnosis. However, here we present a 75-year-old female case of amyloid ß-related angiitis that did not initially show these lesions. The patient developed right homonymous hemianopia and aphasia, and subsequently became comatose. Her brain lesions progressed extensively from the left occipital lobe to the bilateral cerebral hemispheres, with diffused leptomeningeal lesions and scattered DWI high-intensity lesions. After pathological diagnosis, steroid treatment improved her symptoms as well as imaging findings. No hemorrhagic lesions were detected in the T2*-weighted imaging performed before treatment. However, susceptibility-weighted imaging performed after treatment showed a number of lesions with microbleeding. The clinical features of amyloid ß-related angiitis that do not show hemorrhagic lesions at onset should be investigated for rapid therapeutic intervention in the future.

Rapid Cognitive Decline and Recurrent Falls in a 71 Year-Old Man Due to Cerebral Amyloidangiopathy-Related Inflammation (CAA-RI).

Cognitive decline and falls in the elderly are common and are often accepted as natural and inevitable by relatives and health care professionals, but frequently there are specific and treatable diseases that should be revealed. In our case, cerebral amyloid angiopathy-related inflammation (CAA-RI) was causative for neuro-psychiatric symptoms and worsening of gait in a 71 year-old man with recurrent falls and decline of gait and cognition. Cerebral amyloidangiopathy (CAA) is an important cause of cerebrovascular disorders in the elderly, characterized by leukoencephalopathy combined with lobar or small cortical hemorrhage due to amyloid deposition in cortical and leptomeningeal vessels. In several conditions, amyloid deposition can provoke inflammation or edema that lead to -normally reversible- encephalopathy. CAA-RI is then characterized by subacute neurobehavioral symptoms, headache, seizures or stroke-like signs. The first therapeutic option after confirming the diagnosis is treatment with glucocorticoids. Despite treatment with prednisolone, our patient could not regain his unrestricted mobility and self-help competence. Our report aims to sharpen awareness for CAA and its inflammatory form (CAA-RI) in healthcare professionals involved in medical care of the elderly and provide a short summary of this disease.

The relationship between brain microbleeds and homeostatic markers in the treatment of ischemic stroke.

OBJECTIVES: There is no definitive data regarding the usefulness of Brain microbleeds (BMBs) as an imaging marker with homeostatic markers to predict intracerebral hemorrhage (ICH) and ischemic stroke risk to personalize decisions on anticoagulation in AF. In this study, we prospectively evaluated clinical, radiological homeostatic biomarkers and their association with stroke outcomes in 73 AF-related ischemic stroke patients. METHODS: All BMBs were measured manually on Susceptibility-Weighted Imaging (SWI). The levels of NT-pro-BNP, hs-CRP, FVII, FVIII and vWF were studied as homeostatic markers. For all patients, we calculated CHADS2, CHA2DS2-VASc, HAS-BLED scores and modified Rankin Scale (mRS) scores. Functional independence and good clinical outcome were defined as a mRS score of 0-2. RESULTS: The mean age of the study population was 69.74 ± 9.79 years, and 36 patients were female. The leading vascular risk factor was hypertension (61%). BMBs were determined in 20 patients (27.4%) on SWI, 12 patients had less than five lesions. Presence of BMBs lesions on SWI was significantly associated with age and hypertension (p = .020) and congestive heart failure (p = .011). The median CHA2DS2-VASc score in patients was 4.96 ± 1.54. CHA2DS2-VASc score (p = .042), CHADS2 score (p = .037) and HAS- BLED score (p = .033) were significantly related with the presence of BMBs in the study patients. Among homeostatic markers, the levels of NT-pro-BNP, hs-CRP, and vWF were significantly associated with the presence of microbleeds (p = .013, p = .029, p = .020, respectively). CONCLUSION: Pathogenesis of AF is involved abnormal changes of hemostasis, endothelial dysfunction, antithrombotic state and inflammation. The homeostatic markers, which play role in these pathways, and the presence of BMBs could use to form a prognostic clinic assessment tool to predict bleeding risk.

Thrombolysis-related Multiple Lobar Hemorrhaging in Cerebral Amyloid Angiopathy with Extensive Strictly Lobar Cerebral Microbleeding.

A hemi-paralyzed 86-year-old man was diagnosed with ischemic stroke and underwent thrombolysis. Pre-thrombolysis brain magnetic resonance imaging revealed extensive strictly lobar cerebral microbleeding (CMB). Post-thrombolytic computed tomography revealed asymptomatic multiple intracerebral hemorrhaging (ICH). His age, CMB topography, and decreased cerebral spinal fluid amyloid-ß 40 and 42 levels were compatible with a diagnosis of cerebral amyloid angiopathy (CAA). There is no consensus on the safety of thrombolysis for acute stroke patients with CAA. Patients with CAA might have a higher incidence of thrombolysis-related ICH than those without CAA.

Longitudinal noninvasive magnetic resonance imaging of brain microhemorrhages in BACE inhibitor-treated APP transgenic mice.

Currently, several immunotherapies and BACE (Beta Site APP Cleaving Enzyme) inhibitor approaches are being tested in the clinic for the treatment of Alzheimer's disease. A crucial mechanism-related safety concern is the exacerbation of microhemorrhages, which are already present in the majority of Alzheimer patients. To investigate potential safety liabilities of long-term BACE inhibitor therapy, we used aged amyloid precursor protein (APP) transgenic mice (APP23), which robustly develop cerebral amyloid angiopathy. T2*-weighted magnetic resonance imaging (MRI), a translational method applicable in preclinical and clinical studies, was used for the detection of microhemorrhages throughout the entire brain, with subsequent histological validation. Three-dimensional reconstruction based on in vivo MRI and serial Perls' stained sections demonstrated a one-to-one matching of the lesions thus allowing for their histopathological characterization. MRI detected small Perls' positive areas with a high spatial resolution. Our data demonstrate that volumetric assessment by noninvasive MRI is well suited to monitor cerebral microhemorrhages in vivo. Furthermore, 3 months treatment of aged APP23 with the potent BACE-inhibitor NB-360 did not exacerbate microhemorrhages in contrast to Aß-antibody ß1. These results substantiate the safe use of BACE inhibitors regarding microhemorrhages in long-term clinical studies for the treatment of Alzheimer's disease.

Investigating microbleeding in cerebral ischemia rats using susceptibility-weighted imaging.

PURPOSE: To detect the distribution and prevalence of cerebral microbleeding (CMB) in rats after acute ischemic stroke using susceptibility-weighted imaging (SWI). METHOD: After middle cerebral artery occlusion, 3T MR scanning was performed on 10 rats at 4h and 24h after ischemia. T2-weighted images (T2WI), T2 maps and diffusion-weighted images (DWI) were generated to estimate the severity of the brain ischemia. The SWI data were used to analyze location counts, size and distribution of the CMBs. The brain injury was evaluated and determined by hematoxylin and eosin (H&E) staining. RESULT: At 24h after onset of ischemia, 13 CMBs were found in seven of the nine ischemic rats, whereas only two CMBs were found at 4h after ischemia onset in one of the nine ischemic rats. All visible CMBs detected in the SWI data were located in the ischemic lateral cortex, with diameters ranging from 0.2 to 0.5mm. In addition, we observed thickened vessels near the CMBs in the ischemic hemisphere in the SWI minimum intensity projections that did not appear in the symmetrical regions on the contralateral hemisphere. Histopathological results confirmed the CMBs, and increased microvascular density was observed in the ipsilateral hemisphere. CONCLUSION: SWI technique allows the detection of CMBs and the accompanying thickened vessels in vivo in a rat model of cerebral ischemia, which appear to be challenging tasks using T2WI and DTI. The results reported in this work provide a better understanding of the pathophysiological mechanism of acute stroke.