scholarly journals PSEN1 Compound Heterozygous Mutations Associated with Cerebral Amyloid Angiopathy and Cognitive Decline Phenotype

2021 ◽  
Vol 22 (8) ◽  
pp. 3870
Author(s):  
Ilaria Palmieri ◽  
Marialuisa Valente ◽  
Lisa Maria Farina ◽  
Simone Gana ◽  
Brigida Minafra ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Cognitive Decline ◽  
Cerebral Amyloid Angiopathy ◽  
Presenilin 1 ◽  
Compound Heterozygous ◽  
Amyloid Angiopathy ◽  
First Case ◽  
Cerebral Amyloid ◽  
Compound Heterozygous Mutations ◽  
The Impact

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the deposition of amyloid beta-peptide (Aβ) aggregates. Aβ aggregates lead to vessel rupture and intracerebral hemorrhages, detected by magnetic resonance imaging (MRI). Presenile CAA is usually genetically determined by mutations in the amyloid precursor protein (APP) gene. However, mutations after codon 200 in the presenilin 1 (PSEN1) gene have been reported to facilitate CAA onset. Here, we analyzed the genetic bases in a patient of 55 years old affected by CAA and cognitive decline. DNA was isolated and genetic analysis was performed by Next-Generation Sequencing (NGS). RNA was extracted and retro-transcribed to perform segregation analysis by TOPO-TA cloning. WB analysis was carried out to check the impact of the mutations on protein. Two compound heterozygous mutations in PSEN1 exon 10, such as a novel stop-gain mutation (c.1070C > G) and a pathogenic splice variant (c.1129A > T), were found by NGS. Both mutations altered the presenilin 1 protein, truncating its C-terminal portion. This is the first case of CAA and cognitive decline caused by two compound mutations in PSEN1. With this report, we suggest extending the genetic analysis to PSEN1 when cerebral microbleeds are observed by MRI investigation in a patient affected by presenile cognitive decline.

scholarly journals Successful electroconvulsive therapy for depression in a man with cerebral amyloid angiopathy

2021 ◽  
Vol 14 (2) ◽  
pp. e238922
Author(s):  
Geert Schurgers ◽  
Baer M G Arts ◽  
Alida A Postma ◽  
Anna de Kort
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Electroconvulsive Therapy ◽  
Severe Depression ◽  
Amyloid Angiopathy ◽  
Amyloid Beta Protein ◽  
Cerebral Blood Vessels ◽  
Safety Measures ◽  
Aβ Clearance ◽  
Cerebral Amyloid ◽  
The Impact

Cerebral amyloid angiopathy (CAA) is a condition characterised by accumulation of amyloid beta protein (Aβ) in the wall of cerebral blood vessels which increases the risk of intracranial haemorrhage and contributes to cognitive impairment. We describe the case of a man around the age of 70 with ‘probable’ CAA according to the modified Boston criteria and severe depression whose depression was treated successfully with electroconvulsive therapy (ECT). To the best of our knowledge, there are no earlier published reports of ECT in a patient with CAA. We briefly discuss possible safety measures for these patients, the impact of ECT on cognition in CAA and a possible influence of ECT on Aβ clearance.

Subacute Cognitive Decline in an 86-Year-Old Woman With Prior Lobar Intracerebral Hemorrhage

2021 ◽  
pp. 192-194
Author(s):  
Stephen W. English ◽  
James P. Klaas
Keyword(s):  
Intracerebral Hemorrhage ◽  
Cognitive Decline ◽  
Temporal Lobe ◽  
Cerebral Amyloid Angiopathy ◽  
Mass Effect ◽  
Amyloid Angiopathy ◽  
Left Temporal Lobe ◽  
Epileptiform Discharges ◽  
Cerebral Amyloid ◽  
T2 Hyperintensity

An 86-year-old woman with a history of hypertension, hyperlipidemia, coronary artery disease, and hypothyroidism sought care for subacute, progressive cognitive decline. Five months earlier, she was hospitalized for a small, left temporal, lobar, intracerebral hemorrhage with associated receptive aphasia. Over the next several months, she had a precipitous cognitive decline. She was prescribed memantine by her primary physician because of concern for dementia. One month before seeking care, she was found unconscious in her bathroom, which was believed to be an unwitnessed seizure. Brain magnetic resonance imaging 1 month before the current evaluation showed a prior, small, left temporal hemorrhage and diffuse lobar microhemorrhages on gradient echo imaging, focal leptomeningeal gadolinium enhancement in the left temporal lobe, and multifocal T2 hyperintensity with mass effect, maximal in the left temporal lobe. Electroencephalography showed multifocal, independent epileptiform discharges. She underwent open biopsy of the left temporal lobe, which indicated focal granulomatous inflammation causing vascular destruction, with β‎-amyloid plaques within the cortical and leptomeningeal vessels. The findings were consistent with a diagnosis of amyloid-β‎-related angiitis in the setting of severe cerebral amyloid angiopathy. Because of concern for subclinical seizures and epileptiform discharges on electroencephalography, the patient was started on levetiracetam without substantial change in her mental status. After the biopsy findings demonstrated inflammatory changes consistent with amyloid-β‎-related angiitis, she was started on intravenous methylprednisolone, followed by transition to prednisone. After 6 months of treatment, she had significant clinical and radiographic improvement. Follow-up magnetic resonance imaging at that time showed interval improvement in the T2 hyperintensity and mass effect in the left temporal lobe. She was again independent with her activities of daily living, and memantine was discontinued. Cerebral amyloid angiopathy encompasses a heterogeneous group of diseases characterized by amyloid-β‎ peptide deposition. The most common clinical manifestation of cerebral amyloid angiopathy is lobar intracerebral hemorrhage, which can be multifocal and recurrent but can also result in cerebral ischemia and ischemic leukoencephalopathy.

083 Response to immunosuppressive therapy in cerebral amyloid angiopathy-related inflammation

2018 ◽  
Vol 89 (6) ◽  
pp. A33.3-A34
Author(s):  
Jasmin Tilling ◽  
Benjamin Trewin ◽  
Stanley Levy
Keyword(s):  
White Matter ◽  
Cognitive Decline ◽  
Cerebral Amyloid Angiopathy ◽  
White Matter Hyperintensities ◽  
Neurological Deficits ◽  
Amyloid Angiopathy ◽  
Dramatic Improvement ◽  
Age Related ◽  
Cerebral Amyloid ◽  
The Brain

IntroductionCerebral amyloid angiopathy (CAA) is a common age-related condition characterised by amyloid beta-peptide deposition affecting the medium sized cortical and leptomeningeal arteries, arterioles and capillaries. CAA-related Inflammation (CAA-I) is an increasingly recognised variant of CAA, which is thought to be due to perivascular auto-inflammation in response to amyloid deposition. We describe the clinical course of two cases of probable CAA-I.CasesA 71 year old man presented with new-onset seizures, headaches and subacute cognitive decline. MRI of the brain demonstrated confluent subcortical T2 white matter hyperintensities and cerebral oedema, with predominantly superimposed widespread cortico-subcortical micro-haemorrhages, in keeping with the diagnosis of CAA-I. A course of immunosuppresive therapy was commenced with five days of intravenous methylprednisolone, resulting in marked radiological and clinical improvement within two weeks.A 76 year old female presented with subacute cognitive dysfunction and apraxia, and transient left-sided weakness. MRI scan of the brain initially demonstrated a right temporo-occipital infarct, leading to primary treatment for stroke, but subsequently evolved to reveal diffuse multi-lobar T2 white matter hyperintensities with leptomeningeal involvement. A provisional diagnosis of CAA-I was made and following a poor clinical response to a trial of corticosteroid therapy, treatment with intravenous cyclophosphamide was commenced.ConclusionThese cases emphasise the importance of CAA-I as part of the differential diagnosis in patients presenting with symptoms of subacute cognitive decline, seizures, headaches and focal neurological deficits, given the potential for dramatic improvement with readily accessible immunosuppressive therapies.

scholarly journals Cortical Thickness and Its Association with Clinical Cognitive and Neuroimaging Markers in Cerebral Amyloid Angiopathy

2021 ◽  
pp. 1-9
Author(s):  
Arsenije Subotic ◽  
Cheryl R. McCreary ◽  
Feryal Saad ◽  
Amanda Nguyen ◽  
Ana Alvarez-Veronesi ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Cerebral Amyloid Angiopathy ◽  
Cortical Thickness ◽  
Vascular Reactivity ◽  
Cortical Atrophy ◽  
White Matter Hyperintensity ◽  
Amyloid Angiopathy ◽  
Healthy Controls ◽  
Normative Study ◽  
Cerebral Amyloid

Background: Cerebral amyloid angiopathy (CAA) contributes to brain neurodegeneration and cognitive decline, but the relationship between these two processes is incompletely understood. Objective: The purpose of this study is to examine cortical thickness and its association with cognition and neurodegenerative biomarkers in CAA. Methods: Data were collected from the Functional Assessment of Vascular Reactivity study and the Calgary Normative Study. In total, 48 participants with probable CAA, 72 cognitively normal healthy controls, and 24 participants with mild dementia due to AD were included. Participants underwent an MRI scan, after which global and regional cortical thickness measurements were obtained using FreeSurfer. General linear models, adjusted for age and sex, were used to compare cortical thickness globally and in an AD signature region. Results: Global cortical thickness was lower in CAA compared to healthy controls (mean difference (MD) –0.047 mm, 95% confidence interval (CI) –0.088, –0.005, p = 0.03), and lower in AD compared to CAA (MD –0.104 mm, 95% CI –0.165, –0.043, p = 0.001). In the AD signature region, cortical thickness was lower in CAA compared to healthy controls (MD –0.07 mm, 95% CI –0.13 to –0.01, p = 0.02). Within the CAA group, lower cortical thickness was associated with lower memory scores (R2 = 0.10; p = 0.05) and higher white matter hyperintensity volume (R2 = 0.09, p = 0.04). Conclusion: CAA contributes to neurodegeneration in the form of lower cortical thickness, and this could contribute to cognitive decline. Regional overlap with an AD cortical atrophy signature region suggests that co-existing AD pathology may contribute to lower cortical thickness observed in CAA.

scholarly journals 437 - COGNITIVE, PATHOLOGICAL, GENETIC AND NEURO-RADIOLOGICAL CORRELATES OF CEREBRAL AMYLOID ANGIOPATHY

2020 ◽  
Vol 32 (S1) ◽  
pp. 154-155
Author(s):  
Kasia G. Rothenberg
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Cerebral Amyloid Angiopathy ◽  
Cerebral Artery ◽  
Inflammatory Reaction ◽  
Oral Steroid ◽  
Amyloid Angiopathy ◽  
Word Finding ◽  
Cerebral Amyloid ◽  
Intravenous Steroids

Background:Cerebral Amyloid Angiopathy related inflammatory process (CAA-ri), a rare condition caused by an inflammatory reaction occurring within essential cerebral blood vessels against beta-amyloid deposits, leads to subclinical cognitive decline. Often misdiagnosed as dementia, this process can be treated through aggressive immunosuppression, thereby reversing much of the cognitive impairment.Case Report:We report a 69 year old female who came to the clinic for a second opinion and had received a previous diagnosis of Alzheimer’s Dementia (AD) from an outside hospital two years prior. She presented with her husband who provided some key aspects of the history. The husband reported two years of worsening of memory, while the patient denied her symptoms. Per husband and patient, she was able to perform activities of daily living (ADLs), including bathing, dressing and toileting, but had difficulties with many instrumental ADLs (IADLs). The clinical course was somewhat fluctuating with progressive cognitive symptoms and significant word-finding difficulties. Patient had been started on Donepezil 5 mg daily by her primary provider.Results:On examination, the patient did exhibit significant word-finding difficulties and scored 12/30 on the Montreal Cognitive Assessment (MoCA), indicating moderate cognitive impairment. The Patient was as well confused and disoriented to time and place. Neurological examination was otherwise unremarkable. Magnetic Resonance Imaging (MRI) studies were ordered and showed patchy and diffuse T2/FLAIR hyper intensities and particularly concentrated in the posterior cerebral artery and inferior division of the middle cerebral artery. These findings were consistent with cerebral amyloid angiopathy related inflammation (CAA-ri). Besides susceptibility weighted image (SWI) was showing multiple widely distributed microhemorrhages typical for CAA.To address the acute inflammatory reaction the patient was hospitalized and received high dose, 3 day course of intravenous steroids, followed by an oral steroid taper. The treatment had to be monitored due to an unrelated hypertensive emergency and WPW syndrome (both newly diagnosed and treated emergently) thus the Patient was hospitalized for a 3 days and discharged on oral steroids tapper in improved condition.Additionally, imaging showed that the patient’s hippocampal volumes were within normal range so this particular imaging biomarker didn’t support the diagnosis of AD. CSF biomarkers analysis didn’t support the diagnosis of AD either since had p-Tau levels were found to be within normal limits. Patient was found to be homozygous for the APOE e4 gene. Follow-up evaluation (including a repeat MRI study) was performed 2 months later showed clinical recovery and near complete resolution of diffuse hyperintensities, suggesting inflammation had resolved. Both the patient and the husband reported significant improvement in orientation and other aspects of cognition including working memory. The Patient scored 26/30 on MoCA.Discussion:Cerebral amyloid angiopathy (CAA) has been commonly associated with brain hemorrhages in the elderly, but the inflammatory subtype CAA-I occur much less frequently and may be often misdiagnosed as a cancerous process (Ronsin et al. 2016). In a recent systematic review by Caldas A et al. 2015, of the 155 patients with documented CAA-I, almost half displayed some form of cognitive impairment and 86% received corticosteroids. Nearly half of the cases improved following treatment.Conclusion:We present a case of a patient previously diagnosed with AD, upon further investigation, likely CAA-I, treated aggressively with intravenous steroids to good effect. Although rare, CAA-I is a reversible disorder that may be masked by a dementia or/and delirious process and should be considered in patients showing relatively rapid and fluctuating cognitive decline.

scholarly journals Case Report: Probable Cerebral Amyloid Angiopathy-Related Inflammation During Bevacizumab Treatment for Metastatic Cervical Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Tatiana Koudriavtseva ◽  
Svetlana Lorenzano ◽  
Vincenzo Anelli ◽  
Domenico Sergi ◽  
Annunziata Stefanile ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Endothelial Cells ◽  
Cerebral Amyloid Angiopathy ◽  
Vascular Endothelial Cells ◽  
Tumor Development ◽  
Amyloid Angiopathy ◽  
Vascular Endothelial ◽  
First Case ◽  
Bevacizumab Treatment ◽  
Cerebral Amyloid

Bevacizumab is an anti-angiogenic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF) that induces the proliferation and migration of vascular endothelial cells thus, promoting vasculogenesis. Bevacizumab inhibits cancer angiogenesis, which is fundamental for either tumor development, exponential growth, or metastatic spread by supplying nutrients and oxygen. We report a new possible adverse event of bevacizumab, a Cerebral Amyloid Angiopathy-Related Inflammation (CAARI), in a 72-year-old woman with metastatic cervical cancer. After six cycles every three weeks of chemotherapy (cisplatin, paclitaxel, bevacizumab) and following two maintenance bevacizumab administrations, the patient presented a worsening confusional state. The MRI scan showed bilateral asymmetric temporo-parieto-occipital hyperintensity with numerous cortical microbleeds indicative of a CAARI. After stopping bevacizumab treatment, steroid therapy was administered resulting in rapid clinical improvement. The subsequent neurological and oncological follow-up was negative for recurrence. The patient was a heterozygote carrier for apolipoprotein-E ε4 that increases the risk of sporadic Cerebral Amyloid Angiopathy (CAA), which is characterized by beta-amyloid accumulation and fibrinoid necrosis in cerebral vasculature leading to micro/macrohemorrhages and dementia. Moreover, CAA is present in 30% of people aged over 60 years without dementia. In the brains of CAA patients, there is a proinflammatory state with cerebrovascular endothelial cell alteration and elevated levels of either adhesion molecules or inflammatory interleukins that increase the blood–brain barrier permeability. Moreover, CAARI is an inflammatory form of CAA. Inhibition of VEGF, which has anti-apoptotic, anti-inflammatory, and pro-survival effects on endothelial cells, impairs their regenerative capacity and increases expression of proinflammatory genes leading to weakened supporting layers of blood vessels and, hence, to damaged vascular integrity. In our patient, bevacizumab administration may have further increased permeability of cerebral microvasculature likely impaired by an underlying, asymptomatic CAA. To our knowledge, this is the first case reporting on the development of probable CAARI during bevacizumab treatment, which should alert the clinicians in case of neurological symptom onset in older patients under anti-angiogenic therapy.

Association of Presenilin-1 Polymorphism With Cerebral Amyloid Angiopathy in the Elderly

Stroke ◽  
1997 ◽  
Vol 28 (11) ◽  
pp. 2219-2221 ◽  
Author(s):  
Masahito Yamada ◽  
Nobuyuki Sodeyama ◽  
Yoshinori Itoh ◽  
Naomi Suematsu ◽  
Eiichi Otomo ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
The Elderly ◽  
Presenilin 1 ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid
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