Familial cerebral amyloid disorders with prominent white matter involvement.

Familial cerebral amyloid disorders are characterized by the accumulation of fibrillar protein aggregates, which deposit in the parenchyma as plaques and in the vasculature as cerebral amyloid angiopathy (CAA). Amyloid ß (Aß) is the most common of these amyloid proteins, accumulating in familial and sporadic forms of Alzheimer's disease and CAA. However, there are also a number of rare, hereditary, non-Aß cerebral amyloidosis. The clinical manifestations of these familial cerebral amyloid disorders are diverse, including cognitive or neuropsychiatric presentations, intracerebral hemorrhage, seizures, myoclonus, headache, ataxia, and spasticity. Some mutations are associated with extensive white matter hyperintensities on imaging, which may or may not be accompanied by hemorrhagic imaging markers of CAA; others are associated with occipital calcification. We describe the clinical, imaging, and pathologic features of these disorders and discuss putative disease mechanisms. Familial disorders of cerebral amyloid accumulation offer unique insights into the contributions of vascular and parenchymal amyloid to pathogenesis and the pathways underlying white matter involvement in neurodegeneration. With Aß immunotherapies now entering the clinical realm, gaining a deeper understanding of these processes and the relationships between genotype and phenotype has never been more relevant.

Tumefactive cerebral amyloid angiopathy - related inflammation.

INTRODUCTION: Cerebral amyloid angiopathy-related inflammation (CAA-ri) derives from inflammatory response to ß-amyloid (Aß) protein deposition within the cerebral blood vessel walls. We report a case that accentuates those clinical and imaging features that can contribute to raise suspicion for the condition and lead to early treatment initiation. CASE PRESENTATION: A 72-year-old man was referred with one-month history of cognitive decline along with behavioral alterations. Brain MRI showed fluid attenuated inversion recovery (FLAIR) asymmetrical multifocal white matter hyperintensities (WMHs) along with multiple cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS) on T2*-weighted gradient-recalled echo (T2*-GRE) images. Metabolic, infectious, and neoplastic causes were excluded, and subsequently corticosteroids were administered to the patient resulting in clinical recovery. Imaging on follow-up disclosed remission of WMHs, while CMBs load increased significantly. DISCUSSION: Clinical neurologists' acquaintance with the clinical and imaging features of CAA-ri allows prompt diagnosis and medication initiation, that is essential for a conceivably treatable condition.

The presence of circulating human apolipoprotein J reduces the occurrence of cerebral microbleeds in a transgenic mouse model with cerebral amyloid angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by amyloid-ß (Aß) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aß aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of ß-amyloidosis with prominent CAA. METHODS: Twenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aß levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings. RESULTS: rhApoJ-treated APP23 presented fewer cortical CMBs (50-300 µm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 µm) (p = 0.002) than saline-treated mice, independently of Aß brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036). CONCLUSIONS: Chronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.

Occult Amyloid-ß-Related Angiitis: Neuroimaging Findings at 1.5T, 3T, and 7T MRI.

Cerebral amyloid angiopathy (CAA) is a progressive neurodegenerative small vessel disease that is associated with intracranial hemorrhage and cognitive impairment in the elderly. The clinical and radiographic presentations have many overlapping features with vascular cognitive impairment, hemorrhagic stroke, and Alzheimer disease (AD). Amyloid-ß-related angiitis (ABRA) is a form of primary CNS vasculitis linked to CAA, with the development of spontaneous autoimmune inflammation against amyloid in the vessel wall with resultant vasculitis. The diagnosis of ABRA and CAA is important. ABRA is often fatal if untreated and requires prompt immunosuppression. Important medical therapies such as anticoagulation and antiamyloid agents for AD are contraindicated in CAA. Here, we present a biopsy-proved case of ABRA with underlying occult CAA. Initial 1.5T and 3T MR imaging did not suggest CAA per the Boston Criteria 2.0. ABRA was not included in the differential diagnosis due to the lack of any CAA-related findings on conventional MR imaging. However, a follow-up 7T MR imaging revealed extensive cortical/subcortical cerebral microbleeds, cortical superficial siderosis, and intragyral hemorrhage in extensive detail throughout the supratentorial brain regions, which radiologically supported the diagnosis of ABRA in the setting of CAA. This case suggests an increased utility of high-field MR imaging to detect occult hemorrhagic neuroimaging findings with the potential to both diagnose more patients with CAA and diagnose them earlier.

Cerebral Amyloid Angiopathy-Related Inflammation and Biopsy-Positive Primary Angiitis of the CNS: A Comparative Study.

BACKGROUND AND OBJECTIVES: Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS. METHODS: Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk. RESULTS: This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS (p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04). CONCLUSION: Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

Temporal Characterization of the Amyloidogenic APPswe/PS1dE9;hAPOE4 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aß) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers (APOE4) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aß immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene (APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aß deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aß, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.

Association of Alzheimer's Disease and Other Neuropathologies With Functional Disability in Persons With and Without Dementia.

BACKGROUND: Dementia results from multiple neuropathologies causing cognitive impairment sufficiently severe to affect functional status. However, these pathologies and functional impairment are common in persons without dementia. We examined the association of Alzheimer's disease (AD) and multiple other neuropathologies with instrumental and basic activities of daily living in persons with and without dementia. METHODS: Participants were 1 509 deceased from the Religious Orders Study or Rush Memory and Aging Project. Pathologic AD and 3 other AD indices were examined, in addition to 4 non-AD neurodegenerative pathologies: cerebral amyloid angiopathy (CAA), hippocampal sclerosis, TDP-43, and Lewy bodies, and 4 cerebrovascular pathologies: gross- and microinfarctions, athero- and arteriolosclerosis. Functional assessment included Lawton and Katz Index Instrumental and Basic Activities of Daily Living (IADL and BADL). Ordinal regression models adjusted for age, sex, and education were used to examine the association of neuropathologies with IADL and BADL. RESULTS: Alzheimer's disease and the other neuropathologies were associated with impaired IADL (all ps < .001) and with impaired BADL (ps < .01), except for atherosclerosis and CAA, which were not associated with BADL. The effects of most neuropathologies were largely affected by dementia. However, small effects on IADL remained for PHF-tau tangles after adjusting models for dementia. Direct effects of gross infarcts on IADL and BADL and of microinfarcts on BADL remained unchanged after adjusting the models for dementia. CONCLUSIONS: Alzheimer's disease and all other neuropathologies are strongly associated with functional disability. The association of most neuropathologies with disability was eliminated or attenuated by dementia, except for gross infarcts and microinfarcts.

Neuropsychiatric symptoms with focus on apathy and irritability in sporadic and hereditary cerebral amyloid angiopathy.

BACKGROUND: Neuropsychiatric symptoms (NPS) may affect cognition, but their burden in cerebral amyloid angiopathy (CAA), one of the main causes of intracerebral hemorrhage (ICH) and dementia in the elderly, remains unclear. We investigated NPS, with emphasis on apathy and irritability in sporadic (sCAA) and Dutch-type hereditary (D-)CAA. METHODS: We included patients with sCAA and (pre)symptomatic D-CAA, and controls from four prospective cohort studies. We assessed NPS per group, stratified for history of ICH, using the informant-based Neuropsychiatric Inventory (NPI-Q), Starkstein Apathy scale (SAS), and Irritability Scale. We modeled the association of NPS with disease status, executive function, processing speed, and CAA-burden score on MRI and investigated sex-differences. RESULTS: We included 181 participants: 82 with sCAA (mean[SD] age 72[6] years, 44% women, 28% previous ICH), 56 with D-CAA (52[11] years, 54% women, n = 31[55%] presymptomatic), and 43 controls (69[9] years, 44% women). The NPI-Q NPS-count differed between patients and controls (sCAA-ICH+:adj.ß = 1.4[95%CI:0.6-2.3]; sCAA-ICH-:1.3[0.6-2.0]; symptomatic D-CAA:2.0[1.1-2.9]; presymptomatic D-CAA:1.2[0.1-2.2], control median:0[IQR:0-3]), but not between the different CAA-subgroups. Apathy and irritability were reported most frequently: n = 12[31%] sCAA, 19[37%] D-CAA had a high SAS-score; n = 12[29%] sCAA, 14[27%] D-CAA had a high Irritability Scale score. NPS-count was associated with decreased processing speed (adj.ß=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.ß=-0.4[95%CI:-0.6;-0.1]), but not with radiological CAA-burden. Men had NPS more often than women. DISCUSSION: According to informants, one third to half of patients with CAA have NPS, mostly apathy, even in presymptomatic D-CAA and possibly with increased susceptibility in men. Neurologists should inform patients and caregivers of these disease consequences and treat or refer patients with NPS appropriately.

Enhancing Cerebral Amyloid Angiopathy-Related Inflammation Diagnosis With PET Using Pittsburgh Compound B.

ABSTRACT: Cerebral amyloid angiopathy-related inflammation is a rare encephalopathy characterized by inflammation against amyloid protein accumulated in cerebral small vessels. A 50-year-old man was presented with a subacute consciousness disorder. Brain MRI revealed high intensity lesions in the white matter of the right parietal and occipital lobes on fluid-attenuated inversion recovery sequences and cerebral microbleeds in the right parietal and occipital lobes on T2*-weighted images. Pittsburgh compound B-PET demonstrated accumulation in the right temporoparietal lobe, confirming a potential diagnosis of probable cerebral amyloid angiopathy-related inflammation without brain biopsy. Steroid pulse therapy was initiated, with good results.

Surgical intervention for cerebral amyloid angiopathy-related lobar intracerebral hemorrhage: a systematic review.

OBJECTIVE: The risks and benefits of surgery for cerebral amyloid angiopathy (CAA)-related lobar intracerebral hemorrhage (ICH) are unclear. The aim of this study was to systematically review the literature on this topic. METHODS: The authors conducted a systematic review according to the 2020 PRISMA statement. PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier were searched (on December 27, 2022) for relevant articles. Study inclusion criteria were: 1) randomized controlled trial (RCT), cohort study, cross-sectional design, or case series with more than 5 patients; 2) possible, probable, or definite CAA according to the Boston criteria (version 1.0 or 1.5) or autopsy; 3) surgical intervention for acute ICH; and 4) data on peri- and/or postoperative outcomes. Primary outcomes were the presence of intraoperative hemorrhage (IOH), postoperative hemorrhage (POH), and early ICH recurrence. Secondary outcomes were 3-month mortality, late ICH recurrence, functional outcome at discharge, and factors associated with poor outcome. Pooled estimates were calculated, and the Joanna Briggs Institute Critical Appraisal Tool was used to assess risk of bias. RESULTS: Four cohort studies and 15 case series (n = 738 patients, mean age 70 years, 56% women) were included. IOH occurred in 2 (0.6%) of 352 patients. Pooled estimates for POH were 13.0% (30/225) for less than 48 hours and 6.2% (3/437) for 48 hours to 14 days. Overall recurrent ICH (mean follow-up 19 months, n = 5 studies) occurred in 11% of patients. Outcome was predominantly poor with a pooled 3-month mortality rate of 19% and good outcome of 23%. Factors associated with poor outcome were advanced age, poor condition on admission, preexisting dementia, and concomitant intraventricular, subarachnoid, or subdural hemorrhage. All studies contained possible sources of bias and reporting was heterogeneous. CONCLUSIONS: Surgery in CAA-related ICH is safe with no substantial IOH, POH, and early recurrent hemorrhage risk. Outcome appears to be poor, however, especially in older patients, although good quality of evidence is lacking. Patients with CAA should not be excluded from ongoing surgery RCTs in ICH to enable future subgroup analysis of this specific patient population.

[Neuropathology of Disorders Leading to Dementia].

Dementia is characterized by acquired cognitive dysfunction caused by various neurological disorders. Many neurological conditions can cause dementia, including neurodegenerative diseases, vascular disorders, infections, inflammation, demyelination, intoxication, metabolic disorders, tumors, and head trauma. Despite recent developments in biomarkers and imaging techniques, neuropathological examination is necessary for the final diagnosis. Moreover, approximately 11% of the patients with dementia have dual or triple pathological conditions. The coexistence of neurological diseases makes it difficult for neurologists to diagnose patients accurately. Degenerative diseases are characterized by neuronal loss with gliosis in distinct parts of the brain, the presence of neuronal or glial inclusions, and abnormal protein accumulation. Senile plaques and neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease. These findings are characterized by the presence of amyloid ß protein (Aß) and phosphorylated tau protein, respectively. Although vascular dementia is common, it may be difficult to identify the relationship between vascular lesions and cognitive impairment. The incidence of sporadic Aß-type cerebral amyloid angiopathy (CAA) tends to increase with age and causes dementia due to vascular dysfunction and leukoencephalopathy. Furthermore, patients with CAA can develop inflammation. Clinical neurologists should possess a neuropathological perspective for the appropriate diagnosis and management of patients with dementia.

Dominant CST3 variants cause adult onset leukodystrophy without amyloid angiopathy.

Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level.

Temporal Ordering of Biomarkers in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: The temporal ordering of biomarkers for cerebral amyloid angiopathy (CAA) is important for their use in trials and for the understanding of the pathological cascade of CAA. We investigated the presence and abnormality of the most common biomarkers in the largest (pre)symptomatic Dutch-type hereditary CAA (D-CAA) cohort to date. METHODS: We included cross-sectional data from participants with (pre)symptomatic D-CAA and controls without CAA. We investigated CAA-related cerebral small vessel disease markers on 3T-MRI, cerebrovascular reactivity with functional 7T-MRI (fMRI) and amyloid-ß40 and amyloid-ß42 levels in cerebrospinal fluid. We calculated frequencies and plotted biomarker abnormality according to age to form scatterplots. RESULTS: We included 68 participants with D-CAA (59% presymptomatic, mean age, 50 [range, 26-75] years; 53% women), 53 controls (mean age, 51 years; 42% women) for cerebrospinal fluid analysis and 36 controls (mean age, 53 years; 100% women) for fMRI analysis. Decreased cerebrospinal fluid amyloid-ß40 and amyloid-ß42 levels were the earliest biomarkers present: all D-CAA participants had lower levels of amyloid-ß40 and amyloid-ß42 compared with controls (youngest participant 30 years). Markers of nonhemorrhagic injury (>20 enlarged perivascular spaces in the centrum semiovale and white matter hyperintensities Fazekas score, ≥2, present in 83% [n=54]) and markers of impaired cerebrovascular reactivity (abnormal BOLD amplitude, time to peak and time to baseline, present in 56% [n=38]) were present from the age of 30 years. Finally, markers of hemorrhagic injury were present in 64% (n=41) and only appeared after the age of 41 years (first microbleeds and macrobleeds followed by cortical superficial siderosis). CONCLUSIONS: Our results suggest that amyloid biomarkers in cerebrospinal fluid are the first to become abnormal in CAA, followed by MRI biomarkers for cerebrovascular reactivity and nonhemorrhagic injury and lastly hemorrhagic injury. This temporal ordering probably reflects the pathological stages of CAA and should be taken into account when future therapeutic trials targeting specific stages are designed.

Aß-Aggregation-Generated Blue Autofluorescence Illuminates Senile Plaques as well as Complex Blood and Vascular Pathologies in Alzheimer's Disease.

Senile plaque blue autofluorescence was discovered around 40 years ago, however, its impact on Alzheimer's disease (AD) pathology has not been fully examined. We analyzed senile plaques with immunohistochemistry and fluorescence imaging on AD brain sections and also Aß aggregation in vitro. In DAPI or Hoechst staining, the nuclear blue fluorescence could only be correctly assigned after subtracting the blue plaque autofluorescence. The flower-like structures wrapping dense-core blue fluorescence formed by cathepsin D staining could not be considered central-nucleated neurons with defective lysosomes since there was no nuclear staining in the plaque core when the blue autofluorescence was subtracted. Both Aß self-oligomers and Aß/hemoglobin heterocomplexes generated blue autofluorescence. The Aß amyloid blue autofluorescence not only labels senile plaques but also illustrates red cell aggregation, hemolysis, cerebral amyloid angiopathy, vascular plaques, vascular adhesions, and microaneurysms. In summary, we conclude that Aß-aggregation-generated blue autofluorescence is an excellent multi-amyloidosis marker in Alzheimer's disease.

Spatial colocalization of imaging markers in iatrogenic cerebral amyloid angiopathy with the site of surgery: A metaanalysis.

INTRODUCTION: Iatrogenic cerebral amyloid angiopathy (iCAA) is a rare form of CAA. Imaging features are overlapping with spontaneous CAA. However, in iCAA imaging features have not been systematically described so far. The aim of this metaanalysis was to evaluate if any of the described imaging features showed colocalization with the initial site of surgery. MATERIAL AND METHODS: A systematic review of the medical literature was performed. Patients with probable iCAA were included if the route of potential entry of amyloid into the CNS was unambiguous. RESULTS: 24 patients from 19 reports could be included. 84 ICHs were reported. 11 of the first ever ICH (69%, p = 0.0498, Fisher's exact test) occurred ipsilateral to the site of the initial surgery, whereas 59% of all ICH (n = 63, p = 0.126, Fisher's exact test) occurred ipsilateral to the site of the initial surgery. No cerebellar hemorrhages (0%) were reported. In 5 of 8 patients, ipsilateral hemorrhagic and non-hemorrhagic manifestations were present before symptom onset and/or occurrence of ICH. DISCUSSION: This metananalysis of the imaging markers of iCAA revealed a spatial colocalization of first ICH with the site of the surgery. Imaging studies with patients at risk for iCAA after exposure to lyophilized dura should be conducted.

[Two cases of cerebral amyloid angiopathy in which white matter lesions appearing after brain biopsy got improvement without immunotherapy].

The first case was a 75-year-old woman with intermittent sensory impairment of the left hand. FLAIR of the head MRI revealed hyperintensity along the pia mater in the right parieto-temporal lobe with few microbleeds. Our second case was a 78-year-old man who presented with motor aphasia. His MRI showed swollen cortex on FLAIR and cortical hemosiderosis on T2* weighted imaging of the right cerebral hemisphere. Pathological findings indicated the first case as cerebral amyloid angiopathy (CAA)-related inflammation and the second case as CAA. Additionally, after brain biopsy, widespread white matter lesions were detected in the area surrounding the biopsy site. However, both patients showed improvement without immunotherapy. Therefore, it is important to consider whether immunotherapy is required when white matter lesions appear in the area surrounding the biopsy site.

Inhibitor of DNA Binding Protein 3 (ID3) and Nuclear Respiratory Factor 1 (NRF1) Mediated Transcriptional Gene Signatures are Associated with the Severity of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a degenerative vasculopathy. We have previously shown that transcription regulating proteins- inhibitor of DNA binding protein 3 (ID3) and the nuclear respiratory factor 1 (NRF1) contribute to vascular dysregulation. In this study, we have identified sex specific ID3 and NRF1-mediated gene networks in CAA patients diagnosed with Alzheimer's Disease (AD). High expression of ID3 mRNA coupled with low NRF1 mRNA levels was observed in the temporal cortex of men and women CAA patients. Low NRF1 mRNA expression in the temporal cortex was found in men with severe CAA. High ID3 expression was found in women with the genetic risk factor APOE4. Low NRF1 expression was also associated with APOE4 in women with CAA. Genome wide transcriptional activity of both ID3 and NRF1 paralleled their mRNA expression levels. Sex specific differences in transcriptional gene signatures of both ID3 and NRF1 were observed. These findings were further corroborated by Bayesian machine learning and the GeNIe simulation models. Dynamic machine learning using a Monte Carlo Markov Chain (MCMC) gene ordering approach revealed that ID3 was associated with disease severity in women. NRF1 was associated with CAA and severity of this disease in men. These findings suggest that aberrant ID3 and NRF1 activity presumably plays a major role in the pathogenesis and severity of CAA. Further analyses of ID3- and NRF1-regulated molecular drivers of CAA may provide new targets for personalized medicine and/or prevention strategies against CAA.