Plasma Amyloid-Beta Levels in a Pre-Symptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy Pedigree: A Cross-Sectional and Longitudinal Investigation.

Plasma amyloid-beta (Aß) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aß alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aß measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3-4 years later (NC = 8; MC = 9). Plasma Aß1-40 and Aß1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aß1-40: p = 0.001; Aß1-42: p = 0.0004) and T2 (Aß1-40: p = 0.001; Aß1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aß1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aß1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aß may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.

Multiple Approaches to Diffusion Magnetic Resonance Imaging in Hereditary Cerebral Amyloid Angiopathy Mutation Carriers.

Background Cerebral amyloid angiopathy ( CAA ) is a major cause of lobar intracerebral hemorrhage in elderly adults; however, presymptomatic diagnosis of CAA is difficult. Hereditary cerebral hemorrhage with amyloidosis-Dutch type ( HCHWA -D) is a rare autosomal-dominant disease that leads to pathology similar to sporadic CAA . Presymptomatic HCHWA -D mutation carriers provide a unique opportunity to study CAA -related changes before any symptoms have occurred. In this study we investigated early CAA -related alterations in the white matter. Methods and Results We investigated diffusion magnetic resonance imaging ( dMRI ) data for 15 symptomatic and 11 presymptomatic HCHWA -D mutation carriers and 30 noncarrier control participants using 4 different approaches. We looked at (1) the relation between age and global dMRI measures for mutation carriers versus controls, (2) voxel-wise d MRI , (3) independent component-clustered dMRI measures, and (4) structural connectomics between presymptomatic or symptomatic carriers and controls. Fractional anisotropy decreased, and mean diffusivity and peak width of the skeletonized mean diffusivity increased significantly over age for mutation carriers compared with controls. In addition, voxel-wise and independent component-wise fractional anisotropy, and mean diffusivity, and structural connectomics were significantly different between HCHWA -D patients and control participants, mainly in the periventricular frontal and occipital regions and in the occipital lobe. We found no significant differences between presymptomatic carriers and control participants. Conclusions The d MRI technique is sensitive in detecting alterations in symptomatic HCHWA -d carriers but did not show alterations in presymptomatic carriers. This result indicates that d MRI may be less suitable for identifying early white matter changes in CAA .

The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice.

Cerebral amyloid angiopathy (CAA) has never been more relevant. The last 5 years have seen a rapid increase in publications and research in the field, with the development of new biomarkers for the disease, thanks to advances in MRI, amyloid positron emission tomography and cerebrospinal fluid biomarker analysis. The inadvertent development of CAA-like pathology in patients treated with amyloid-beta immunotherapy for Alzheimer's disease has highlighted the importance of establishing how and why CAA develops; without this information, the use of these treatments may be unnecessarily restricted. Our understanding of the clinical and radiological spectrum of CAA has continued to evolve, and there are new insights into the independent impact that CAA has on cognition in the context of ageing and intracerebral haemorrhage, as well as in Alzheimer's and other dementias. While the association between CAA and lobar intracerebral haemorrhage (with its high recurrence risk) is now well recognised, a number of management dilemmas remain, particularly when considering the use of antithrombotics, anticoagulants and statins. The Boston criteria for CAA, in use in one form or another for the last 20 years, are now being reviewed to reflect these new wide-ranging clinical and radiological findings. This review aims to provide a 5-year update on these recent advances, as well as a look towards future directions for CAA research and clinical practice.

Early Magnetic Resonance Imaging and Cognitive Markers of Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: Early markers for cerebral amyloid angiopathy are largely unknown. We aimed to identify which magnetic resonance imaging (MRI) (performed at 7 and 3T) and cognitive markers are an early sign in (pre) symptomatic subjects with hereditary cerebral hemorrhage with amyloidosis-Dutch type. METHODS: Twenty-seven DNA-proven Dutch-type mutation carriers (15 symptomatic and 12 presymptomatic) (mean age of 45.9 years) and 33 controls (mean age of 45.6 years) were included. 7T and 3T MRI was performed, cerebral amyloid angiopathy and small-vessel disease type MRI markers were estimated, and cognitive performance was assessed. Univariate general linear modeling analysis was used to assess the association between MRI markers and cognitive performance on the one hand and on the other, mutation status, adjusted for age, sex, and education. RESULTS: In symptomatic patients, all established cerebral amyloid angiopathy MRI markers (microbleeds, intracerebral hemorrhages, subarachnoid hemorrhages, superficial siderosis, microinfarcts, volume of white matter hyperintensities, and dilated perivascular spaces in centrum semiovale) were increased compared with controls (P<0.05). In presymptomatic subjects, the prevalence of microinfarcts and median volume of white matter hyperintensities were increased in comparison to controls (P<0.05). Symptomatic patients performed worse on all cognitive domains, whereas presymptomatic subjects did not show differences in comparison with controls (P<0.05). CONCLUSIONS: White matter hyperintensities and microinfarcts are more prevalent among presymptomatic subjects and precede cognitive and neuropsychiatric symptoms and intracerebral hemorrhages.

Do Attachment Style and Emotion Regulation Strategies Indicate Distress in Predictive Testing?

Predictive genetic testing for a neurogenetic disorder evokes strong emotions, and may lead to distress. The aim of this study is to investigate whether attachment style and emotion regulation strategies are associated with distress in persons who present for predictive testing for a neurogenetic disorder, and whether these psychological traits predict distress after receiving test results. Self-report scales were used to assess attachment insecurity (anxiety and avoidance) and maladaptive emotion regulation strategies (self-blame, rumination, catastrophizing) in adults at 50 % risk for Huntington's Disease (HD), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), and Hereditary Cerebral Hemorrhage With Amyloidosis - Dutch type (HCHWA-D), when they presented for predictive testing. Distress was measured before testing and twice (within 2 months and between 6 and 8 months) after receiving test results. Pearson correlations and linear regression were used to analyze whether attachment style and emotion regulation strategies indicated distress. In 98 persons at risk for HD, CADASIL, or HCHWA-D, attachment anxiety and catastrophizing were associated with distress before predictive testing. Attachment anxiety predicted distress up to 2 months after testing. Clinicians may consider looking for signs of attachment anxiety and catastrophizing in persons who present for predictive testing, to see who may be vulnerable for distress during and after testing.

Clinical diagnosis and successful treatment of inflammatory cerebral amyloid angiopathy.

INTRODUCTION: Cerebral amyloid angiopathy is a major cause of lobar hemorrhage in older adults, and of microvascular ischemic disease. The rarest form of this disease is an inflammatory form causing seizures. It is important to recognize because the patients usually respond to a brief course of immunosuppression. METHODS: Case report. RESULTS: A 66-year-old man developed gradual cognitive decline, insidiously increasing headaches, and then had a likely seizure. MRI showed diffuse white matter edema, and innumerable superficial microhemorrhages characteristic of amyloid angiopathy. He was empirically treated with oral prednisone and an anticonvulsant. His symptoms improved and the white matter edema resolved over several months. ApoE genotype was 4/4, which is commonly found in inflammatory amyloid angiopathy. CONCLUSIONS: Inflammatory cerebral amyloid angiopathy can be clinically diagnosed and treated without brain biopsy. Clinical diagnosis is important because of the good response to a brief course of steroids in most cases.

[A female patient with late-onset schizophrenia and fear of Katwijk disease]. / Een patiënte met laat ontstane schizofrenie en angst voor de Katwijkse ziekte.

A 66-year-old patient had suffered from late-onset schizophrenia from the age of 44. Her family history included reports of brain haemorrhages, possibly resulting from hereditary amyloidal angiopathy of the Dutch type (Katwijk disease). She was very afraid for having this disease. The progression of the psychiatric symptoms and the age at which they began, led us to suspect an organic process. Differential diagnoses that were discussed included cerebral amyloidal angiopathy, frontal lobe dementia and Huntington's disease.

Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic arteriopathy presenting with migraines, mood disorders, focal neurologic deficits, recurrent ischemic attacks and dementia in young adults. The genesis of this disease relates to missense mutation of the Notch3 gene. We report here a newly identified CADASIL patient and discuss unique vascular lesions observed in the kidney. A 64-year-old female was admitted to our hospital for the investigation of proteinuria, hematuria and progressive neurological abnormalities. Her mother and brother died of cerebral infarction at a relatively young age despite a lack of apparent risk factors for arteriosclerosis. Over the past 4 months before admission, she had suffered from frequent transient ischemic attacks despite appropriate antiplatelet therapy. Blood examination revealed mild renal insufficiency and urinalysis revealed moderate protein excretion and dysmorphic hematuria. Magnetic resonance imaging of the brain revealed multiple infarcts and leukoencephalopathy. Histopathological analysis of the kidney revealed focal segmental mesangial proliferation, the loss and degeneration of arterial medial smooth muscle cells and arterial intimal thickening. Immunofluorescence analysis of glomeruli revealed IgA deposition in the mesangial area. Electron microscope analysis revealed electron-dense deposition also in the mesangial area. In addition, granular osmophilic material (GOM) was observed in the extraglomerular mesangial area and around the vascular smooth muscle cells. Genetic analysis of Notch3 revealed an R141C missense mutation and she was diagnosed with CADASIL complicated with IgA nephropathy. In immunohistological analysis, Notch3 stains were positive in vascular smooth muscle cells of the interlobular arteries and both afferent and efferent arterioles, and weak in the glomerular mesangial area. Antihypertensive treatment using angiotensin II receptor blocker and a low protein diet were initiated, and her urinary protein excretion decreased to 0.2 g/day. However, due to the progression of her neurological abnormalities, she became socially withdrawn. In CADASIL, GOM, abnormal accumulation of Notch3 ectodomain, is thought to induce the degeneration and loss of vascular smooth muscle cells and subsequent intimal thickening. Analysis of our cases provided that these morphological abnormalities were also observed in the CADASIL patient kidney.

[Recurrent intraparenchimal haemorrhages in a patient with cerebral amyloidotic angiopathy: description of one autopsy case]. / Emorragie intracerebrali ricorrenti in paziente con angiopatia cerebrale amiloidea: descrizione di un caso autoptico.

Cerebral amyloidotic angiopathy represents the most frequent cause of lobar haematoma in young patients and represents 5-10% of the non-traumatic cerebral haemorrhages. In the present work, we describe one autoptic case of recurrent cerebral haemorrhages in a 58-year-old woman. Macroscopically in the brain multiple haemorragic areas were present in the right frontal pole, right frontal and temporo-parietal lobes with homolateral ventricular inundation. The histological, histochemical, immunohistochemical, ultrastructural and biomolecular investigations confirmed the presence of amyloid deposits in the middle-size and little-size cerebral arteries. We report, moreover, a novel mutation (Leu705Val) within the Abeta sequence of a AbetaPP in a family with autosomal dominant, recurrent intracerebral hemorrhages beginning in the sixth decade of life.

Microbleeds in hereditary cerebral hemorrhage with amyloidosis-Dutch type.

In a hereditary variant of cerebral amyloid angiopathy (CAA), cerebral hemorrhage with amyloidosis-Dutch type, supratentorial microbleeds were found to occur independently of the presence of hypertension, whereas hypertension probably contributed to the development of cerebellar microbleeds. This predictable hereditary variant of CAA may be a useful model to study microbleeds in relation to CAA.

[Amyloidosis and aging]. / Amylose et vieillissement.

Amyloidosis is a heterogeneous group of extracellular protein deposition diseases. Age-related amyloidosis may be systemic or localized. The systemic forms include associated-myeloma AL amyloidosis and senile systemic amyloidosis which is the only clear-cut systemic form related to age and derived from normal transthyretin. In localized amyloidosis, the fibril protein precursors are synthesized in the tissue involved by the amyloid. In most cases, localized age-related amyloidosis does not appear to cause clinical disease with the exception of amyloid associated with Alzeihmer's disease and type 2 diabetes mellitus. The significance of aortic amyloidosis, amyloidosis of seminal vesicles, amyloid of the endocrine glands, and articular amyloidosis remains unknown.

[Hereditary cerebral amyloid angiopathies]. / Les angiopathies amyloïdes cérébrales héréditaires.

Cerebral amyloid angiopathies are defined by the presence of amyloid substance in the walls of cerebral vessels. All amyloid substances have a particular physico-chemical structure, which imparts certain specific staining properties, but the biochemical composition of different amyloid types varies. Different forms of cerebral amyloid angiopathy have been identified, based on the biochemical nature of the protein deposited (e.g. beta-amyloid, cystatin C, transthyretin, gelsolin, amyloid protein Bri, prion protein). Some cerebral amyloid angiopathies are familial; these prompted genetic studies which in turn led to a better understanding of the genes coding for different amyloid proteins. As a group, cerebral amyloid angiopathies have certain neuropathological lesions in common. Infiltration by amyloid substance results in weakening of the small vessel walls and secondary complications responsible for changes such as microinfarcts and miliary haemorrhages in the cerebral cortex, lobar haemorrhages and/or leucoencephalopathy. These changes form the basis of the neurological complications: meningeal and cerebral haemorrhages, transient ischaemic episodes, vascular dementia. However each type of hereditary cerebral amyloid angiopathy has individual clinical and histopathological features reflecting the severity of arterial involvement, the extent of amyloid deposition within or outside the central nervous system, and the association with other neurodegenarative changes.