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.

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy.

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-ß accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters - amplitude, time-to-peak (TTP), and time-to-baseline (TTB) - and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized ß = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (ß = 8.34 × 10-6, 95%CI [1.84 × 10-6, 1.48 × 10-5], p = 0.02, Adj. R2 = 0.25) and TTB (ß = 6.57 × 10-6, 95%CI [1.92 × 10-6, 1.12 × 10-5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.

Brain Deep Medullary Veins on 7T MRI in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND: Deep medullary vein (DMV) changes occur in cerebral small vessel diseases (SVD) and in Alzheimer's disease. Cerebral amyloid angiopathy (CAA) is a common SVD that has a high co-morbidity with Alzheimer's disease. So far, DMVs have not been evaluated in CAA. OBJECTIVE: To evaluate DMVs in Dutch-type hereditary CAA (D-CAA) mutation carriers and controls, in relation to MRI markers associated with D-CAA. METHODS: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density were quantified on 7 Tesla 3D susceptibility weighted MRI in pre-symptomatic D-CAA mutation carriers (n = 8), symptomatic D-CAA mutation carriers (n = 8), and controls (n = 25). Hemorrhagic MRI markers (cerebral microbleeds, intracerebral hemorrhages, cortical superficial siderosis, convexity subarachnoid hemorrhage), non-hemorrhagic MRI markers (white matter hyperintensities, enlarged perivascular spaces, lacunar infarcts, cortical microinfarcts), cortical grey matter perfusion, and diffusion tensor imaging parameters were assessed in D-CAA mutation carriers. Univariate general linear analysis was used to determine associations between DMV parameters and MRI markers. RESULTS: Quantitative DMV parameters length, tortuosity, inhomogeneity, and density did not differ between pre-symptomatic D-CAA mutation carriers, symptomatic D-CAA mutation carriers, and controls. No associations were found between DMV parameters and MRI markers associated with D-CAA. CONCLUSION: This study indicates that vascular amyloid-ß deposition does not affect DMV parameters. In patients with CAA, DMVs do not seem to play a role in the pathogenesis of MRI markers associated with CAA.

Cerebellar hemorrhages in patients with Dutch-type hereditary cerebral amyloid angiopathy.

BACKGROUND: Recent studies suggest that superficially located cerebellar intracerebral hemorrhage (ICH) and microbleeds might point towards sporadic cerebral amyloid angiopathy (CAA). AIMS: We investigated the proportion of cerebellar ICH and asymptomatic macro- and microbleeds in Dutch-type hereditary CAA (D-CAA), a severe and essentially pure form of CAA. METHODS: Symptomatic patients with D-CAA (defined as ≥1 symptomatic ICH) and presymptomatic D-CAA mutation-carriers were included. We assessed magnetic resonance imaging scans for symptomatic (cerebellar) ICH and asymptomatic cerebellar macro- and microbleeds according to the STRIVE-criteria. Location was assessed as superficial-cerebellar (cortex, vermis or juxta-cortical) or deep-cerebellar (white matter, pedunculi cerebelli and gray nuclei). RESULTS: We included 63 participants (mean age 58 years, 60% women, 42 symptomatic). In total, the 42 symptomatic patients with D-CAA had 107 symptomatic ICH (range 1-7). None of these ICH were located in the cerebellum. Six of 42 (14%, 95%CI 4-25%) symptomatic patients and none of the 21 (0%, 95%CI 0-0%) presymptomatic carriers had ≥ 1 asymptomatic cerebellar macrobleed(s). All macrobleeds were superficially located. Cerebellar microbleeds were found in 40 of 63 (64%, 95%CI 52-76) participants (median 1.0, range 0-159), 81% in symptomatic patients and 29% in presymptomatic carriers. All microbleeds were strictly or predominantly superficially (ratio superficial versus deep 15:1) located. CONCLUSIONS: Superficially located asymptomatic cerebellar macrobleeds and microbleeds are common in D-CAA. Cerebellar microbleeds are already present in the presymptomatic stage. Despite the high frequency of cerebellar micro and macrobleeds, CAA pathology did not result in symptomatic cerebellar ICH in patients with D-CAA.

Sensitivity of the Edinburgh Criteria for Lobar Intracerebral Hemorrhage in Hereditary Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: The Edinburgh computed tomography and genetic criteria enable diagnosis of cerebral amyloid angiopathy (CAA) associated lobar intracerebral hemorrhage (ICH) but have not been validated in living patients. We assessed the sensitivity of the Edinburgh criteria in patients with acute lobar ICH due to Dutch-type hereditary CAA; a genetic and pure form of CAA. METHODS: We retrospectively analyzed computed tomography-scans from a cohort of consecutive Dutch-type hereditary CAA patients who presented with ≥1 episode(s) of acute lobar ICH at the Leiden University Medical Center. Presence of subarachnoid hemorrhage (SAH) and finger-like projections (FLP) were determined. Association of SAH and FLP with ICH volume was analyzed using multivariate linear regression. RESULTS: We included 55 Dutch-type hereditary CAA patients (mean age 56 years, 55% men) with a total of 107 episodes of acute lobar ICH. SAH was present in 82/107 (76%) and FLP in 62/107 (58%), resulting in a sensitivity of 76% for SAH and 58% for FLP. In 56 (52%), both markers were present. Nineteen (18%) lobar ICH showed no SAH extension or FLP. ICH volume was significantly associated with presence of SAH (median volume 4 versus 28 mL; P=0.001) and presence of FLP (median volume 7 versus 39 mL; P<0.001). With an ICH volume of ≥40 mL, the sensitivity of the presence of both SAH and FLP was >81% (95% CI, 70%-92%), whereas in ICH volumes <15 mL the sensitivity was <50%. CONCLUSIONS: The computed tomography-based Edinburgh criteria seem to be a sensitive diagnostic test for CAA-associated lobar ICH, although they should be used with caution in small-sized lobar ICH.

Migraine With Aura as Early Disease Marker in Hereditary Dutch-Type Cerebral Amyloid Angiopathy.

Background and Purpose- To determine whether migraine, which has often been described as an inaugural manifestation in monogenic cerebrovascular syndromes, is associated with cerebral amyloid pathology, we assessed migraine and its correlation with magnetic resonance imaging markers in Hereditary Dutch-Type Cerebral Amyloid Angiopathy (D-CAA or Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch type). Methods- All D-CAA mutation carriers who visited our clinic between 2012 and 2018 were included. Migraine was diagnosed by an interview and classified according to the International Classification of Headache Disorders. Magnetic resonance imaging scans were scored for intracerebral hemorrhage (ICH) location(s) and presence of cortical superficial siderosis. Kaplan Meier survival analysis was used for age of ICH onset in carriers with and without migraine. Correlation with ICH location(s) and cortical superficial siderosis were calculated with Poisson regression analysis adjusted for confounders. Results- We included 86 D-CAA mutation carriers (57% women, mean age 57 years), 48 (56%) suffered from migraine, all with aura. Prevalence was higher than expected compared with the general population (women, P<0.05; men, P<0.001). Migraine was the inaugural symptom in 77% and an isolated symptom in 35% of the carriers. Carriers with and without migraine did not differ for age of first ICH, cortical superficial siderosis prevalence, or occipital ICH. Time between migraine onset and first ICH was 8.5 years. Aura attacks lasting ≥60 minutes signaled acute ICH in 55%. Conclusions- Migraine with aura is an important, often inaugural, symptom in D-CAA. Aura attacks lasting ≥60 minutes may signal acute ICH in D-CAA. Migraine with aura may be regarded as an early marker of disease in hereditary CAA preceding the occurrence of symptomatic ICH by several years.

Amyloid imaging of dutch-type hereditary cerebral amyloid angiopathy carriers.

OBJECTIVE: To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular ß-amyloid (Aß) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) mutation. METHODS: PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB-PET in 19 D-CAA mutation carriers (M+ ; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M- ). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+ , 8 M- ). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aß concentrations in 17 M+ and 11 M- participants who underwent lumbar puncture and compared the findings to PiB-PET and CSF Aß in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. RESULTS: D-CAA M+ showed greater age-dependent FLR PiB retention (p < 0.001) than M- , and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+ , greater FLR PiB retention associated with reduced CSF concentrations of Aß40 (r = -0.55, p = 0.021) but not Aß42 (r = 0.01, p = 0.991). Despite comparably low CSF Aß40 and Aß42, PiB retention was substantially less in D-CAA than ADAD (p < 0.001). INTERPRETATION: Increased PiB retention in D-CAA and correlation with reduced CSF Aß40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019;86:616-625.

Cerebral Amyloid Angiopathy With Vascular Iron Accumulation and Calcification.

Background and Purpose- Previous studies of symptomatic and asymptomatic hereditary cerebral amyloid angiopathy (CAA) patients offered the possibility to study the radiological manifestations of CAA in the early stages of the disease. Recently, a striped cortex, observable as hypointense lines perpendicular to the pial surface on T2*-weighted 7T magnetic resonance imaging (MRI), was detected in 40% of the symptomatic hereditary CAA patients. However, the origin of these MRI contrast changes is unknown. This study aimed at defining the underlying pathology associated with the in vivo observed striped pattern. Methods- Formalin-fixed postmortem brain material including the occipital lobe of 4 hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) cases and 6 sporadic CAA cases were selected from local neuropathology tissue collections. Depending on the availability of the material, intact hemispheres or brain slabs including the occipital lobe of these patients were screened for the presence of a striped cortex. Regions containing the striped cortex were then subjected to high-resolution 7T MRI and histopathologic examination. Results- We found 2 hereditary cerebral hemorrhage with amyloidosis-Dutch type cases and 1 sporadic CAA case with striped patterns in the occipital cortex resembling the in vivo signal. Histopathologic examination showed that the striped pattern in the cortex at 7T MRI is because of iron accumulation and calcification of penetrating arteries. The presence of both nonheme iron and calcification on penetrating arteries causes signal loss and hence the abnormal striped patterns in the cortical ribbon on T2*-weighted MRI. Conclusions- We identified iron accumulation and calcification of the vessel wall in hereditary cerebral hemorrhage with amyloidosis-Dutch type as the histopathologic correlates of the striped cortex observed on in vivo 7T MRI.

Innovative Magnetic Resonance Imaging Markers of Hereditary Cerebral Amyloid Angiopathy at 7 Tesla.

BACKGROUND AND PURPOSE: The aim of the present study is to explore whether using 7 Tesla magnetic resonance imaging, additional brain changes can be observed in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) patients as compared with the established magnetic resonance imaging features of sporadic cerebral amyloid angiopathy. METHODS: The local institutional review board approved this prospective cohort study. In all cases, informed consent was obtained. This prospective parallel cohort study was conducted between 2012 and 2014. We performed T2*-weighted magnetic resonance imaging performed at 7 Tesla in presymptomatic mutation carriers (n=11, mean age 35±12 years), symptomatic HCHWA-D patients (n=15, mean age 45±14 years), and in control subjects (n=29, mean age 45±14 years). Images were analyzed for the presence of changes that have not been reported before in sporadic cerebral amyloid angiopathy and HCHWA-D. Innovative observations comprised intragyral hemorrhaging and cortical changes. The presence of these changes was systematically assessed in all participants of the study. RESULTS: Symptomatic HCHWA-D-patients had a higher incidence of intragyral hemorrhage (47% [7/15], controls 0% [0/29], P<0.001), and a higher incidence of specific cortical changes (40% [6/15] versus 0% [0/29], P<0.005). In presymptomatic HCHWA-D-mutation carriers, the prevalence of none of these markers was increased compared with control subjects. CONCLUSIONS: The presence of cortical changes and intragyral hemorrhage are imaging features of HCHWA-D that may help recognizing sporadic cerebral amyloid angiopathy in living patients.

Cerebrovascular function in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study.

BACKGROUND: Previous work suggests that impairments of cerebrovascular flow or reactivity might be early markers of cerebral amyloid angiopathy (CAA). Hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D) is a genetic form of CAA that can be diagnosed before the onset of clinical symptoms by DNA testing. We aimed to investigate whether haemodynamic measures are decreased in presymptomatic and symptomatic HCHWA-D mutation carriers compared with healthy controls. METHODS: In this case-control study, we included presymptomatic and symptomatic HCHWA-D mutation carriers diagnosed through genetic testing and recruited through the HCHWA-D patient association (Katwijk, Netherlands) and the outpatient clinic of the Department of Neurology of the Leiden University Medical Center (Leiden, Netherlands), and healthy controls. We measured regional cerebral blood flow (rCBF) using pseudo-continuous arterial spin labelling. Quantitative flow was measured by phase-contrast magnetic resonance angiography of the cerebropetal vessels. Vascular reactivity was established by measuring changes in blood-oxygen-level-dependent (BOLD) signal after visual stimulation. Data from presymptomatic and symptomatic individuals were compared with healthy controls using mixed-model regression analysis. FINDINGS: Between May 15, 2012, and December 22, 2015, we investigated cross-sectional imaging data from 27 HCHWA-D mutation carriers (12 presymptomatic and 15 symptomatic) and 33 healthy controls. Compared with controls, symptomatic HCHWA-D carriers had significantly decreased cortical grey matter rCBF in the occipital lobe (mean difference -11·1 mL/100 g per min, 95% CI -2·8 to -19·3; uncorrected p=0·010) and decreased flux in the basilar artery (mean difference -0·9 mL/s, 95% CI -1·5 to -0·2; uncorrected p=0·019). However, we noted no changes in rCBF and flux in presymptomatic carriers compared with controls. Vascular reactivity was significantly decreased in the occipital lobe in both presymptomatic (mean BOLD change 1·1% [SD 0·5], mean difference -0·4% change, 95% CI -0·7 to -0·2; p=0·001; mean time to baseline 10·1 s [SD 7·6], mean difference 4·6 s, 95% CI 0·4 to 8·8; p=0·032) and symptomatic carriers (mean BOLD change 0·4% [SD 0·1], mean difference -0·9%, 95% CI -1·1 to -0·6; p<0·0001; mean time to baseline 20·3 s [SD 8·4], mean difference 13·1 s, 95% CI 9·4 to 16·9; p<0·0001) compared with controls; however, the difference in mean time to peak was only significant for symptomatic carriers (mean difference 12·2 s, 95% CI 8·6 to 15·9; p<0·0001). INTERPRETATION: Our findings suggest that determination of vascular reactivity might be a useful biomarker for early detection of vascular amyloid pathology in sporadic CAA, and a biomarker of efficacy in future intervention trials. Our data indicate that vascular reactivity measurements might be useful for differential diagnosis in dementia to determine the vascular component. FUNDING: USA National Institutes of Health.

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.

ApoA1, ApoJ and ApoE Plasma Levels and Genotype Frequencies in Cerebral Amyloid Angiopathy.

The involvement of apolipoproteins, such as the ApoE4 isoform, in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) highlights the fact that certain lipid carriers may participate in soluble ß-amyloid (Aß) transport. Our general aim was to characterize the soluble levels of the apolipoproteins apoE, apoA1 and apoJ/clusterin and their genotype status in patients with CAA. We analyzed the genotypes frequency of APOA1 (rs5069, rs670), CLU (rs11136000, rs1532278, rs7012010, rs9331888) and APOE (rs429358, rs7412) in a cohort of patients with CAA-associated intracerebral hemorrhage (ICH) (n = 59) and compared the results with those from hypertension-associated ICH (n = 42), AD patients (n = 73) and controls (n = 88). In a subgroup of patients, we also determined the plasma concentrations of apoE, apoA1 and apoJ/clusterin. We found increased plasma apoJ/clusterin levels in CAA patients compared to AD patients or controls after adjusting for sex and age (CAA vs. controls, p = 0.033; CAA vs. AD, p = 0.013). ApoA1 levels were not altered between groups, although a strong correlation was observed between plasma Aß(1-40) and apoA1 among CAA patients (r = 0.583, p = 0.007). Regarding plasma apoE concentration, a robust association between circulating levels and genotype status was confirmed (p < 0.001). Whereas the APOE4 frequency was higher in AD (p < 0.001) and CAA (p = 0.013), the APOA1 and CLU genotypes were not different among groups. In the CAA cohort, the risk-linked CLU variant (C) rs11136000 was associated with white matter hyperintensities (p = 0.045) and the presence of lobar microbleeds (p = 0.023) on MRI. In summary, our findings suggest that apoA1 may act as a physiological transporter of Aß(1-40) and that apoJ/clusterin appears to be a chaperone related to distinctive lesions in CAA brains.

Descriptive analysis of the Boston criteria applied to a Dutch-type cerebral amyloid angiopathy population.

BACKGROUND AND PURPOSE: Validation of the Boston criteria for the in vivo diagnosis of cerebral amyloid angiopathy (CAA) is challenging, because noninvasive diagnostic tests do not exist. Hereditary cerebral hemorrhage with amyloidosis-Dutch type is an accepted monogenetic model of CAA and diagnosis can be made with certainty based on DNA analysis. The aim of this study was to analyze and refine the existing Boston criteria in patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type. METHODS: We performed T2*-weighted MRI in 27 patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type to assess the presence and location of microbleeds, intracranial hemorrhages, and superficial siderosis. Using the Boston criteria, subjects were categorized as having: no hemorrhages, possible CAA, probable CAA, and hemorrhagic lesions not qualifying for CAA. The sensitivity of the Boston criteria was calculated separately using intracranial hemorrhages only and using intracranial hemorrhages and microbleeds. RESULTS: The sensitivity of the Boston criteria for probable CAA increased from 48% to 63% when microbleeds were included. For symptomatic subjects only, the sensitivity was 100%. No hemorrhages were identified in the deep white matter, basal ganglia, thalamus, or brainstem. Superficial siderosis, observed in 6 patients, did not increase the sensitivity of the Boston criteria in our study group. CONCLUSIONS: Our data show that using T2*-weighted MRI and including microbleeds increase the sensitivity of the Boston criteria. The exclusion of hemorrhages in the deep white matter, basal ganglia, thalamus, and brainstem does not lower the sensitivity of the Boston criteria.

Carbon 11-labeled pittsburgh compound B positron emission tomographic amyloid imaging in patients with APP locus duplication.

OBJECTIVE: To investigate amyloid accumulation by carbon 11-labeled Pittsburgh Compound B (11C-PiB) in hereditary cerebral amyloid angiopathy and APP locus duplication. DESIGN, SETTING, AND PATIENTS: Positron emission tomography with 11C-PiB and magnetic resonance imaging were performed for 2 patients, 49-year-old and 60-year-old siblings with APP locus duplication, with hereditary Alzheimer disease and cerebral amyloid angiopathy. MAIN OUTCOME MEASURE: Change in 11C-PiB uptake. RESULTS: Uptake of 11C-PiB was increased especially in the striatum (caudate nucleus to 225% and 280% of the control mean and putamen to 166% and 185% of the control mean) and in the posterior cingulate (to 168% and 198% of the control mean), and it was marginally increased in other cortical brain areas. The pattern of increased 11C-PiB uptake was different from that seen in sporadic Alzheimer disease. CONCLUSIONS: Amyloid imaging with 11C-PiB positron emission tomography is a useful tool for detecting in vivo amyloid accumulation in patients with hereditary cerebral amyloid angiopathy. However, the pattern of 11C-PiB accumulation differs between patients with typical AD and patients with APP locus duplication.

Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.

The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in > 90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.