Abstract
Background: A subset of patients with cerebral amyloid angiopathy (CAA) present with cognitive symptoms, seizures, headaches, T2-hyperintense MRI lesions, and neuropathologic evidence of CAA-associated vascular inflammation.
Objective: To analyze the risk factors, diagnostic characteristics, and long-term course of this disorder.
Methods: We assessed 14 consecutive patients with pathologically diagnosed CAA-related inflammation, 12 with available neuroimaging and follow-up data. Patients were evaluated for MRI appearance, APOE genotype, and clinical course over a 46.8 ± 29.1-month follow-up.
Results: Baseline MRI scans were characterized by asymmetric T2-hyperintense lesions extending to the subcortical white matter and occasionally the overlying gray matter, with signal properties suggesting vasogenic edema. Subjects could be divided into three groups based on response to immunosuppressive treatment: monophasic improvement (7/12), initial improvement followed by symptomatic relapse (3/12), and no evident response to treatment (2/12). The volume of MRI hyperintensities correlated with the severity of clinical symptoms. One patient experienced symptomatic intracerebral hemorrhage within a region of recurrent MRI hyperintensity. The APOE ε4/ε4 genotype was strongly associated with CAA-related inflammation, present in 76.9% (10/13) of subjects vs 5.1% (2/39) with symptomatic but noninflammatory CAA (p < 0.0001).
Conclusion: Cerebral amyloid angiopathy–related inflammation represents a clinically, pathologically, radiographically, and genetically distinct disease subtype with implications for clinical practice and ongoing immunotherapeutic approaches to Alzheimer disease.
Although intracerebral hemorrhage (ICH) is the most commonly recognized clinical manifestation of cerebral amyloid angiopathy (CAA), an important subset of patients present instead with subacute cognitive decline, seizures, headaches, and hyperintensities on T2- or fluid-attenuated inversion recovery- (FLAIR-) weighted MRI1 (hence referred to as T2-hyperintense lesions). Neuropathologic examination of these patients has generally revealed inflammation of CAA-affected vessels,1–4 apparently representing an immune response to the vascular deposits of β-amyloid (Aβ). Many of the clinical reports have noted apparent response to immunosuppressive treatment, indicating that this syndrome may be a treatable form of CAA. Spontaneously occurring inflammatory CAA also appears to have clinical, radiographic, and pathologic similarities to the meningoencephalitis developed by some patients with Alzheimer disease (AD) immunized to Aβ.5–7 The similarities between these inflammatory conditions raise the possibility that CAA-related inflammation may play an important role in the clinical response to anti-Aβ immunotherapy.
Many questions regarding CAA-related inflammation remain unanswered. It is unclear, for example, why it occurs in only a subset of patients with advanced CAA. A candidate risk factor is the APOE ε4/ε4 genotype, previously identified in a high proportion (5/7, 71%) of characterized patients.1 Another question is whether CAA-related inflammation can recur after immunosuppressive therapy is complete. To address these questions and to explore the relationship between MRI appearance and clinical symptoms, we examined the long-term clinical and radiographic course of subjects with inflammatory CAA.
METHODS
Subjects.
We reviewed records of all patients seen at the Massachusetts General Hospital (MGH) between July 1994 and June 2006 who were diagnosed pathologically with CAA-related inflammation. Subjects were identified from our prospective cohort of patients diagnosed with CAA and from review of the database maintained by the MGH Neuropathology Laboratory as described.1 Fourteen potentially eligible patients were identified for this study, comprising the seven subjects reported in 20041 and seven additional subjects seen subsequent to that report. All pathologic samples used to establish the presence of CAA-related inflammation were reviewed by a study neuropathologist to confirm the presence of inflammatory infiltrate surrounding or within vessels with CAA and the absence of other contributing vascular pathologies. Of the 14 potentially eligible subjects, follow-up clinical data and high-quality digital files of MRI scans at baseline and follow-up were available from 12. The other two provided no further information on clinical course, one declining research participation and the other being lost to follow-up. DNA samples for determination of APOE genotype8 were available from 13 of the 14 eligible subjects.
The subjects diagnosed with CAA-related inflammation were compared for demographic factors, clinical presentation, and APOE genotype to subjects with pathologically diagnosed CAA without evidence of inflammation identified by the search methods described above. We also performed a systematic qualitative MRI comparison (see below) with 1) 10 consecutive CAA subjects without evidence of inflammation (3 diagnosed pathologically, 7 by multiple lobar hemorrhages on neuroimaging),9 and 2) 10 consecutive patients diagnosed with the reversible posterior leukoencephalopathy (RPL) syndrome.10 The RPL group comprised all subjects in whom this syndrome was radiographically diagnosed (with resolution of white matter hyperintensities on follow-up MRI) between 2002 and 2006 on systematic search of the MGH Radiology Department database. Causes of RPL in these subjects included hypertensive encephalopathy, acute renal failure, eclampsia, and cisplatin treatment.
Patients with CAA-related inflammation received treatment, follow-up examinations, and neuroimaging according to the recommendations of their treating physicians. In addition, their clinical course was followed by systematic telephone interview of patient or caregiver by study investigators at 6-month intervals.11 Subjects were followed until death or the end of the study in August 2006 (mean follow-up of 46.8 ± 29.1 months for the 12 subjects with follow-up information).
Statistical comparisons of demographic, genetic, or radiographic measurements were performed by Fisher exact test for categorical variables and Student t test for continuous variables. The study was performed in accordance with the guidelines of the institutional review board of MGH and with consent of subjects or family members.
MRI acquisition and analysis.
MRI was performed using a 1.5 T scanner according to routine clinical protocols and acquisition parameters as described.12 Sequences included axial FLAIR-weighted, fast-spin echo T2-weighted, gradient-echo susceptibility-weighted, and pregadolinium T1-weighted images. Postgadolinium T1-weighted images were obtained in 8 of 12 subjects with available neuroimaging, and diffusion-weighted images including maps of apparent diffusion coefficient (ADC) were obtained in 9.
T2-weighted hyperintense lesions were segmented preferentially on FLAIR sequences and the lesion volume computed and normalized to head size by two readers blinded to clinical characteristics as described.12,13 For comparison of the qualitative MRI features of CAA-related inflammation vs noninflammatory CAA or RPL, groups of MRI scans were presented to an experienced, CAQ-certified neuroradiologist without knowledge of the clinical diagnosis. Each group of scans was systematically characterized for lesion location, extent, T1 and T2 intensity, and symmetry.
RESULTS
Baseline characteristics and clinical course.
We identified 14 patients with pathologically proven CAA-associated inflammation, including 7 reported previously.1 All patients presented with subacute cognitive decline or seizure (tables 1 and 2) with the exception of a 66-year-old woman presenting with lobar intracerebral hemorrhage (ICH) who declined to participate in research and was excluded from further analyses. The APOE ε4/ε4 genotype was markedly overrepresented among patients with CAA-related inflammation, appearing in 10 of 13 (76.9%) subjects with available genetic information compared with 2 of 39 (5.1%) subjects with pathologically confirmed noninflammatory CAA (odds ratio [OR] 61.7, 95% CI 7.2 to 706, p < 0.0001). Patients with CAA-related inflammation were also younger and more likely to be male than those with noninflammatory CAA (table 1).
Table 1 Clinical, demographic, and genetic characteristics of patients with CAA and CAA-associated inflammation
Table 2 Patients with CAA-associated inflammation categorized by clinical course
Of 12 subjects with follow-up information, all received anti-inflammatory treatment (table 2) either immediately post brain biopsy (typically a 3- to 14-day tapering course of dexamethasone) or for an additional prolonged course (typically 1 or more months of oral prednisone or pulsed cyclophosphamide). Based on their posttreatment clinical course (table 2), subjects could be divided into those who improved shortly following treatment and had no further clinical flares of symptoms (“improved,” n = 7), those who initially improved but experienced subsequent clinical flares of encephalopathy, seizure, or severe headache (“relapsing,” n = 3), and those who had no clinical response to anti-inflammatory treatment (“stable/progressive,” n = 2). There were no evident differences in type or duration of initial anti-inflammatory treatment, age, gender, or APOE genotype among the three subgroups.
For the improved and relapsing groups, cognition improved and seizures resolved within 1 to 2 weeks of treatment onset. The improved subjects remained free of further symptoms (seizure, acute encephalopathy, severe headache, symptomatic ICH, or dementia) during a mean follow-up period of 45.1 ± 33.3 months. Conversely, the three subjects in the relapsing subgroup each experienced one to two flares of symptoms over 37.3 ± 13.3 months of follow-up. All symptomatic recurrences occurred while the patients were not receiving immunosuppressive treatments (range of intervals off medication 1 month to 2.5 years). One patient (table 2, Subject 8) experienced two recurrences of symptoms (primarily subacute cognitive decline) with prompt response to corticosteroid after the first event, an equivocal response to cyclophosphamide after the second event, followed by a symptomatic ICH during a period of treatment with mycophenolate. Another subject in this group developed a flare of subtle cognitive impairment and headaches with equivocal improvement in response to a second course of corticosteroids, whereas a third subject with recurrent cognitive symptoms is currently awaiting follow-up evaluation. Of the two “stable/progressive” subjects, one was treated with corticosteroids without improvement until death from pneumonia after 38 months, and the other was treated with corticosteroids plus cyclophosphamide for 18 months and has shown no or minimal improvement over 94 months of follow-up.
MRI appearance and correlation with clinical course.
MRI at presentation was characterized by large confluent areas of predominantly white matter hyperintense signal on T2- or FLAIR-weighted images (figures 1 and 2). These lesions involved one or more cortical territories per patient, distributed approximately equally across the frontal, parietal, temporal, and occipital lobes without evident preferential laterality. Gradient-echo susceptibility-weighted images demonstrated multiple scattered cortical/subcortical microbleeds in a distribution distinct from the white matter lesions.
Figure 1 Initial MRI appearance of cerebral amyloid angiopathy–related inflammation
The images from this 62-year-old man (Subject 2, table 2) demonstrate a left temporo-occipital lesion with white matter hyperintensity on fluid-attenuated inversion recovery sequence (A), increased apparent diffusion coefficient (B), and hypointensity on T1-weighted sequence (C) consistent with vasogenic edema. The size of this lesion decreased dramatically after a course of IV methylprednisolone and oral prednisone.
Figure 2 Recurrent MRI lesion and intracerebral hemorrhage (ICH) in relapsing patient
Fluid-attenuated inversion recovery images from this 65-year-old man (Subject 8, table 2) demonstrate initial resolution of a left parietal hyperintensity (A and B), followed by recurrence in a similar location 15 months after initial presentation (C). This lesion also resolved radiographically (not shown), but a symptomatic ICH occurred in the same location 18 months after presentation (D).
Volumetric analysis of the T2-hyperintense lesions on serial scans revealed close correlation with clinical course (figure 3). Subjects in the improved group showed an abrupt fall in T2 lesion volume between baseline and first posttreatment follow-up MRI scan without substantial increase on further follow-up imaging. Lesion volumes on the first posttreatment follow-up in this group averaged 78.0 ± 19.4% smaller than at presentation. Relapsing subjects demonstrated a similar initial reduction in hyperintense lesion volume. Recurrences of clinical symptoms, however, were accompanied by growth of hyperintense lesions in the vicinity of the initial lesions (figure 2). Stable/progressive subjects had mild increases in hyperintense lesion volume on follow-up imaging without evidence of a reversible component. Four subjects with multiple scans prior to starting treatment demonstrated stable or progressive lesion volumes (figure 3, A and B), suggesting that lesion resolution was dependent on immunosuppressive therapy.
Figure 3 Changes in T2-hyperintense lesion volume
Total volume of hyperintensities (normalized to correct for head size) was calculated from T2/fluid-attenuated inversion recovery images and plotted as a function of time since initiation of treatment (negative time values reflecting scans performed prior to treatment initiation). Subjects are divided into “improved” (A), “relapsing” (B), and “stable/progressive” (C) according to their clinical course. Filled symbols indicate MRI scans performed just prior to initiation of a course of treatment.
To define the qualitative radiographic characteristics of CAA-related inflammation, we compared presentation scans from these subjects with those from patients with CAA without clinical evidence of inflammation or from patients with RPL. In a comparison performed without knowledge of diagnosis, the CAA-related inflammation group was characterized by 1) large, patchy or confluent T2-hyperintense lesions extending through the subcortical white matter and less consistently involving the overlying gray matter, 2) hypointense lesions on corresponding T1-weighted images (figure 1), and 3) asymmetry. Diffusion-weighted sequences showed increased ADC (figure 1), consistent with vasogenic edema. The lesions showed little or no enhancement with gadolinium. This pattern was readily distinguished from that seen in patients with noninflammatory CAA (characterized by more symmetric periventricular or scattered subcortical white matter T2-hyperintense lesions with little T1 hypointensity) or patients with RPL (symmetric T2 hyperintense lesions in the posterior periventricular and subcortical white matter also with little T1 hypointensity).
DISCUSSION
Vascular inflammation appears to occur in a substantial proportion of patients with symptomatic CAA.1 Although the frequency of this condition may be overestimated by the patients’ tendency to be referred to specialty centers and come to brain biopsy, the fact that most patients with CAA do not undergo brain biopsy or autopsy suggests that it may also be underrecognized. The current report, though based on a small number of subjects, represents the largest and longest follow-up study in this disorder and offers several insights. Most cases appear to be monophasic once treated, but CAA-related inflammation can also be a relapsing disorder; the proportion crossing over from “improved” to “relapsing” disease will likely increase with longer follow-up. Our data also demonstrate a characteristic MRI appearance of large, confluent, asymmetric T2-hyperintense lesions extending through the subcortical white and often the cortical gray matter with signal characteristics suggestive of vasogenic edema and show a good correlation between these lesions and clinical status. Finally, this report confirms a strong overrepresentation of the APOE ε4/ε4 genotype.
The appearance of APOE ε4/ε4 in fully three-fourths of inflammatory subjects is both intriguing and difficult to explain. Given the overrepresentation of this genotype in our earlier report,1 the occurrence of ε4/ε4 in five of six newly genotyped subjects in the current study can be considered confirmation of a prespecified hypothesis, supporting an underlying biologic association. Although APOE ε4 is known to associate with increased burden of Aβ deposition in vessels,8,14,15 the apparent predilection for ε4/ε4 in particular may be suggestive of a more specific effect of this genotype on the immune response to vascular Aβ, a possibility that clearly requires further experimental investigation.
The reversible, asymmetric T2-hyperintense lesions associated with inflammatory CAA appear to represent a distinct process from the more symmetric chronic white matter lesions in typical patients with advanced CAA.12,16 Among subjects with a clinical response to immunosuppressive therapy, the lesion volume declined from a median of 92.5 to 16 cm3 (table 2), the latter figure similar to the volume of (irreversible) white matter T2 hyperintensities (19.7 cm3) measured in 42 consecutive patients with apparently noninflammatory CAA.12 The asymmetric appearance of the reversible hyperintensities suggests that these edema-like lesions occur in confined regions rather than distributing evenly throughout subcortical white matter. Interestingly, recurrences and the one instance of subsequent ICH occurred in the same lobar regions as the initial lesions (figure 2), a further indication of the anatomic specificity of this process within individuals. Although CAA pathology and hemorrhages17 tend to cluster in space, the full explanation for the focal nature of the CAA-related inflammatory changes remains to be determined.
The distinctive pattern of asymmetric MRI lesions in CAA-related inflammation appears to be distinguishable from both noninflammatory CAA and RPL from other causes. This observation raises the possibility that in the appropriate clinical setting, this pattern of T2-hyperintense white matter lesions together with multiple cortical/subcortical microbleeds might prove sufficient to diagnose CAA-related inflammation without necessitating brain biopsy. Once diagnosed, patients appear generally to require immunosuppressive therapy for their symptoms to remit. (Spontaneous radiographic and clinical improvement in CAA has been observed, although in a patient without demonstrated inflammation.)3 Sufficient data are not available at this point to identify an optimal immunosuppressive regimen. Finally, patients who respond to immunosuppression can be tapered off treatment and followed clinically or radiographically for signs of recurrence.
Part of the interest in CAA-related inflammation arises from its similarities to the meningoencephalitis developed by a subset of patients with AD receiving experimental vaccination to Aβ. Like the patients with the spontaneous syndrome described here, the vaccinated subjects demonstrated seizures or subacute cognitive dysfunction, extensive T2/FLAIR hyperintensities, and neuropathologic evidence of advanced CAA with perivascular and meningeal inflammation.5–7 A more recent phase II study of anti-Aβ monoclonal antibody infusion in patients with AD revealed similar reversible hyperintense lesions in three subjects and associated cognitive changes in one,18 raising the possibility (still to be confirmed pathologically) that passive immunization to Aβ may be associated with some of the same vascular effects as active immunization. The suggestion that the immune response to CAA may be a major consideration in AD immunotherapy highlights the importance of identifying molecular risk factors or other detection methods for a patient’s risk of CAA-related inflammation.
Footnotes
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Received September 7, 2006. Accepted in final form December 22, 2006.
Disclosure: The authors report no conflicts of interest.
REFERENCES
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