Box 9.
Cerebral amyloid angiopathy (CAA)
| Generals |
– Frequent cause of intracerebral hemorrhage (ICH) and cognitive impairment in the elderly – Age-dependent incidence (rare < 60 yo) – No clinical overlap between CAA and non-central nervous system systemic amyloidosis |
|||
| Clinical features & diagnosis | Acute lobar intracerebral hemorrhage (ICH, commonly older adults) |
MRI: – Commonly in posterior (temporal and occipital) lobar brain regions – Possible cerebellum involvement (with a predilection for cortex and vermis) – Possible extension into the subarachnoid (± “finger-like” projections [55]), subdural spaces, and into ventricles (less frequent) – Leptomeningeal vessels deposition: (1) Potential source for isolated convexity subarachnoid hemorrhage (cSAH) (2) cortical superficial siderosis (cSS, in chronic phase along with cortical microbleeds [CMBs] on T2*sequences) |
||
| Transient focal neurologic episodes (TFNE, aka “amyloid spells”): recurrent, brief and stereotyped spells of cortical symptoms (e.g., weakness, numbness, paresthesia, etc.) | MRI with gradient echo or other T2*-weighted sequences identifies cSAH, cSS, or cortical microbleeds (CMBs) in the region of cortex corresponding to TFNE symptoms | |||
|
Cerebral amyloid angiopathy-related inflammation (CAA-ri, inflammatory response to amyloid deposition): – Acute/subacute/progressive cognitive decline (~ 75%), headache (~ 40%), ↓ consciousness, behavioral change, or focal neurological signs (e.g., seizures ~ 30%) – Younger than those with others CAA-related manifestations |
MRI (with contrast ┼): – T2/FLAIR patchy or confluent immediately subcortical white matter hyperintensities (leukoencephalopathy) in subcortical white matter (often asymmetric) + multiple lobar microhemorrhages (microbleeds) on T2* sequences – Gadolinium enhancement in ~ one-third of cases -CAA-ri [2] – No evidence of large– or medium-vessel vasculitis on (MRA or angiography) |
|||
| Cognitive impairment (coexisting AD and/or VCI) | MRI: variable overlap of typical imaging-findings of CAA, VCI and AD | |||
|
Incidental imaging findings → Chronic evidence of asymptomatic bleeding detected on brain MRI of patients with or without lobar hemorrhage Include: – (Cortical) microbleeds (microhemorrhages, up to about 25% elderly population): 2–10 mm focal areas of hemosiderin deposition on T2*-sequences (predilection for the cerebral cortex) – Cortical superficial siderosis ¶ (cSS, maybe the chronic form of acute convexity subarachnoid hemorrhage related to CAA; up to 60% of CAA): | ||||
|
MRI hemorrhagic findings (imaging-based diagnosis of CAA): ∙ Modified Boston criteria [36]: combination of clinical, radiographic and pathological criteria. Four tiers: (i) Definite (post-mortem) (ii) Probable with supporting pathological evidence (iii) Probable CAA, with MRI: – Multiple hemorrhages restricted to lobar, cortical, or cortical-subcortical regions (cerebellar hemorrhages allowed) without another cause, or – Single lobar, cortical, or cortical-subcortical hemorrhage and focal (three or fewer sulci) or disseminated (more than three sulci) cortical superficial siderosis without another cause (iv) Possible CAA, with MRI: – A single lobar, cortical, or cortical-subcortical hemorrhage without another cause, or – Focal or disseminated cortical superficial siderosis without another cause ∙ CAA-ri → symptomatic patients with diagnostic imaging evidence of inflammation and CAA-related hemorrhagic findings plus exclusion of other causes [11] Amyloid-PET (using early-phase 11C-PiB PET Δ) and (resting-state [18F])FDG-PET: – Lower occipital/posterior cingulate (O/PC) tracer uptake ratio in probable CAA than AD – Regions with high PiB uptake area associated with subsequent hemorrhage [26] τ-PET: not useful |
MRI non-hemorrhagic findings: – Acute ischemic microinfarcts: asymptomatic punctate hyperintense lesions on DWI[71] – Cerebral atrophy (most pronounced in occipital regions and more severe in higher cortical microbleeds burden – WMH (T2/FLAIR): frequently small-vessel disease – Centrum semiovale dilated perivascular spaces ◊ |
|||
|
Pitfalls: – Patients with isolated incidental hemorrhagic imaging findings (i.e., a single CMB or equivocal cSS) should undergo to follow-up to detect the development of progressive subclinical findings to further support the diagnosis of CAA (sec. modified Boston Criteria) – Consider lobar extension of a hypertensive hemorrhage, hemorrhagic transformation of an ischemic stroke, hemorrhagic venous infarction from cerebral venous thrombosis, hemorrhage of AVM, and hemorrhagic tumor as differentials of nontraumatic lobar ICH – Microbleeds commonly arise from either CAA or hypertensive vasculopathy (small-vessel disease) § – Mind the possible development of CAA-ri-like findings (aka “Amyloid Related Imaging Abnormalities”, ARIA) in patients treated with anti-beta-amyloid immunotherapy for AD ¥ [3, 68] – AD, VCI, and CAA MRI findings may coexist | ||||
┼ Notably, MRI with contrast should be performed in only a few cases in the assessment of dementia, in particular, contrast-enhanced MRI should be performed only in a few cases in the evaluation of dementia, especially in subacute/acute and rapidly progressive cases
¶ If disseminated, cSS indicates a higher risk for future ICH. Notably, neither cSS nor superficial siderosis involving the cerebellum or brainstem is specific of CCA (possible comparison in, e.g., reversible cerebral vasoconstriction syndrome, primary angiitis of the CNS, bacterial endocarditis, hyperperfusion syndrome after carotid endarterectomy, cerebral venous sinus thrombosis, posterior reversible encephalopathy syndrome, dural tear and craniospinal surgery, etc.) [9, 33, 37]
Δ The early-phase 11c-PiB PET help differentiate probable CAA from probable AD. Early-phase amyloid PET images are used as a surrogate for brain perfusion, as opposed to the standard late-phase 11c-PiB PET/CT which reflects binding to aβ deposits
◊ When predominantly placed in the centrum semiovale, the dilated perivascular spaces are frequently associated with CAA [72]
§ Microbleeds are not specific for CAA as they can be seen in multiple conditions, including, hypertension, cerebral cavernous malformations, coagulopathy, thrombocytopenia, anticoagulant medications, CNS vasculitis, infective endocarditis, end-stage kidney failure. Moreover, beside conditions above-mentioned, microbleeds are also more prevalent among users of antiplatelet agents [24]. Notably, while microbleeds (in general) are not specific of CAA, cortical ones (i.e., those limited to the cerebral and/cerebellar cortex and vermis), suggest CAA [48] (although not pathognomonic). In contrast, deep microbleeds (those involving the basal ganglia, thalamus, or pons) are presumably of hypertensive microangiopathic origin
¥ In those with ad treated with immunotherapy, CAA may develop because of the rapid destruction of parenchymal aβ, and/or ARIA may be triggered if CAA is preexistent to the immunotherapy