Familial British dementia with cerebellar amyloid deposition
55 year old English-descent female presents with one-year history of word finding difficulty, amnesia and mild ataxia. Her mother has died from hemorrhagic stroke in her 70's.
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Numerous dark hemosiderin deposits in the cerebellum with a few scattered supratentorially on SWI.
Extensive and confluent white matter hyperintensities (Fazekas grade 3) bilaterally on FLAIR.
Global mild-moderate atrophy affecting the body of corpus callosum.
Reduced perfusion in the left and posterior area on ASL.
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Significant left inferior temporal metabolism with moderate extension to parietal/precuneus area.
Cerebral amyloid angiopathy (CAA) is a vasculopathy with amyloid deposition in the blood vessel wall. In the past, diagnosis of CAA is determined pathologically by congophilic staining of amyloid fibril in the tunica media and adventitia.
The introduction of T2*/gradient-echo MRI sequence has allowed a reliable detection of cerebral microbleeds that were previously undetected in other sequences. Recently, susceptibility weighted imaging (SWI) sequence further improves the signal-to-noise and spatial resolution for detecting the microbleeds in CAA 1. Common radiological features of CAA are dark punctate lesions in the cerebral peripheries, which represent hemosiderin deposits from the microbleeds.
This patient presents with mild ataxia, intermittent vomiting and an amnestic presentation of dementia, which has been described in a case report of ‘familial cerebellar ataxia with cerebrovascular amyloid’2. Similar features have been reported in other studies 3,4,5, and subsequently, the gene mutation BRI2 in Chromosome 13 (a.k.a. ITM2B gene) has been found in these British families. This condition is recognized as familial British dementia with amyloid angiopathy (FBD). It is an autosomal dominant condition which presents in the sixth decade with dementia, progressive spastic tetraparesis and cerebellar ataxia. The latter may represent a cerebellar preponderance of amyloid angiopathy, as demonstrated in the SWI study above. Cerebellar manifestation of CAA is less common than in the supratentorium, and it should prompt clinicians to review the family history.
CAA is a common cause of vascular dementia, and usually, gene mutation (e.g. ApoE4) does not bear the vascular changes on post-mortem examination 6. However, the delineation may be less clear in some familial CAA.
Not only the BRI2 gene mutation is associated with CAA, it is associated with amyloid depositions in the brain parenchyma, similar to Alzheimer’s disease (AD). BRI2 gene seems to mediate the amyloid beta precursor protein in the amyloid cascade 7. To illustrate the overlapping AD pathology in the patient, there is a reduced metabolism in the left temporal-parietal and precuneus in the SPECT. There is also a reduction of blood flow to the left and posterior area in the arterial spin labeling study.
Other systemic amyloid depositions (e.g. in pancreas) have been also described in cases of familial British dementia 8. However, this genetic CAA is a separate entity to the primary amyloidosis. For further classification of CAA (e.g. sporadic vs. familial) and its clinical manifestation, see review by Yamada, 2015 9.
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- 4. Simon Mead, Merle James-Galton, Tamas Revesz, R. Bala Doshi, George Harwood, E. Lee Pan, Jorge Ghiso, Blas Frangione, Gordon Plant; Familial British dementia with amyloid angiopathy: Early clinical, neuropsychological and imaging findings. Brain 2000; 123 (5): 975-991.
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