Hyposmia in G2019S LRRK2-related parkinsonism: clinical and pathologic data.

BACKGROUND: Mutations in PARK8 (LRRK2) are associated with autosomal dominant parkinsonism and Parkinson disease (PD). Hyposmia is present in at least 80% of patients with PD and an accumulation of alpha-synuclein (alpha-syn) is seen in the olfactory pathways. In this study we have clinically examined olfaction and pathologically examined the rhinencephalon in individuals carrying the G2019S LRRK2 mutation. METHODS: The University of Pennsylvania Smell Test (UPSIT) was used to evaluate the sense of smell in 19 parkinsonian and two asymptomatic carriers of the G2019S mutation and compared with groups of patients with PD and healthy controls. Postmortem examination of alpha-syn accumulation in the rhinencephalon was also carried out in four parkinsonian carriers of the G2019S mutation. RESULTS: The mean UPSIT score in G2019S parkinsonian carriers was lower than that in healthy controls (p < 0.001) and similar to that found in patients with PD (p > 0.999). Smell tests in two asymptomatic carriers of the G2019S mutation were in the normal range. Postmortem studies of the olfactory pathways in one of the patients who had been clinically tested, and found to have hyposmia, and three other cases with the G2019S mutation, revealed alpha-syn deposition in the olfactory pathways in all cases. CONCLUSIONS: Odor identification is diminished in LRRK2 G2019S mutation parkinsonism but the asymptomatic carriers of the mutation had normal olfaction. We found alpha-syn accumulation with Lewy bodies in the rhinencephalon in all four cases examined pathologically.

Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia.

Familial British dementia (FBD), pathologically characterized by cerebral amyloid angiopathy (CAA), amyloid plaques, and neurofibrillary degeneration, is associated with a stop codon mutation in the BRI gene resulting in the production of an amyloidogenic fragment, amyloid-Bri (ABri). The aim of this study was to assess the distribution of ABri fibrillar and nonfibrillar lesions and their relationship to neurofibrillary pathology, astroglial and microglial response using immunohistochemistry, confocal microscopy, and immunoelectron microscopy in five cases of FBD. Abnormal tau was studied with immunoblotting. We present evidence that ABri is deposited throughout the central nervous system in blood vessels and parenchyma where both amyloid (fibrillar) and pre-amyloid (nonfibrillar) lesions are formed. Ultrastructurally amyloid lesions appear as bundles of fibrils recognized by an antibody raised against ABri, whereas Thioflavin S-negative diffuse deposits consist of amorphous electron-dense material with sparse, dispersed fibrils. In contrast to nonfibrillar lesions, fibrillar ABri is associated with a marked astrocytic and microglial response. Neurofibrillary tangles and neuropil threads occurring mainly in limbic structures, are found in areas affected by all types of ABri lesions whereas abnormal neurites are present around amyloid lesions. Immunoblotting for tau revealed a triplet electrophoretic migration pattern. Our observations confirm a close link between ABri deposition and neurodegeneration in FBD.