ARTICLESAmyloid-β peptide (Aβ) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Aβ in a transgenic mouse model of AD reduces both age-related accumulation of Aβ in the brain 1 and associated cognitive impairment 2,3 . Here we present the first analysis of human neuropathology after immunization with Aβ (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Aβ plaques; (ii) those areas of cortex that were devoid of Aβ plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Aβ-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Aβ immunotherapy in mouse models of AD 1-6 and suggest that the immune response generated against the peptide elicited clearance of Aβ plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).A 72-year-old woman with a 5-year history of gradually progressive memory impairment presented with worsening confusion and disorientation. Her Mini Mental State Examination (MMSE) score (23/30) represented a three-point deterioration in two years. She had global cognitive impairment and satisfied the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association's criteria for probable AD, with no cardiovascular risk factors and a modified Haschinski score <4. Therapy with rivastigmine tartrate, a cholinesterase inhibitor, resulted in improvements in the Alzheimer's Disease Assessment Scale cognitive section (ADAS cog), MMSE, clock drawing and verbal fluency, but ten months later she had returned to baseline levels on all these parameters. The patient was then enrolled in a randomized, double-blind, multiple-dose immunogenicity study of Aβ42 (AN-1792; Elan Pharmaceuticals). She received her first injection, containing 50 µg of AN-1792, in July 2000. This was repeated 4, 12 and 24 weeks later with no apparent adverse effects. A fifth injection with a reformulated preparation containing polysorbate-80, subsequently used in a multinational phase 2a trial, was given 36 weeks after the first injection. Four weeks after her last injection, her cognitive test results were unchanged (MMSE 23), but at six weeks she suddenly became unwell with dizzy spells, drowsiness, an unstable gait and fever. Two weeks after that, she deteriorated such that an MMSE could not be performed. Neuroimaging (Fig. 1a) showed extensive bilateral alterations in the cerebral white matter and enhancement on the b...

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Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.

p38 MAPK is a potential therapeutic target in bladder cancer and this strategy warrants further development in this disease. It may also allow combination therapy strategies to be developed in conjunction with EGFR or HER2 inhibition.