Clinical Course of Patients with Familial Early-Onset Alzheimer’s Disease Potentially Lacking Senile Plaques Bearing the E693Δ Mutation in Amyloid Precursor Protein

Abstract

Background/Aims: Oligomeric amyloid β (Aβ) is currently considered to induce Alzheimer’s disease (AD). We examined 2 patients with familial AD who possessed the Osaka (E693Δ) mutation in amyloid precursor protein. To the best of our knowledge, these patients are the first AD cases presumably affected with Aβ oligomers in the absence of senile plaques, and they support the Aβ oligomer hypothesis. Methods: We evaluated the clinical course, neuropsychological data, cerebrospinal fluid biomarker levels, magnetic resonance imaging (MRI) scans, fluorodeoxyglucose-positron emission tomography (PET) scans, and Pittsburgh compound B (PiB)-PET images of these patients. Results: In the early stages, these patients developed memory disturbances in a similar rate to patients with sporadic AD. Despite their memory disturbances, both patients showed only limited brain atrophy on MRI and little amyloid accumulation on PiB-PET. Subsequent to the development of memory disturbances, both patients suffered from motor dysfunction, probably due to cerebellar ataxia, and, within a few years, the patients fell into an apallic state. Conclusions: Familial AD patients with Osaka (E693Δ) mutation show severe dementia, cerebellar ataxia, and gait disturbances.

Clinical Features of Pittsburgh Compound-B-Negative Dementia

“…According to recent reports, 2 AD cases that were rated as PiB-negative by PiB-PET showed different primary findings -in one diffuse plaques were the primary pathological feature [3] and in the other PiB-negative Aβ accumulation was the primary finding [4]. In addition, it has been reported that PiB-PET revealed no amyloid accumulation in the cerebral cortex in cases of familial AD [5]. DLB is the second most common cause of dementia after AD in neurodegenerative disorders [6]; hence, DLB seems to be important in the differential diagnosis of PiB-negative dementia.…”

Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

“…Two of these studies showed good correlation with known patient pathology, whilst the study reporting increased Aβ42:Aβ40 levels cannot be validated to the patient pathology since this mutation has not been well characterized. One study also reported an increase in Aβ oligomers in the analysed neural cells and astrocytes [44], which again correlates well with the patient's phenotype [59]. Increased p-tau has been observed in patients from two different studies [43,58] and total tau has also been reported [58].…”

The Roles of Genetics in Aβ related Alzheimer's Diseases

“…APPswe mutation carriers absorbed more PiB in cortex, with the cerebral glucose metabolic rate reduced, which was especially obvious in the striatum. The Aβ 42 level in CSF was increased significantly [33]. In contrast with the cerebro-absorption of 11C-PiB in sporadic AD patients, FAD with APP mutation carriers show large increases in absorption in striatum, posterior cingulate (caudate nucleus, putamen), while absorption in other cortical areas also show small increases [34].…”

“…A wide range of imaging modalities, such as MRI (Magnetic Resonance Imaging), functional MRI, 11C-PiB (carbon 11-labeled Pittsburgh Compound B) PET (positron emission tomography) imaging have been utilized in supporting AD research [32,33]. In particular, some of these techniques enable the in situ detection and monitoring of senile plagues in AD patients [34].…”

“…However, senile plaques are rarely seen, which may be due to low level of accumulation of Aβ in vivo [32]. According to 11C-labeled PiB-PET and 18F-FDG-PET imaging, a significant difference between the Arctic APP (APParc) and Sweden (APPswe) mutations on APP has been observed [33]. APParc mutation carriers show low level of absorption of PiB in cortex, while the rate of glucose metabolism in the brain and the Aβ 42 levels in cerebral spinal fluid (CSF) are low.…”