Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

Abstract

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-␤ protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n ϭ 5) and symptomatic (n ϭ 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n ϭ 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n ϭ 12) and controls from the general population (n ϭ 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

P2‐203: Phenotypic Similarities between Late‐Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single‐Family Case‐Control Study

“…Hallucinations and delusions were reported more frequently in PSEN1 A79V MCs from this family, as has been noted previously in individuals with ADAD. 44,45 These findings demonstrate that the clinical phenotypes of late-onset ADAD and LOAD can overlap, and suggest that previously reported clinical (e.g., seizures, early myoclonus, spastic paraparesis, dysarthria, and rapid decline [9][10][11][12][13][14][15][16][17][18] ) and neuropathological differences (e.g., altered cerebral Aβ 42 and neurofibrillary tangle deposition, increased prevalence of cerebral amyloid angiopathy, and formation of "cotton wool" plaques 6,12,16,[19][20][21][22][23][24][25][26][27] ) may reflect age-or mutation-dependent effects.…”

“…7,8 Also, ADAD may be characterized by clinical features that are unusual in LOAD, including pyramidal signs, hypo/hyperkinetic movement disorders, ataxia, and early myoclonus and seizures. [9][10][11][12][13][14][15][16][17][18] Additional differences in the pattern of cerebral Aβ 42 deposition are reported in some ADAD cases, including 6,16,19,20 higher Aβ 42 burden and greater densities of neurofibrillary tangles; [21][22][23] increased Aβ 42 deposition within the cerebellum [24][25][26] and basal ganglia; 19,20 ; and higher prevalence of cerebral amyloid angiopathy and large diffuse so-called "cotton wool" plaques. 12,22,24,27 Such clinical and pathological differences may challenge whether findings from studies of early-onset ADAD, including current trials of anti-amyloid therapies, 28 can be extrapolated to the understanding of the far more common LOAD.…”

Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

“…Recently, several of our group used PiB PET to demonstrate fibrillar A␤ burden in 5 asymptomatic presenilin 1 (PS1) mutation carriers from a kindred with dominantly inherited earlyonset AD, 3 of whom performed within the normal range on all neuropsychological tests and who were 6-13 years younger than the kindred's reported mean age at symptomatic onset (22). The pattern of fibrillar A␤ burden in the asymptomatic PS1 carriers, and also in the symptomatic PS1 carriers from another kindred, was characterized by much higher deposition in the striatum than in the cerebral cortex, different from the less prominent striatal deposition in older persons with or without probable AD.…”

Target-Specific PET Probes for Neurodegenerative Disorders Related to Dementia

“…Studies of amyloid imaging in subjects at risk for developing AD will be of great importance. An early high PIB retention in the striatum was reported in presymptomatic carriers of presenilin-1 mutation (132). Similarly, an increased PIB uptake also in the striatum and posterior cingulate was observed in patients with amyloid precursor protein locus duplication and cerebral amyloid angiopathy (133).…”