Citations

AbstractIntroductionBiomarkers for Alzheimer's disease (AD) pathophysiology have been developed that focus on various levels of brain organization. However, no robust biomarker of large‐scale network failure has been developed. Using the recently introduced cascading network failure model of AD, we developed the network failure quotient (NFQ) as a biomarker of this process.MethodsWe developed and optimized the NFQ using our recently published analyses of task‐free functional magnetic resonance imaging data in clinically normal (n = 43) and AD dementia participants (n = 28) from the Alzheimer's Disease Neuroimaging Initiative. The optimized NFQ (oNFQ) was then validated in a cohort spanning the AD spectrum from the Mayo Clinic (n = 218).ResultsThe oNFQ (d = 1.25, 95% confidence interval [1.25, 1.26]) had the highest effect size for differentiating persons with AD dementia from clinically normal participants. The oNFQ measure performed similarly well on the validation Mayo Clinic sample (d = 1.44, 95% confidence interval [1.43, 1.44]). The oNFQ was also associated with other available key biomarkers in the Mayo cohort.DiscussionThis study demonstrates a measure of functional connectivity, based on a cascading network failure model of AD, and was highly successful in identifying AD dementia. A robust biomarker of the large‐scale effects of AD pathophysiology will allow for richer descriptions of the disease process and its modifiers, but is not currently suitable for discriminating clinical diagnostic categories. The large‐scale network level may be one of the earliest manifestations of AD, making this an attractive target for continued biomarker development to be used in prevention trials.

SummaryTwo patients who shared similar presenting clinical features of anterograde and retrograde autobiographical amnesia typical of transient epileptic amnesia (TEA) underwent prolonged video electroencephalogram (VEEG) monitoring and were found to have sleep‐activated epileptiform activity and frequent subclinical bitemporal seizures predominantly during sleep. Case 1 is a 59‐year‐old woman whose presenting complaint was memory impairment. Over 18 months, she had three distinct 8‐h‐long episodes of confusion and disorientation with persistent anterograde and retrograde autobiographical amnesia. VEEG recorded frequent interictal bitemporal sharp waves confined to sleep, and 14 subclinical seizures, also mostly during sleep. Case 2 is a 50‐year‐old woman with known focal epilepsy also presented with memory complaints. Over the course of 1 year, she had two discrete 2‐h‐long episodes of amnesia, with ongoing anterograde and retrograde autobiographical amnesia. VEEG recorded independent bitemporal sharp waves, and 14 subclinical seizures during sleep and drowsiness. Memory impairment improved in both patients with successful treatment of their seizures. Although the etiology of accelerated long‐term forgetting (ALF) and remote memory impairment (RMI) in transient epileptic amnesia (TEA) is unknown, these cases suggest frequent sleep‐related seizures may contribute, and they highlight the importance of video‐EEG monitoring.

ObjectivePatients with probable dementia with Lewy bodies (DLB) often have Alzheimer's disease (AD)‐related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV‐1451 uptake in patients with probable DLB, compared to AD, and its relationship to β‐amyloid deposition on PET.MethodsConsecutive patients with clinically probable DLB (n = 19) from the Mayo Clinic Alzheimer's Disease Research Center underwent magnetic resonance imaging, AV‐1451, and Pittsburgh compound‐B (PiB) PET examinations. Age‐ and sex‐matched groups of AD dementia (n = 19) patients and clinically normal controls (n = 95) from an epidemiological cohort served as a comparison groups. Atlas‐ and voxel‐based analyses were performed.ResultsThe AD dementia group had significantly higher AV‐1451 uptake than the probable DLB group, and medial temporal uptake completely distinguished AD dementia from probable DLB. Patients with probable DLB had greater AV‐1451 uptake in the posterior temporoparietal and occipital cortex compared to clinically normal controls, and in probable DLB, the uptake in these regions correlated with global cortical PiB uptake (Spearman rho = 0.63; p = 0.006).InterpretationMedial temporal lobe AV‐1451 uptake distinguishes AD dementia from probable DLB, which may be useful for differential diagnosis. Elevated posterior temporoparietal and occipital AV‐1451 uptake in probable DLB and its association with global cortical PiB uptake suggest an atypical pattern of tau deposition in DLB. ANN NEUROL 2017;81:58–67