Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study.

Background: The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed.

Methods: For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families.

Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease.

Objective: To evaluate alterations in cerebral blood flow (CBF) using arterial spin-labeled MRI in autosomal dominant Alzheimer disease (ADAD) mutation carriers (MCs) in relation to cerebral amyloid and compared with age-matched healthy controls.

Background: Recent work has identified alterations in CBF in elderly subjects with mild cognitive impairment and Alzheimer dementia using MRI. However, similar studies are lacking in ADAD.

Chronic dizocilpine (MK-801) reversibly delays GABA(A) receptor maturation in cerebellar granule neurons in vitro.

We investigated the effect of chronically blocking NMDA receptor stimulation to examine changes in GABA(A) receptor expression and pharmacology in cerebellar granule cells at different stages of maturation. We have previously shown that NMDA-selective glutamate receptor stimulation alters GABA(A) receptor pharmacology in cerebellar granule neurons in vitro by altering the levels of selective subunits. When NMDA receptor stimulation is blocked with MK-801 during the first week in vitro, a decrease in the alpha1, gamma2S, and gamma2L receptor subunit mRNAs occurred.

GABA and NMDA in the prevention of apoptotic-like cell death in vitro.

We have shown recently that cerebellar granule neurons die in the absence of depolarizing concentrations of KCl through an apoptosis-like process. To study the contributions of inhibitory (gamma-aminobutyric acid; GABA) and excitatory (glutamate) neurotransmitters in the prevention of apoptotic-like cell death in cultures grown in the presence of reduced concentrations of KCl (12.5 mM), we treated these cultures either acutely or chronically with GABA, bicuculline methiodide, a GABAA receptor antagonist, N-methyl-D-aspartate (NMDA) and/or the NMDA receptor antagonist, MK-801.

Chronic flumazenil alters GABA(A) receptor subunit mRNA expression, translation product assembly and channel function in neuronal cultures.

Flumazenil competitively blocks the pharmacological effects of both positive and negative allosteric modulators acting at the benzodiazepine binding sites of gamma-aminobutyric acid (GABA(A)) receptors. Using quantitative reverse transcription polymerase chain reaction, label-fracture immunocytochemistry and whole-cell patch-clamp recordings, we determined changes in the contents of selected GABA(A) receptor subunit mRNA(s), in their translation products and in the electrophysiological characteristics of the receptor channels in cultured cerebellar granule cells treated daily with flumazenil (10 microM) for 4 days in vitro. The contents of the alpha1 and alpha6 receptor subunit mRNAs were significantly increased in the flumazenil-treated group as compared with the dimethyl sulfoxide vehicle-treated control group, whereas there were no significant differences in the absolute amounts of the beta2, beta3, gamma2S, gamma2L++ + and delta receptor subunit mRNAs.