Alzheimer Disease: Sperling R

Carrillo MC, Blackwell A, Hampel H, Lindborg J, Sperling R, Schenk D, Sevigny JJ, Ferris S, Bennett DA, Craft S, Hsu T, Klunk W. · Alzheimer's Association, Chicago, IL, USA. · Alzheimers Dement. · Pubmed #19328456 No free full text.

Abstract: The purpose of the Alzheimer's Association Research Roundtable meeting was to discuss the potential of finding diagnostic tools to determine the earliest risk factors for Alzheimer's disease (AD). Currently, drugs approved for AD address symptoms which are generally manifest after the disease is already well-established, but there is a growing pipeline of drugs that may alter the underlying pathology and therefore slow or halt progression of the disease. As these drugs become available, it will become increasingly imperative that those at risk for AD be detected and possibly treated early, especially given recent indications that the disease process may start decades before the first clinical symptoms are recognized. Early detection must go hand-in-hand with qualified tools to determine the efficacy of drugs in people who may be asymptomatic or who have only very mild symptoms of the disease. Devising strategies and screening tools to identify and monitor those at risk in order to perform "prevention" trials is seen by many as a top public-health priority, made all the more urgent by an impending growth in the elderly population worldwide.

Sperling R. · Department of Neurology, Memory Disorders Unit, Brigham and Women's Hospital, Alzheimer's Disease Research Center, Boston, MA 02215, USA. · Ann N Y Acad Sci. · Pubmed #17413017 No free full text.

Abstract: Functional magnetic resonance imaging (fMRI) is a noninvasive neuroimaging technique that can be used to study the neural correlates of complex cognitive processes, and the alterations in these processes that occur in the course of normal aging or superimposed neurodegenerative disease. Our studies have focused on the neural substrates of successful associative encoding, particularly of face-name associations. We have found that the specific regions of the hippocampus and prefrontal cortices are critical for successful memory in both young and healthy older subjects. Our fMRI studies, as well as those of several other groups, have consistently demonstrated that, compared to cognitively intact older subjects, patients with clinical Alzheimer's disease (AD) have decreased fMRI activation in the hippocampus and related structures within the medial temporal lobe during the encoding of new memories. More recently, fMRI studies of subjects at risk for AD, by virtue of their genetics or evidence of mild cognitive impairment (MCI), have yielded variable results. Some of these studies, including our own, suggest that there may be a phase of paradoxically increased activation early in the course of prodromal AD. Further studies to validate fMRI in these populations are needed, particularly longitudinal studies to investigate the pattern of alterations in functional activity over the course of prodromal AD and the relationship to AD pathology.

Chappell AS, Gonzales C, Williams J, Witte MM, Mohs RC, Sperling R. · Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. · Neurology. · Pubmed #17389305 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and safety of the positive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid modulator LY451395 in patients with mild to moderate Alzheimer disease (AD) (Mini-Mental State Examination scores 14 to 26). METHODS: One hundred eighty-one patients were randomized to treatment in an 11-week, double-blind, placebo-controlled trial. Patients received either LY451395 0.2 mg BID for 28 days and 1.0 mg BID thereafter (n = 90) or placebo (n = 91). The primary outcome measurement was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) with several secondary outcome measurements: Clinician's Interview-Based Impression of Change, Trail Making Part A, Stylus Tapping Test, Single Digit Modality Test, and Neuropsychiatric Inventory (NPI). RESULTS: Baseline demographics were similar between the two groups. Patients did not show any mean change from baseline in the ADAS-Cog after treatment with LY451395 for 4 weeks (p = 0.60) or 8 weeks (p = 0.83). The only secondary outcome measurement that showed changes from baseline compared with placebo was the NPI Total Score: p = 0.06 (marginal significance) after 4 weeks of treatment and p = 0.03 after 8 weeks of treatment. Ninety-two percent of LY451395-treated patients and 95% of placebo-treated patients completed the trial. Adverse events were experienced by 83% of LY451395-treated patients and 86% of placebo-treated patients, the majority of which were rated mild in severity. CONCLUSION: Patients treated with LY451395 did not show a statistically significant separation from patients taking placebo on the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the primary outcome measure.

Lange N, Lake S, Sperling R, Brown J, Routledge C, Albert M, Heckers S. · Department of Psychiatry, Harvard Medical School, Boston, MA, USA. · Stat Med. · Pubmed #14716733 No free full text.

Abstract: Among the many diseases that affect the hippocampus, a small yet highly important brain region responsible for memory and identity, Alzheimer's disease and schizophrenia are among the most devastating. We describe a two-stage, region-of-interest based linear mixed model approach to the analysis of a longitudinal functional magnetic resonance (FMRI) study of human memory function under several drug challenges. We then describe a Monte Carlo approach to testing members of nested hierarchies of linear models in a stereological study of different types and locations of human hippocampal neurons. Last, we attempt to draw the attention of the biostatistical community interested in imaging neuroscience to the intriguing complexities of human hippocampal research in early Alzheimer's disease, schizophrenia and other brain diseases via brain imaging methods.

Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL. · Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · J Clin Invest. · Pubmed #12897209 links to  free full text

Abstract: Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid beta protein (Abeta) in brain regions serving memory and cognition. In animal models of AD, immunization with Abeta results in the clearance of Abeta deposits from the brain. However, a trial of vaccination with synthetic human Abeta1-42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Abeta in middle-aged and elderly healthy subjects and in patients with AD. A significantly higher proportion of healthy elderly subjects and patients with AD had strong Abeta-reactive T cell responses than occurred in middle-aged adults. The immunodominant Abeta epitopes in humans resided in amino acids 16-33. Epitope mapping enabled the identification of MHC/T cell receptor (TCR) contact residues. The occurrence of intrinsic T cell reactivity to the self-antigen Abeta in humans has implications for the design of Abeta vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process.

Johnson KA, Lopera F, Jones K, Becker A, Sperling R, Hilson J, Londono J, Siegert I, Arcos M, Moreno S, Madrigal L, Ossa J, Pineda N, Ardila A, Roselli M, Albert MS, Kosik KS, Rios A. · Radiology and Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Neurology. · Pubmed #11402113 No free full text.

Abstract: OBJECTIVE: To investigate the influence of the presenilin-1 gene (PS-1) mutation on regional cerebral perfusion, SPECT was evaluated in 57 individuals. The subjects were members of a large pedigree from Colombia, South America, many of whom carry a PS-1 mutation for early-onset AD. METHODS: Members of this large kindred who were cognitively normal and did not carry the PS-1 mutation (n = 23) were compared with subjects who were carriers of the mutation but were asymptomatic (n = 18) and with individuals with the mutation and a clinical diagnosis of AD (n = 16). Cerebral perfusion was measured in each subject using hexamethylpropyleneamine oxime SPECT. The data were analyzed in two ways: 1) Mean cerebral perfusion in each of 4320 voxels in the brain was compared among the groups using t-tests (t-maps); and 2) each individual received a weighted score on 20 vectors (factors), based on a large normative sample (n = 200), using a method known as singular value decomposition (SVD). RESULTS: Based on t-maps, subjects with the PS-1 mutation who were asymptomatic demonstrated reduced perfusion in comparison with the normal control subjects in the hippocampal complex, anterior and posterior cingulate, posterior parietal lobe, and anterior frontal lobe. The AD patients demonstrated decreased perfusion in the posterior parietal and superior frontal cortex in comparison with the normal control subjects. Discriminant function analysis of the vector scores derived from SVD (adjusted for age and gender) accurately discriminated 86% of the subjects in the three groups (p < 0.0005). CONCLUSION: Regional cerebral perfusion abnormalities based on SPECT are detectable before development of the clinical symptoms of AD in carriers of the PS-1 mutation.