Alzheimer Disease: Small GW

Small GW. · No affiliation provided · Int Psychogeriatr. · Pubmed #10189595 No free full text.

This publication has no abstract.

Kepe V, Huang SC, Small GW, Satyamurthy N, Barrio JR. · Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, California 90095, USA. · Methods Enzymol. · Pubmed #17046657 No free full text.

Abstract: One of the major neuropathological changes characteristic of Alzheimer's disease (AD) are deposits of beta-amyloid plaques and neurofibrillary tangles in neocortical and subcortical regions of the AD brain. The histochemical detection of these lesions in postmortem brain tissue is necessary for definitive diagnosis of AD. Methods for their in vivo detection would greatly aid the diagnosis of AD in early stages when neuronal loss and related functional impairment are still limited and also open the opportunity for effective therapeutic interventions. Positron emission tomography (PET) using an appropriate radiolabeled imaging probe with high binding affinity for these lesions is one of such techniques. We have developed 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP), a naphthalene-based radiofluorinated PET imaging probe with binding affinity for amyloid and amyloid-like structures, and applied it for in vivo brain imaging of patients with Alzheimer's disease and cognitively normal controls with PET. Analysis of in vivo [F-18]FDDNP imaging data using Logan plot graphical analysis with the cerebellum as a reference region was performed, and the binding levels in several areas of neocortex were determined. We observed increased levels of [F-18]FDDNP binding in patients in several neocortical regions in Alzheimer's disease compared with the cerebellum. In contrast, control subjects have uniformly low levels of [F-18]FDDNP binding in all areas, which is comparable to that of cerebellum.

Small GW, Kepe V, Barrio JR. · Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, Alzheimer's Disease Center, University of California, Los Angeles, California 90024, USA. · Curr Opin Psychiatry. · Pubmed #17012932 No free full text.

Abstract: PURPOSE OF REVIEW: Recent technological developments in neuroimaging have led to new technologies that provide measures of the cerebral pathology of neurodegeneration in living humans. The purpose of this review is to provide background behind these developments and update readers on new findings. RECENT FINDINGS: Several imaging methods using positron emission tomography have provided measures of amyloid senile plaques in the brain of demented patients and patients with early memory symptoms. ([F-18]FDDNP)-positron emission tomography provides measures of both amyloid plaques and neurofibrillary tangles. Initial results indicate that the pattern of binding values in Alzheimer's disease is consistent with the known neuropathology from autopsy studies, and patients with mild cognitive impairment, who are at risk of Alzheimer's disease, show binding values intermediate between Alzheimer's disease and normal aging. 2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP) positron emission tomography also shows a pattern of neuropathology distribution for frontotemporal dementia that differs from that of Alzheimer's disease. SUMMARY: In-vivo imaging of cerebral pathology offers the potential for more effective and earlier diagnosis and use of these technologies as surrogate markers to test novel treatments aimed at preventing or eliminating cerebral plaque and tangle accumulation.

Small GW, Kaufer D, Mendiondo MS, Quarg P, Spiegel R. · UCLA Neuropsychiatric Institute, Los Angeles, CA 90024-1759, USA. · Int J Clin Pract. · Pubmed #15853867 No free full text.

Abstract: This analysis aimed to assess mini-mental state examination (MMSE) scores in patients with Alzheimer's disease who received rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, for up to 5 years. Rivastigmine data came from two pooled open-label extensions of four 6-month, randomised, placebo-controlled trials. Projections of decline, had the same patients not been treated, were made using a baseline-dependent mathematical model. MMSE data were available for 1998 rivastigmine-treated patients and 657, 298 and 83 were still on treatment at 3, 4 and 5 years, respectively. The mean (+/-SD) baseline MMSE score was 19.3 (+/-4.9). Projected mean scores in model-based untreated patients declined below 10 points on the MMSE at about 3 years, while the mean MMSE score of patients who remained on rivastigmine stayed above 10 points for 5 years.

Small GW. · Center on Aging, Neuropsychiatric Institute, David Geffen School of Medicine at UCLA, Los Angeles, Calif. 90024, USA. · Dement Geriatr Cogn Disord. · Pubmed #14676466 No free full text.

Abstract: Due to similar presenting symptoms, many physicians find it difficult to distinguish cases of dementia with Lewy bodies (DLB) from Alzheimer's disease or Parkinson's disease with dementia. The pathologic diagnosis of DLB has improved because of the discovery of probes for alpha-synuclein, a protein found in Lewy bodies. However, pathologic diagnosis can be employed postmortem only, and therefore diagnostic techniques that can be employed to guide patient management are still needed. Consensus criteria have been developed for establishing a clinical diagnosis of DLB, but they lack sensitivity. Therefore, a review of the recent literature was conducted to establish whether neuroimaging studies are useful diagnostic tools to help differentiate these syndromes. At least six types of tests can be used to image the brain of patients with dementia. Structural studies (x-ray, magnetic resonance imaging and computerized tomography) can disclose the presence of stroke sequelae and other lesions, whereas functional studies (magnetic resonance spectroscopy, positron emission tomography and single-photon emission computed tomography) can disclose metabolic and blood flow alterations that may be characteristic for different types of dementia. Although more formal studies are needed to confirm that these imaging techniques are reliable diagnostic tools for DLB and permit the establishment of guidelines for their use, neuroimaging techniques currently are being employed in practice to differentiate dementia types as a guide to treatment.

Agdeppa ED, Kepe V, Liu J, Small GW, Huang SC, Petric A, Satyamurthy N, Barrio JR. · Department of Molecular and Medical Pharmacology, Laboratory of Structural Biology and Molecular Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. · Mol Imaging Biol. · Pubmed #14667495 No free full text.

Abstract: This article presents a comprehensive review of the in vitro and in vivo detection of neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (SPs), neuropathological lesions found in the brains of the Alzheimer's disease (AD) patients, using FDDNP and its analogs. FDDNP and its analogs have excellent ability to bind to NFTs and SPs in vitro as shown by binding assays, confocal fluorescence microscopy with stained AD brain tissue and digital autoradiography with [18F]FDDNP. [18F]FDDNP-PET molecular imaging permits detection of these pathologies in living subjects. The discovery of a new binding site to Abeta(1-40) fibrils as a result of FDDNP binding also opens a therapeutic opportunity for early treatment of Alzheimer's disease. FDDNP shares a previously unrecognized common binding site on Abeta(1-40) fibrils and senile plaques with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., naproxen and ibuprofen). Naproxen, ibuprofen and even FDDNP significantly inhibit aggregation of the Abeta(1-40) peptide in the micromolar range. This new binding site on Abeta(1-40) fibrils also offers a molecular template for design of anti-aggregation drugs without the secondary effects of NSAIDs. Therefore it is anticipated that a new vision for prevention, early diagnosis and treatment of Alzheimer's disease would be rapidly developing.

Small GW, Agdeppa ED, Kepe V, Satyamurthy N, Huang SC, Barrio JR. · Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA. · J Mol Neurosci. · Pubmed #12540059 No free full text.

Abstract: Cerebral neurofibrillary tangles (NFTs) accumulate in a predictable sequence decades before the clinical symptoms of Alzheimer's disease emerge, and the degree of tangle degeneration correlates with the severity of cognitive impairment. A valid in vivo marker of tangle burden, therefore, would be useful for presymptomatic and symptomatic disease detection and treatment monitoring. Recent advances using positron emission tomography (PET) indicate the feasibility of in vivo imaging that provides a combined signal of both neurofibrillary tangles and senile plaques. Such results are encouraging that a tangle-specific marker will be found; however, several methodological issues first need to be addressed, including scanner spatial resolution in the relatively small brain regions where tangles accumulate. NFT-specific imaging probes will need to be lipophilic in order to cross the blood-brain barrier and neuronal membranes and have a high binding affinity to NFTs with minimal nonspecific binding, which would result in a high signal-to-background ratio in PET images.

Small GW. · Department of Psychiatry and Biobehavioral Sciences and the Center on Aging, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA. · Adv Drug Deliv Rev. · Pubmed #12453673 No free full text.

Abstract: The neuropathological and cognitive changes preceding Alzheimer's disease appear to begin subtly decades before symptoms of the disease make the clinical diagnosis obvious. Clinical trials have begun to focus on preventive treatments designed to slow age-related cognitive decline and delay the onset of Alzheimer's disease in people with only mild memory complaints. Because people with few cognitive deficits represent a heterogeneous population, prevention studies require large samples in order to detect active drug effects. To address such challenges, recent neuroimaging studies have focused on middle-aged and older adults with only mild memory complaints and evaluated results according to the major known genetic risk for Alzheimer's disease, the apolipoprotein E-4 (APOE-4) allele. In studies using positron emission tomography during mental rest and functional magnetic resonance imaging during memory task performance, brain patterns differ according to genetic risk and are useful in predicting future decline measures and following disease progression in clinical trials.

Small GW. · Department of Psychiatry and Biobehavioral Sciences and the Center on Aging, University of California, Los Angeles School of Medicine, USA. · J Mol Neurosci. · Pubmed #12212776 No free full text.

Abstract: Recent evidence points to the importance of neuropathological and cognitive changes preceding Alzheimer's disease (AD), and clinical trials have begun to focus on preventive treatments designed to slow age-related cognitive decline and delay the onset of AD in people with age-associated memory impairment (AAMI). Studying subjects with few deficits leads to diagnostic heterogeneity and a need for larger samples in order to detect active drug effects. In this report, I review results of recent studies designed to address such issues. Middle-aged and older adults with mild memory complaints were studied using brain imaging and measures of the major known genetic risk for AD, the apolipoprotein E-4 (APOE-4) allele. In a study of positron emission tomography during mental rest, glucose metabolic rates were significantly lower in APOE-4 carriers in brain regions affected by AD. Another study using functional magnetic resonance imaging showed increased brain activation during memory tasks in APOE-4 carriers in similar brain regions. Longitudinal follow-up after 2 yr indicated the potential utility of such brain-imaging measures, combined with genetic-risk information, as surrogate markers in treatment trials for AAMI to prevent further cognitive decline. Current development focuses on novel technologies using positron emission tomography to directly image the neuritic plaques and neurofibrillary tangles of AD in order to provide more specific measures of disease progression in future clinical trials.

Jann MW, Shirley KL, Small GW. · Department of Clinical and Administrative Sciences, Southern School of Pharmacy, Mercer University, Atlanta, Georgia 30341, USA. · Clin Pharmacokinet. · Pubmed #12162759 No free full text.

Abstract: Cholinesterase inhibitors are the 'first-line' agents in the treatment of Alzheimer's disease. This article presents the latest information on their pharmacokinetic properties and pharmacodynamic activity. Tacrine was the first cholinesterase inhibitor approved by regulatory agencies, followed by donepezil, rivastigmine and recently galantamine. With the exception of low doses of tacrine, the cholinesterase inhibitors exhibit a linear relationship between dose and area under the plasma concentration-time curve. Cholinesterase inhibitors are rapidly absorbed through the gastrointestinal tract, with time to peak concentration usually less than 2 hours; donepezil has the longest absorption time of 3 to 5 hours. Donepezil and tacrine are highly protein bound, whereas protein binding of rivastigmine and galantamine is less than 40%. Tacrine is metabolised by hepatic cytochrome P450 (CYP) 1A2, and donepezil and galantamine are metabolised by CYP3A4 and CYP2D6. Rivastigmine is metabolised by sulfate conjugation. Two cholinesterase enzymes are present in the body, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Tacrine and rivastigmine inhibit both enzymes, whereas donepezil and galantamine specifically inhibit AChE. Galantamine also modulates nicotine receptors, thereby enhancing acetylcholinergic activity at the synapse. These different pharmacological profiles provide distinctions between these agents. Cholinesterase inhibitors show a nonlinear relationship between dose and cholinesterase inhibition, where a plateau effect occurs. Cholinesterase inhibitors display a different profile as each agent achieves its plateau at different doses. In clinical trials, cholinesterase inhibitors demonstrate a dose-dependent effect on cognition and functional activities. Improvement in behavioural symptoms also occurs, but without a dose-response relationship. Gastrointestinal adverse events are dose-related. Clinical improvement occurs with between 40 and 70% inhibition of cholinesterase. A conceptual model for cholinesterase inhibitors has been proposed, linking enzyme inhibition, clinical efficacy and adverse effects. Currently, measurement of enzyme inhibition is used as the biomarker for cholinesterase inhibitors. New approaches to determining the efficacy of cholinesterase inhibitors in the brain could involve the use of various imaging techniques. The knowledge base for the pharmacokinetics and pharmacodynamics of cholinesterase inhibitors continues to expand. The increased information available to clinicians can optimise the use of these agents in the management of patients with Alzheimer's disease.

Small GW. · Department of Psychiatry and Biobehavioral Sciences, the Neuropsychiatric Institute, the Alzheimer's Disease Center, and the Center on Aging, University of California at Los Angeles, USA. · Am J Geriatr Psychiatry. · Pubmed #11069266 No free full text.

Abstract: The author summarizes the American Association for Geriatric Psychiatry Senior Investigator Award presentation delivered at the 13th Annual Meeting March 12-15, 2000, in Miami Beach, Florida, and reviews his research studies that define a trajectory leading to investigations of early detection and prevention of Alzheimer's disease (AD). Themes and critical transitions that fostered the research are emphasized, and effective collaboration, mentoring, and timing are discussed. These studies have combined neuroimaging and genetic methods to identify subjects before they develop AD, so that interventions might delay dementia onset. The eventual goal is to translate the clinical research discoveries into modern clinical practice.

Small GW. · No affiliation provided · West J Med. · Pubmed #10639858 links to  free full text

This publication has no abstract.

Orgogozo JM, Small GW, Hammond G, Van Baelen B, Schwalen S. · Université de Bordeaux 2-Hôpital Pellegrin, Bordeaux, France. · Curr Med Res Opin. · Pubmed #15537482 No free full text.

Abstract: BACKGROUND: Galantamine is an acetylcholinesterase inhibitor that modulates nicotinic receptors. It is effective in mild to moderate Alzheimer's disease (AD) but no trial has focused exclusively on mild AD. We performed a post-hoc sub-set analysis using data from four randomised trials to explore the efficacy of galantamine versus placebo in mild AD. METHODS: Participants in all studies met NINCDS-ADRDA criteria for probable AD. We examined data from patients with baseline Mini Mental State Examination (MMSE) 21-24 who received galantamine 24 mg/day (GAL) or placebo (PLAC). Scores for the Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog), Clinician's Interview-Based Impression of Change (CIBIC), Disability Assessment for Dementia (DAD), and ACDS-ADL scales were compared. RESULTS: Of the 694 patients (362 GAL, 332 PLAC, mean baseline MMSE 22.4 +/- 1.1, mean age 74 +/- 7.9 years), 65% completed 6 months treatment (223 GAL, 229 PLAC). Mean change in ADAS-cog at 6 months was -1.5 (95% confidence interval -2.2, -0.8, p < 0.001) for GAL and +0.2 (-0.6, 0.9, p = 0.72) for PLAC. This difference was statistically significant (p = 0.001). Significantly more patients receiving galantamine were classified as 'improved' using the CIBIC (26.9% GAL vs 14.3% PLAC, p < 0.001). Galantamine was generally well tolerated; most common adverse events were nausea, vomiting and diarrhoea. CONCLUSIONS: Pooled data from four randomised trials of patients with mild AD indicate that patients who received galantamine 24 mg/day for 6 months improved cognition more often than those who received placebo and that a higher proportion receiving galantamine were globally improved. This suggests that patients with mild AD benefit from galantamine treatment.

Kurz AF, Erkinjuntti T, Small GW, Lilienfeld S, Damaraju CR. · Department of Psychiatry and Psychotherapy, Technische Universitaet Munchen, Munich, Germany. · Eur J Neurol. · Pubmed #14641507 No free full text.

Abstract: The relationship between cholinergic dysfunction and cognitive and functional impairment in patients with vascular dementia (VaD) and Alzheimer's disease (AD) with cerebrovascular disease (CVD) suggests a potential role for cholinomimetic therapy. Initial studies of galantamine demonstrated cognitive, behavioral, and functional benefits in these populations. 326 patients with VaD or AD with CVD who completed an initial 12-month trial were treated with galantamine 24 mg/day in a 24-month, open-label extension. This interim analysis was performed at month 12 of the open-label extension (248 completed the trial). Galantamine (up to 24 months total) was well tolerated in both groups. The most frequently reported adverse events, characteristic of older dementia patients, included depression, agitation, and insomnia. Gastrointestinal adverse events were less common than initially, indicating declining incidence with long-term therapy. Patients taking galantamine for the entire study demonstrated the least cognitive decline on AD Assessment Scale-cog/11: 2.7 points vs. 3.1 points in those given placebo initially (P < 0.001 and P = 0.003, respectively). The long-term benefits of galantamine were evident in both groups; cognitive baseline levels were maintained for approximately 21 months in VaD patients and for 12 months in patients with AD with CVD. Long-term (up to 24 months) galantamine therapy in patients with VaD and AD with CVD is well tolerated and associated with prolonged maintenance of cognitive function.

Erkinjuntti T, Kurz A, Small GW, Bullock R, Lilienfeld S, Damaraju CV, Anonymous00331. · Department of Clinical Neurosciences, Helsinki University Central Hospital, Helsinki, Finland. · Clin Ther. · Pubmed #12860497 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) are the most common types of dementia worldwide. Galantamine, an acetylcholinesterase inhibitor and allosteric nicotinic modulator, has shown broad clinical benefits in patients with mild to moderate dementia due to AD, probable VaD, or AD with cerebrovascular disease (CVD)-so-called mixed dementia. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profiles of galantamine 24 mg/d in patients with VaD or AD with CVD over the longer term (>6 months). METHODS: This was an open-label extension of a 6-month double-blind study of galantamine. Patients who had been randomized to receive galantamine 24 mg/d or placebo in the double-blind phase were eligible to continue open-label treatment with galantamine 24 mg/d for 6 months. The primary efficacy end point was change in cognition, based on scores on the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11). Secondary measures included changes in functional ability (as measured on the Disability Assessment for Dementia [DAD]) and behavior (as measured on the Neuropsychiatric Inventory [NPI]). Safety and tolerability were also monitored. RESULTS: Four hundred fifty-nine patients (240 men, 219 women; mean [SE] age, 75.2 [0.33] years) entered the open-label phase. Of these patients, 195 (42.5%) had a diagnosis of probable VaD, and 238 (51.9%) had a diagnosis of AD with CVD; the remainder had an inconclusive diagnosis. At month 12 of the study, improvements from baseline (the start of the double-blind phase) in ADAS-cog/11 scores were observed in both the group that received placebo during the double-blind phase (placebo/galantamine group: -0.3 point; 95% CI, -1.64 to 1.06) and the group that received galantamine during the double-blind phase (galantamine/galantamine group: -0.9 point; 95% CI, -1.73 to 0.03). Improvement in functional ability was demonstrated by statistically significant mean (SE) changes from baseline in DAD score in both the placebo/galantamine group (-7.4 [1.68]; P < or = 0.001) and the galantamine/galantamine group (-3.6 [1.33]; P < or = 0.01). There was no significant change in mean (SE) NPI scores in either group (0.2 [0.98] and 0.1 [0.70], respectively). Galantamine treatment was well tolerated. CONCLUSIONS: In these patients with VaD and AD with CVD, galantamine treatment produced similar sustained benefits in terms of maintenance of or improvement in cognition (ADAS-cog/11), functional ability (DAD), and behavior (NPI) after 12 months.

Silverman DH, Small GW. · Department of Molecular and Medical Pharmacology, School of Medicine, University of California, Los Angeles 90095-6942, USA. · Am J Psychiatry. · Pubmed #12202266 links to  free full text

This publication has no abstract.

Schneider LS, Tariot PN, Lyketsos CG, Dagerman KS, Davis KL, Davis S, Hsiao JK, Jeste DV, Katz IR, Olin JT, Pollock BG, Rabins PV, Rosenheck RA, Small GW, Lebowitz B, Lieberman JA. · Clinical Antipsychotic Trials of Intervention Effectiveness Program of the National Institute of Mental Health at the University of North Carolina, Chapel Hill, NC, USA. · Am J Geriatr Psychiatry. · Pubmed #11739062 No free full text.

Abstract: The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented.

Mega MS, Cummings JL, O'Connor SM, Dinov ID, Reback E, Felix J, Masterman DL, Phelps ME, Small GW, Toga AW. · Department of Neurology, University of California at Los Angeles School of Medicine, 90095-1769, USA. · Neuropsychiatry Neuropsychol Behav Neurol. · Pubmed #11234910 No free full text.

Abstract: OBJECTIVE: The objective of this study was to identify the relation between the cognitive benefit seen with the cholinesterase inhibitor metrifonate and changes in brain metabolism as visualized with [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET). BACKGROUND: The regional metabolic correlates of treatment with cholinesterase inhibitors are poorly understood. METHODS: Six patients with mild to moderate Alzheimer disease (AD) were evaluated before and after treatment with the long-lasting cholinesterase inhibitor metrifonate. Patients were given 60 or 80 mg of metrifonate per day (based on weight) for 6 to 12 weeks. Clinical evaluations included the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Imaging was carried out using FDG-PET. The PET studies, registered to a probabilistic anatomic atlas, were normalized across the group's mean intensity levels and subjected to voxel-by-voxel subtraction of the posttreatment minus pretreatment studies. Subvolume thresholding corrected random lobar noise to produce a three-dimensional functional significance map. RESULTS: The criteria for cognitive improvement with treatment were met for the MMSE (>2 points improvement from baseline), and the drawing subscale of the ADAS-cog was significantly improved with treatment. The three-dimensional significance map revealed a significant metabolic increase of the dorsolateral frontoparietal network on the left and bilateral temporal cortex with metrifonate treatment. CONCLUSION: The clinical benefits observed in AD with cholinesterase inhibitor therapy are associated with a metabolic increase of heteromodal cognitive and medial temporal networks.

Lavretsky H, Siddarth P, Kepe V, Ercoli LM, Miller KJ, Burggren AC, Bookheimer SY, Huang SC, Barrio JR, Small GW. · Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095-9668, USA. · Am J Geriatr Psychiatry. · Pubmed #19472439 No free full text.

Abstract: OBJECTIVES: Amyloid senile plaques and tau neurofibrillary tangles are neuropathologic hallmarks of Alzheimer disease, which may be associated with mild cognitive impairment (MCI) or mood and anxiety symptoms years before the dementia diagnosis. To address this issue, the authors obtained positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to amyloid plaques and neurofibrillary tangles, to determine whether symptoms of depression and anxiety in nondemented subjects were associated with increased FDDNP-PET binding values. METHODS: Forty-three middle-aged and elderly volunteers received clinical and FDDNP-PET assessments. Subjects were nondemented--23 of them were diagnosed with MCI and 20 were cognitively normal. Subjects with a diagnosis of major depression or an anxiety disorder were excluded. Correlations between standardized measures of depressive and anxiety symptoms and regional FDDNP binding values were calculated. RESULTS: The MCI and comparison subjects did not differ by the depression and anxiety scores. In the MCI group, depression scores correlated with lateral temporal and trait anxiety scores correlated with posterior cingulate FDDNP binding. In the comparison group, depression scores correlated with medial temporal, and trait anxiety scores correlated with medial temporal and frontal FDDNP binding. DISCUSSION: This is the first report to demonstrate a relationship between the severity of depression and anxiety symptoms and FDDNP binding values in nondemented middle age and older individuals. The results suggest a relationship between relatively mild mood symptoms and biomarkers of cerebral amyloid and tau deposition and vary according to degree of cognitive impairment. The presence of MCI may signify different pathophysiological mechanisms underlying mood and anxiety symptoms.

Ercoli LM, Siddarth P, Kepe V, Miller KJ, Huang SC, Cole GM, Lavretsky H, Bookheimer SY, Kim J, Phelps ME, Barrio JR, Small GW. · Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095-9668, USA. · Am J Geriatr Psychiatry. · Pubmed #19390297 No free full text.

Abstract: OBJECTIVE: The authors explored whether positron emission tomography (PET) with 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl) amino]-2-naphthyl} ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro, might identify homogeneous subgroups of persons in middle-aged and older persons with mild cognitive impairment (MCI) or normal cognition. PARTICIPANTS: Fifty-six subjects (MCI, N = 29; normal cognition, N = 27). MEASUREMENTS: FDDNP-PET scans were performed. Logan parametric images were produced using cerebellum as a reference region, and relative distribution volumes were obtained for regions of interest (ROIs) known to accumulate plaques and tangles in Alzheimer disease (AD). Cluster analysis was used to identify subgroups of subjects according to FDDNP signal distribution. Once the FDDNP clusters were identified, the authors then characterized the clusters also with respect to diagnosis and cognitive test performances and conducted analyses on cluster differences in these variables. RESULTS: The authors identified three FDDNP clusters: high signal in lateral temporal and posterior cingulate ROIs (high temporal-posterior cingulate HT/PC); low signal in all ROIs (low global [LG] cluster); high frontal and parietal signal with intermediate temporal and posterior cingulate signal (HF/PA). Most MCI subjects belonged to the HT/PC and HF/PA clusters, whereas most cognitively normal subjects were in the LG cluster. On cognitive tests, the HT/PC and the HF/PA clusters performed significantly worse than LG but did not significantly differ from each other. CONCLUSIONS: This approach may be useful in identifying potential high-risk imaging cluster patterns. Longitudinal follow-up would be performed to determine the association of these subgroups with diagnostic and functional outcome.

Small GW, Siddarth P, Burggren AC, Kepe V, Ercoli LM, Miller KJ, Lavretsky H, Thompson PM, Cole GM, Huang SC, Phelps ME, Bookheimer SY, Barrio JR. · Semel Institute, 760 Westwood Plaza, Ste 88-201, Los Angeles, CA 90024, USA. · Arch Gen Psychiatry. · Pubmed #19124691 links to  free full text

Abstract: CONTEXT: Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer disease that accumulate in the brains of people without dementia years before they develop dementia. Positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), which binds to plaques and tangles in vitro, demonstrate increased cerebral binding in patients with Alzheimer disease compared with cognitively intact controls. Here we investigated whether known risk factors for Alzheimer disease and dementia are associated with FDDNP-PET binding. OBJECTIVE: To determine if impaired cognitive status, older age, apolipoprotein E-4 (APOE-4) genetic risk for Alzheimer disease, family history of dementia, and less education are associated with increased regional cerebral FDDNP-PET binding. DESIGN: Cross-sectional clinical study. SETTING: A university research institute. PARTICIPANTS: Volunteer sample of 76 middle-aged and older persons without dementia (mean age, 67 years) including 36 with mild cognitive impairment. Of the 72 subjects with genetic data, 34 were APOE-4 carriers. MAIN OUTCOME MEASURES: The FDDNP-PET signal in brain regions of interest, including medial and lateral temporal, posterior cingulate, parietal, and frontal. RESULTS: For all regions studied, cognitive status was associated with increased FDDNP binding (P < .02 to .005). Older age was associated with increased lateral temporal FDDNP binding. Carriers of APOE-4 demonstrated higher frontal FDDNP binding than noncarriers. In the mild cognitive impairment group, age was associated with increased medial and lateral temporal FDDNP binding, and APOE-4 carriers had higher medial temporal binding than noncarriers. CONCLUSIONS: Impaired cognitive status, older age, and APOE-4 carrier status are associated with increased brain FDDNP-PET binding in persons without dementia, consistent with previous clinical and postmortem studies associating these risk factors with amyloid plaque and tau tangle accumulation. Stratifying subject groups according to APOE-4 carrier status, age, and cognitive status may therefore be an informative strategy in future clinical trials using FDDNP-PET.

Boxer AL, Rabinovici GD, Kepe V, Goldman J, Furst AJ, Huang SC, Baker SL, O'neil JP, Chui H, Geschwind MD, Small GW, Barrio JR, Jagust W, Miller BL. · Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94143-1207, USA. · Neurology. · Pubmed #17636066 No free full text.

Abstract: OBJECTIVE: To compare the in vivo uptake of two amyloid-binding PET agents, PIB and FDDNP, in human subjects with a prion protein (PrP) gene (PRNP) mutation that produces a clinical syndrome similar to Alzheimer disease (AD). BACKGROUND: Amyloid imaging with specific PET ligands offers great promise for early detection and differential diagnosis of AD. Genetic forms of prion disease can present with clinical features that resemble AD, and at autopsy may show deposition of mutant PrP-amyloid. FDDNP binds to PrP-amyloid in postmortem human specimens, but has not been reported in vivo in prion disease. The ability of PIB to bind PrP-amyloid is not known. METHODS: Two brothers with a 6 octapeptide repeat insertion mutation (6-OPRI) in the PRNP gene underwent clinical, structural MRI, and FDG-PET evaluations. One brother received a PIB-PET evaluation, while the other received an FDDNP-PET scan. PET results were compared with five normal subjects and five individuals with AD scanned with either agent. RESULTS: PIB uptake was similar to controls in one brother, while FDDNP uptake was intermediate between AD and controls in the other brother. CONCLUSIONS: Different amyloid-binding agents may have differential sensitivity to prion-related brain pathology. A combination of amyloid imaging agents may be useful in the diagnosis of early-onset dementia.

Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, Lavretsky H, Burggren AC, Cole GM, Vinters HV, Thompson PM, Huang SC, Satyamurthy N, Phelps ME, Barrio JR. · Department of Psychiatry and Biobehavioral Sciences and the Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at the University of California, Los Angeles, USA. · N Engl J Med. · Pubmed #17182990 links to  free full text

Abstract: BACKGROUND: Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease that accumulate in the cortical regions of the brain in persons with mild cognitive impairment who are at risk for Alzheimer's disease. Noninvasive methods to detect these abnormal proteins are potentially useful in developing surrogate markers for drug discovery and diagnostics. METHODS: We enrolled 83 volunteers with self-reported memory problems who had undergone neurologic and psychiatric evaluation and positron-emission tomography (PET). On the basis of cognitive testing, 25 volunteers were classified as having Alzheimer's disease, 28 as having mild cognitive impairment, and 30 as having no cognitive impairment (healthy controls). PET was performed after injection of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro. All subjects also underwent 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET, and 72 underwent magnetic resonance imaging (MRI). RESULTS: Global values for FDDNP-PET binding (average of the values for the temporal, parietal, posterior cingulate, and frontal regions) were lower in the control group than in the group with mild cognitive impairment (P<0.001), and the values for binding in the group with mild cognitive impairment were lower than in the group with Alzheimer's disease (P<0.001). FDDNP-PET binding differentiated among the diagnostic groups better than did metabolism on FDG-PET or volume on MRI. CONCLUSIONS: FDDNP-PET scanning can differentiate persons with mild cognitive impairment from those with Alzheimer's disease and those with no cognitive impairment. This technique is potentially useful as a noninvasive method to determine regional cerebral patterns of amyloid plaques and tau neurofibrillary tangles.

Lin PI, Martin ER, Bronson PG, Browning-Large C, Small GW, Schmechel DE, Welsh-Bohmer KA, Haines JL, Gilbert JR, Pericak-Vance MA. · Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. · Neurology. · Pubmed #16832079 No free full text.

Abstract: BACKGROUND: Previous linkage studies have shown that chromosome 12 harbors susceptibility genes for late-onset Alzheimer disease (LOAD). However, association studies of several candidate genes on this chromosome region have produced ambiguous results. A recent study reported the association between the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene on chromosome 12p and the risk of LOAD. METHODS: The authors conducted family-based and case-control association studies in two independent LOAD data sets on 12 single-nucleotide polymorphisms (SNPs) in the GAPD gene and its paralogs. RESULTS: No association was found of the GAPD gene with LOAD in the family-based data set, but marginal evidence of association was seen in the later-onset subgroup when age at onset was stratified. The SNP rs2029721 in one GAPD pseudogene was also found to be associated with risk for LOAD in the unrelated case-control data set (p = 0.003). CONCLUSIONS: The GAPD gene and its pseudogene may play a role in the development of late-onset Alzheimer disease. However, the effect, if any, is likely to be limited.

Kepe V, Barrio JR, Huang SC, Ercoli L, Siddarth P, Shoghi-Jadid K, Cole GM, Satyamurthy N, Cummings JL, Small GW, Phelps ME. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. · Proc Natl Acad Sci U S A. · Pubmed #16407119 links to  free full text

Abstract: 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT(1A)) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT(1A) receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 +/- 0.07; ADs 1.18 +/- 0.26) and also in raphe nuclei (controls 0.63 +/- 0.09; ADs 0.37 +/- 0.20). When volume losses are included, 5-HT(1A) losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT(1A) receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT(1A) receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 +/- 0.04, ADs 0.72 +/- 0.04; posterior cingulate gyrus: controls 1.05 +/- 0.09, ADs 0.79 +/- 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.