Alzheimer Disease: Gilman S

Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M, Anonymous00150. · Dementia Research Centre, Institute of Neurology, London, UK. · Neurology. · Pubmed #15883317 No free full text.

Abstract: BACKGROUND: Alzheimer disease (AD) is characterized by progressive cerebral atrophy that may be measured using MRI. Reported are MRI findings of a Phase IIa immunotherapy trial in AD prematurely terminated owing to meningoencephalitis in a subset of patients. OBJECTIVE: To assess cerebral volume changes in patients immunized with AN1792 (beta-amyloid [Abeta] 1 to 42) who were antibody responders (anti-AN1792 IgG titer of > or =1:2,200) compared with placebo patients. METHODS: This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 mug plus QS-21 50 mug included 372 patients with probable AD. Patients received one to three injections of AN1792/QS-21 or saline and were assessed for 12 months. Volumetric MRI was performed pre dose and at month 12 or early termination. Brain, ventricular, and hippocampal volume changes were measured from registered scan pairs. RESULTS: Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 +/- 1.98 vs 2.04 +/- 1.74%; p = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 +/- 0.75 vs 0.48 +/- 0.40%; p < 0.001), and a nonsignificant greater hippocampal volume decrease (3.78 +/- 2.63 vs 2.86 +/- 3.19%; p = 0.124) than placebo patients (n = 57). Increased losses in brain volume were not reflected in worsening cognitive performance; a composite z score across a Neuropsychological Test Battery showed differences favoring antibody responders over placebo (0.03 +/- 0.39 vs -0.24 +/- 0.45; p = 0.008). CONCLUSIONS: A dissociation between brain volume loss and cognitive function was observed in AN1792/QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts.

Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM, Anonymous00149. · Department of Neurology, University of Michigan, 300 N. Ingalls 3D15, Ann Arbor, MI 48109-0489, USA. · Neurology. · Pubmed #15883316 No free full text.

Abstract: BACKGROUND: AN1792 (beta-amyloid [Abeta]1-42) immunization reduces Abeta plaque burden and preserves cognitive function in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients. METHODS: This randomized, multicenter, placebo-controlled, double-blind trial of IM AN1792 225 microg plus the adjuvant QS-21 50 microg (300 patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-Mental State Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety and tolerability were evaluated, and pilot efficacy (AD Assessment Scale-Cognitive Subscale [ADAS-Cog], MRI, neuropsychological test battery [NTB], CSF tau, and Abeta42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer > or = 1:2,200). RESULTS: Following reports of meningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274 patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups for ADAS-Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical Global Impression of Change, but analyses of the z-score composite across the NTB revealed differences favoring antibody responders (0.03 +/- 0.37 vs -0.20 +/- 0.45; p = 0.020). In the small subset of subjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; p < 0.001). CONCLUSION: Although interrupted, this trial provides an indication that Abeta immunotherapy may be useful in Alzheimer disease.

Gilman S, Koeppe RA, Little R, An H, Junck L, Giordani B, Persad C, Heumann M, Wernette K. · Department of Neurology, University of Michigan, Ann Arbor, MI 48109-0489, USA. · Exp Neurol. · Pubmed #15629765 No free full text.

Abstract: We compared the relative utility of neuropsychological testing and positron emission tomography (PET) with [18F]fluorodeoxyglucose ([18F]FDG) in differentiating Alzheimer's disease (AD) from dementia with Lewy bodies (DLB). We studied 25 patients with AD, 20 with DLB, and 19 normal elderly controls. There was no difference between patient groups for MMSE, confrontational naming, or verbal learning. The DLB group was significantly more impaired than the AD group for verbal fluency, and the AD group was significantly more impaired than the DLB group for verbal delayed recall. The DLB group had greater difficulty than the AD group on a visual discrimination task that does not require motor functioning, but the difference did not reach significance. Family ratings of motor functioning suggested significantly greater impairment in DLB patients than in AD patients. PET studies revealed significantly lower local cerebral metabolic rates for glucose (lCMRglc) for visual cortex (Brodmann areas 17, 18, and 19) in the DLB than the AD group, but no differences for other regions commonly affected in AD, including posterior cingulate, superior parietal lobe, lateral temporal lobe, and the prefrontal region. Motor ratings were significantly correlated with lCMRglc in all areas of cerebral cortex, including Brodmann areas 17, 18, and 19. The results demonstrate a similar profile of cerebral hypometabolism in the two patient groups except in the visual cortex, where the DLB group shows markedly lower lCMRglc than the AD group. Neuropsychological testing also differentiates the groups, and family ratings of motor functioning are as robust as PET in these later stages of the disorders.

Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. · Federation of Neurology, CHU Pellegrin, Bordeaux, France. · Neurology. · Pubmed #12847155 No free full text.

Abstract: BACKGROUND: AD is characterized by cerebral deposition of beta-amyloid plaques with amyloid beta-peptide (Abeta) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Abeta42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Abeta42 (AN1792) with QS-21 as adjuvant. METHODS: Three hundred seventy-two patients with mild to moderate AD were randomized to receive IM injections of AN1792 or placebo (4:1) at baseline and at months 1, 3, 6, 9, and 12 in a multicenter Phase II safety, tolerability, and pilot efficacy study. Dosing was terminated after four early reports of meningoencephalitis, but follow-up continued. The study remains blinded, and further results will be reported after its termination. RESULTS: Symptoms and laboratory findings consistent with meningoencephalitis occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo (p = 0.020). Sixteen of the 18 had received two doses, one had received one dose, and one had received three doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Abeta42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas six remain with disabling cognitive or neurologic sequelae. All 18 patients remain alive to date (December 31, 2002), 6 months to >1 year after symptom onset. CONCLUSIONS: Postvaccination meningoencephalitis occurred without clear relation to serum anti-Abeta42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Abeta immunotherapy for AD.

Khachaturian ZS, Snyder PJ, Doody R, Aisen P, Comer M, Dwyer J, Frank RA, Holzapfel A, Khachaturian AS, Korczyn AD, Roses A, Simpkins JW, Schneider LS, Albert MS, Egge R, Deves A, Ferris S, Greenberg BD, Johnson C, Kukull WA, Poirier J, Schenk D, Thies W, Gauthier S, Gilman S, Bernick C, Cummings JL, Fillit H, Grundman M, Kaye J, Mucke L, Reisberg B, Sano M, Pickeral O, Petersen RC, Mohs RC, Carrillo M, Corey-Bloom JP, Foster NL, Jacobsen S, Lee V, Potter WZ, Sabbagh MN, Salmon D, Trojanowski JQ, Wexler N, Bain LJ. · Lou Ruvo Brain Institute, Las Vegas, NV 89106, USA. · Alzheimers Dement. · Pubmed #19328434 No free full text.

Abstract: This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Koeppe RA, Gilman S, Junck L, Wernette K, Frey KA. · Division of Nuclear Medicine, Department of Radiology, The University of Michigan, Ann Arbor, MI, USA. · Alzheimers Dement. · Pubmed #18632004 No free full text.

Abstract: BACKGROUND: Several progressive neurologic disorders begin with cognitive decline or parkinsonism, notably Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). We used positron emission tomography (PET) in attempts to differentiate these disorders. METHODS: We performed PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) to examine blood-to-brain ligand transport (K(1)) and striatal monoaminergic presynaptic binding (distribution volume [DV]) in 25 DLB, 30 PD, and 25 AD patients and 57 elderly controls (NC). RESULTS: [11C]DTBZ DV was decreased significantly in caudate nucleus, anterior putamen, and posterior putamen in DLB and PD compared with AD and NC. DLB and PD groups showed an anterior-to-posterior gradient of binding loss relative to NC, least in caudate nucleus and largest in posterior putamen. The gradient was significantly steeper in PD than DLB. Both PD and DLB showed significantly greater interhemispheric striatal binding asymmetry than NC, and PD had greater asymmetry than DLB. Cerebral cortical [11C]DTBZ K(1) was decreased diffusely by 4% to 8% in PD. Larger K(1) deficits occurred in AD and DLB temporoparietal and prefrontal association cortices and posterior cingulate cortex. Greater reduction of K(1) occurred in occipital cortex in DLB than AD. Receiver operating characteristic curve analyses distinguished DLB from AD more effectively on the basis of striatal DV than occipital K(1) and distinguished DLB from PD more effectively on the basis of cerebral cortical K(1) than striatal DV patterns. Overall, 90% of cases were properly classified by combining these measures. CONCLUSIONS: PET with [11C]DTBZ can differentiate DLB from both PD and AD in a single neuroimaging study.

Koeppe RA, Gilman S, Joshi A, Liu S, Little R, Junck L, Heumann M, Frey KA, Albin RL. · Division of Nuclear Medicine, Department of Radiology, University of Michigan School of Medicine, 3480 Kresge III, Box 0552, Ann Arbor, MI 48109, USA. · J Nucl Med. · Pubmed #15937303 links to  free full text

Abstract: Accurate, early differentiation of dementias will become increasingly important as new therapies are introduced. Differential diagnosis by standard clinical criteria has limited accuracy. PET offers the potential to increase diagnostic accuracy. (18)F-FDG studies detect metabolic abnormalities in demented patients, but with limited specificity. PET also offers the ability to quantify other biochemical markers that can yield additional useful diagnostic information. We demonstrate that (+)-(11)C-dihydrotetrabenazine ((11)C-DTBZ) studies, which provide an index of nigrostriatal terminal density (distribution volume; DV), also provide a measure of transport (K(1)) that produces information comparable to the metabolic measure of (18)F-FDG. METHODS: Fifty-two patients and 19 control subjects underwent both (11)C-DTBZ and (18)F-FDG PET scans. Seven had the clinical diagnosis of frontotemporal dementia (FTD), 25 had Alzheimer's disease (AD), and 20 had dementia with Lewy bodies (DLB). DTBZ scans provided maps of K(1) and DV, whereas (18)F-FDG scans provided maps of glucose metabolism. Correlation analyses were performed between the different PET measures both within and across subjects. Discriminant analysis using logistic regression compared the performance of (11)C-DTBZ K(1) and (18)F-FDG in differentiating subject groups. Three experienced PET researchers participated in an interrater reliability study using both (11)C-DTBZ K(1) and (18)F-FDG images. RESULTS: Within-subject correspondence between (11)C-DTBZ K(1) and (18)F-FDG measures was high, with correlations averaging 0.92. Correlations between the (11)C-DTBZ DV and either K(1) or (18)F-FDG were far lower, averaging 0.37 and 0.31, respectively, indicating the much higher degree of similarity in information provided by K(1) and (18)F-FDG compared with the very different information provided by (11)C-DTBZ DV. Discriminant analysis demonstrated that (11)C-DTBZ K(1) and (18)F-FDG yielded similar levels of sensitivity and specificity for differentiating the subjects in this study. Including (11)C-DTBZ DV in addition to either K(1) or (18)F-FDG improved discrimination between groups. The raters classified PET scans nearly equivalently using K(1) and (18)F-FDG. CONCLUSION: Multiple PET measures, whether 2 parameters from a single PET study such as (11)C-DTBZ K(1) and DV, or 2 parameters from different studies such as (18)F-FDG and (11)C-DTBZ DV, offer complementary information useful for diagnosing dementias. K(1) and DV images generated from a single (11)C-DTBZ scan provide as much diagnostic information as 2-scan studies using both (11)C-DTBZ and (18)F-FDG.

Gilman S, Koeppe RA, Little R, An H, Junck L, Giordani B, Persad C, Heumann M, Wernette K. · Department of Neurology, University of Michigan, Ann Arbor, MI 48109-0316, USA. · Ann Neurol. · Pubmed #15174011 No free full text.

Abstract: We used positron emission tomography (PET) with (+)-[(11)C]dihydrotetrabenazine ([+]-[(11)C]DTBZ) to examine striatal monoaminergic presynaptic terminal density in 20 patients with dementia with Lewy bodies (DLB), 25 with Alzheimer's disease (AD), and 19 normal elderly controls. Six DLB patients developed parkinsonism at least 1 year before dementia (DLB/PD) and 14 developed dementia before parkinsonism or at about the same time (DLB/AD). Striatal mean binding potential was decreased by 62 to 77% in the DLB/PD group and 45 to 67% in the DLB/AD compared to AD and control. Binding was lower in the DLB/PD group than the DLB/AD, but the differences reached only marginal significance in the caudate nucleus. No differences were found between AD and control groups though a few AD patients had binding values below the range of the controls. Subsequent neuropathological examination in one AD patient revealed both AD and DLB changes despite the absence of clinical parkinsonism. Both DLB groups had an anterior to posterior binding deficit gradient relative to controls, largest in posterior putamen, smaller in anterior putamen, smallest in caudate nucleus. The DLB/AD group showed significant binding asymmetry only in posterior putamen. We conclude that PET with (+)-[(11)C]DTBZ differentiates DLB from AD, and decreased binding in AD may indicate subclinical DLB pathology in addition to AD pathology.

Grundman M, Gilman S, Black RS, Fox NC, Koller M. · No affiliation provided · Neurology. · Pubmed #18725601 No free full text.

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Schenk DB, Gilman S. · No affiliation provided · Neurology. · Pubmed #16769971 No free full text.

This publication has no abstract.