Alzheimer Disease: Sabbagh MN

Connor DJ, Sabbagh MN, Cummings JL. · Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ, USA. · Alzheimers Dement. · Pubmed #19012863 No free full text.

Abstract: BACKGROUND: The Neuropsychiatric Inventory (NPI) is commonly used in dementia trials to quantify and qualitate changes in psychiatric symptoms. METHODS: A questionnaire was administered to clinical trial raters to assess whether they were being trained to administer and score the NPI differently between clinical trial protocols. RESULTS: Responses to the survey indicated that there are differences between clinical trials protocols in how the instrument is administered and scored. DISCUSSION: Clarification of administration and scoring rules are provided, including the behavioral sampling period, whether premorbid characteristics are considered, and what behaviors are considered in rating frequency, severity, and caregiver distress.

Griffin-Pierce T, Silverberg N, Connor D, Jim M, Peters J, Kaszniak A, Sabbagh MN. · Department of Anthropology, University of Arizona, Tucson, AZ, USA. · Alzheimers Dement. · Pubmed #18631981 No free full text.

Abstract: Little is known about Alzheimer's disease (AD) and related neurodegenerative diseases in American Indian (AI) populations. To provide appropriate health care to elder AIs, whose population is expected to increase dramatically during the next 50 years, it is imperative to attain a better understanding of the interaction of culture and disease in this underserved population. Raising awareness in the AI population regarding the nature of dementia as it compares to normal aging and the development of culturally appropriate instruments to detect and stage AD are essential for future health care efforts. Barriers restricting clinical service to this population include historical factors relating to access to health care, cultural beliefs regarding aging, demographic diversity of the population, competing epidemiologic risk factors, and lack of proper assessment tools for clinicians.

Quinn J, Sabbagh MN. · No affiliation provided · Neurology. · Pubmed #18606962 No free full text.

This publication has no abstract.

Jacobson SA, Sabbagh MN. · Research Cleo Roberts Center for Clinical Research, Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ 85351, USA. · Expert Opin Drug Metab Toxicol. · Pubmed #18798705 No free full text.

Abstract: BACKGROUND: There is substantial evidence from preclinical studies that cholinesterase inhibitors affect basic processes that have been implicated in Alzheimer's disease (AD) pathogenesis, suggesting that these drugs should have both disease-modifying and neuroprotective effects in humans. The evidence seems to be strongest in relation to donepezil, which is the focus of this review. OBJECTIVE: To summarize the preclinical literature regarding the effects of donepezil on cellular and molecular processes underlying AD. Second, to suggest reasons for the apparent disparity between robust preclinical effects and modest clinical effects of this drug and others in its class. METHODS: Articles retrieved from PubMed searches were critically reviewed and selected for relevance to the current topic. RESULTS/CONCLUSION: Donepezil has numerous cellular and molecular effects that should influence AD progression.

Sabbagh MN, Richardson S, Relkin N. · Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ, USA. Marwan. · Alzheimers Dement. · Pubmed #18631986 No free full text.

Abstract: The era of disease modification as a therapeutic option for Alzheimer's disease (AD) is upon us. With dozens of novel drugs in development, there is more need than ever to develop biomarkers that distinguish normal aging from AD and AD from other dementias, track changes over time as disease progresses, and respond to interventions. Future trials will need to weight biomarker outcomes equal to cognitive outcomes especially when the biomarkers are linked to specific mechanisms, such as changes to beta amyloid (Abeta) deposition or brain volume. Since the advent of donepezil as a treatment for AD, new mechanisms of action of this molecule have been discovered. In this perspective, we review trial design and discuss the use of biomarkers by using lessons learned from previous trials conducted with cholinergic therapy.

Thind K, Sabbagh MN. · The Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ 85351, USA. · Panminerva Med. · Pubmed #18091671 No free full text.

Abstract: Although Alzheimer's disease (AD) has been investigated for more than 100 years, it was not until the 60s that quantitative measures of the disease progression and severity in relation to function and neuropathology were made by Blessed and his colleagues. With the increasing understanding of the pathological changes of AD that take place, there is growing interest in identifying which pathological marker most reliably predicts the dementia and the cognitive profile. Markers of pathology that have been investigated include senile plaques, neurofibrillary tangles, synaptic loss, and neurochemical changes. Many clinical measures have been evaluated as well including Clinical Dementia Rating, Mini Mental State Examination, and Functional Assessment Staging as ways of both predicting the presence of pathological changes of AD as well as correlating with the specific measures of pathology. Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress through AD. This review will summarize evidence of which neuropathological change correlates robustly with cognitive decline and which cognitive index predicts pathological changes in AD. In general, tangles and synaptic loss are better correlates of cognitive decline and correlate better.

Sabbagh MN, Lukas RJ, Sparks DL, Reid RT. · The Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ 85351, USA. · J Alzheimers Dis. · Pubmed #12446934 No free full text.

Abstract: Cholinergic dysfunction is one of the cornerstones of Alzheimer's disease (AD) pathology. Reviewed here is evidence evaluating relationships between smoking, nicotine exposure, nicotinic cholinergic signaling, and AD. Epidemiological studies initially indicating a lower incidence of AD in smokers now suggest conflicting results. Clinicopathological findings also are mixed as to how smoking behavior affects manifestation of AD markers. Studies that show nicotine-induced increases in nicotinic acetylcholine receptors (nAChR) and protection against age-related nAChR decline contrast, perhaps in a functionally relevant way, to losses of nAChR in AD. Although epidemiological, clinicopathological, and functional studies in humans do not present a cohesive picture, much in vitro data suggests neuroprotective properties of nicotine when used in models of neurodegenerative disorders. Studies of nicotine and nicotinic agonist effects on cognitive function in the non-demented and in AD are not compelling. More work is needed to ascertain whether acute or repetitive activation of nAChR with acute or intermittent exposure to nicotine or the persistent inactivation of nAChR with chronic nicotine exposure is a therapeutic objective and/or explains any pro-cognitive effects of those drugs. Other studies show complex interactions between nAChR, nicotinic agonists, and agents implicated in AD etiology. Thus, while controversies still exist, ongoing research is illuminating how nicotinic receptor changes and functions may be relevant to clinical, pathological and neurochemical changes that occur in AD.

Sparks DL, Kryscio RJ, Sabbagh MN, Connor DJ, Sparks LM, Liebsack C. · Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City AZ, USA. · Curr Alzheimer Res. · Pubmed #18690839 No free full text.

Abstract: Statins have been reported to reduce the risk and be of benefit in the treatment of Alzheimer's disease (AD). Individuals enrolling in the randomized controlled trial testing two anti-inflammatory agents for primary prevention of AD (Alzheimer's Disease Anti-inflammatory Prevention Trial; ADAPT) were allowed the elective use of statins. Our objective was to assess whether statin use is associated with reduced risk of incident AD among ADAPT participants. In primary ADAPT study , participants were assessed annually for cholesterol levels and cognitive status. If impairment in cognition was noted, a dementia evaluation was performed. Onset of mild cognitive impairment (MCI) or AD was taken as the date of this evaluation. Time-to-onset was analyzed in six-month intervals following enrollment. Without knowledge of primary treatment assignment in ADAPT, participants were grouped by their self-reported use of lipid-lowering agents (LLA). In the current ancillary ADAPT study we found that elective statin use was associated with significantly reduced risk of incident AD after adjustment for age, gender, education and Apolipoprotein E (ApoE) genotype. The findings were similar when comparing all LLA use (statin and non-statin LLA) to non-LLA use. Cholesterol levels were lower among statin users compared with non-LLA users, but the MMSE scores were equivalent. The data suggest that statin therapy may be of benefit in reducing the risk of AD.

Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Petanceska S, Browne P, Wassar D, Johnson-Traver S, Lochhead J, Ziolkowski C. · SunHealth Research Institute, USA. · Curr Alzheimer Res. · Pubmed #15974900 No free full text.

Abstract: Cholesterol-induced production of amyloid beta (Abeta) as a putative neurotoxin in Alzheimer's disease (AD), along with epidemiological evidence, suggests that statin drugs may provide benefit in treatment of the disorder. We tested the effect of once daily atorvastatin calcium (80 mg; two 40 mg tablets) on cognitive and/or behavioral decline in patients with mild-to-moderate AD. The study was designed as a pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to study medication employing last-observation-carried-forward (LOCF) ANCOVA as the primary statistical method of assessment. Alternate statistical methods were employed to further explore the effect of atorvastatin treatment on progression of deterioration. Of the 98 individuals with mild-to-moderate AD (Mini-Mental State Examination score of 12-28) providing Informed Consent, 71 were eligible for randomization, 67 were randomized and 63 completed the 3-month visit and were statistically evaluable. The primary outcome measures were change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) performance and the Clinical Global Impression of Change (CGIC). Secondary outcome measures included the MMSE, Geriatric Depression Scale (GDS), the Neuropsychiatric Inventory (NPI) and the ADCS Activities of Daily Living inventory (ADCS-ADL). Tertiary outcome measures included levels of total circulating cholesterol, LDL and VLDL, and circulating activity of the free radical scavenger enzymes superoxide dismutase (SOD) and glutathione peroxidase (GpX). Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared to placebo, but did not elicit a difference in circulating SOD or GpX activities. The observed beneficial clinical effect reached significance for the GDS (p = 0.040) and the ADAS-cog at 6 months (p = 0.003), was all but significant for the ADAS-cog (p = 0.055) at 12 months, and was of marginal significance for the CGIC (p = 0.073) and NPI (p = 0.071) at 12 months when employing the primary statistical approach (ANCOVA with LOCF). Application of repeated measures ANCOVA statistics revealed the difference was significant for the CGIC and marginally significant for the ADAS-cog, but not significant for the other clinical indices. This evaluation indicated significant time-by-treatment interactions (altered progression) for the ADAS-cog and MMSE, but not the CGIC. Application of random intercept regression analysis revealed a significant difference for the CGIC, ADAS-cog and MMSE. Regression analysis also indicated that atorvastatin produced change in the slope of deterioration on the MMSE. Accordingly, atorvastatin therapy may be an effective treatment and may slow the progression of AD among mild-to-moderately affected patients.

Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. · Author Affiliations: Sun Health Research Institute, Sun City, AZ 85351, USA. · Arch Neurol. · Pubmed #15883262 links to  free full text

Abstract: BACKGROUND: Laboratory evidence of cholesterol-induced production of amyloid beta as a putative neurotoxin precipitating Alzheimer disease, along with epidemiological evidence, suggests that cholesterol-lowering statin drugs may favorably influence the progression of the disorder. OBJECTIVE: To determine if treatment with atorvastatin calcium affects the cognitive and/or behavioral decline in patients with mild to moderate Alzheimer disease. DESIGN: Pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40-mg tablets) or placebo using last observation carried forward analysis of covariance as the primary method of statistical assessment. PARTICIPANTS: Individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination score of 12-28) were recruited. Of the 98 participants providing informed consent, 71 were eligible for randomization, 67 were randomized, and 63 subjects completed the 3-month visit and were considered evaluable. MAIN OUTCOME MEASURES: The primary outcome measures were change in Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Global Impression of Change Scale scores. The secondary outcome measures included scores on the Mini-Mental State Examination, Geriatric Depression Scale, the Neuropsychiatric Inventory Scale, and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. The tertiary outcome measures included total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels. RESULTS: Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared with placebo. This beneficial effect reached significance for the Geriatric Depression Scale and the Alzheimer's Disease Assessment Scale-cognitive subscale at 6 months and was significant at the level of a trend for the Alzheimer's Disease Assessment Scale-cognitive subscale, Clinical Global Impression of Change Scale, and Neuropsychiatric Inventory Scale at 12 months assessed by analysis of covariance with last observation carried forward. CONCLUSION: Atorvastatin treatment may be of some clinical benefit and could be established as an effective therapy for Alzheimer disease if the current findings are substantiated by a much larger multicenter trial.

Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R, Eschbacher J, White CL, Akiyama H, Caviness J, Shill HA, Connor DJ, Sabbagh MN, Walker DG, Anonymous00049. · Sun Health Research Institute, Sun City, AZ 85351, USA. · Acta Neuropathol. · Pubmed #19399512 No free full text.

Abstract: The two current major staging systems in use for Lewy body disorders fail to classify up to 50% of subjects. Both systems do not allow for large numbers of subjects who have Lewy-type alpha-synucleinopathy (LTS) confined to the olfactory bulb or who pass through a limbic-predominant pathway that at least initially bypasses the brainstem. The results of the current study, based on examination of a standard set of ten brain regions from 417 subjects stained immunohistochemically for alpha-synuclein, suggest a new staging system that, in this study, allows for the classification of all subjects with Lewy body disorders. The autopsied subjects included elderly subjects with Parkinson's disease, dementia with Lewy bodies, incidental Lewy body disease and Alzheimer's disease with Lewy bodies, as well as comparison groups without Lewy bodies. All subjects were classifiable into one of the following stages: I. Olfactory Bulb Only; IIa Brainstem Predominant; IIb Limbic Predominant; III Brainstem and Limbic; IV Neocortical. Progression of subjects through these stages was accompanied by a generally stepwise worsening in terms of striatal tyrosine hydroxylase concentration, substantia nigra pigmented neuron loss score, Mini Mental State Examination score and score on the Unified Parkinson's Disease Rating Scale Part 3. Additionally, there were significant correlations between these measures and LTS density scores. It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases.

Sabbagh MN, Tariot PN. · Cleo Roberts Center, Banner Sun Health Research Institute, Sun City, AZ, USA. · Alzheimers Dement. · Pubmed #19328441 No free full text.

This publication has no abstract.

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.

Ignatov I, Belden C, Jacobson S, Connor D, Sabbagh MN. · The Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ, USA. · J Alzheimers Dis. · Pubmed #19158419 No free full text.

Abstract: The objective of this study was to describe a case of Alzheimer's disease in an ApoE epsilon2/epsilon2 homozygote. ApoE epsilon2/epsilon2 is the rarest of the apolipoprotein E genotypes, representing only 1.4% of the population. There is only one case reported in the literature of a nonagenarian with minimal cognitive changes whose brain showed AD pathology on postmortem study. Here we report an 87-year-old ApoE epsilon2/epsilon2 female who meets clinical criteria for Alzheimer's disease, with confirmation from neuropsychological testing and PET scan. Clinical course is typical for Alzheimer's disease with decline on the Mini-Mental Status Examination from a score of 25 to 19 over 3.5 years. The patient is currently treated with donepezil and memantine. In conclusion, a clinically confirmed case of Alzheimer's disease is rare in Apo E2 homozygotes but can occur.

Roher AE, Esh CL, Kokjohn TA, Castaño EM, Van Vickle GD, Kalback WM, Patton RL, Luehrs DC, Daugs ID, Kuo YM, Emmerling MR, Soares H, Quinn JF, Kaye J, Connor DJ, Silverberg NB, Adler CH, Seward JD, Beach TG, Sabbagh MN. · The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, AZ, USA. · Alzheimers Dement. · Pubmed #19118806 No free full text.

Abstract: BACKGROUND: We evaluated the amounts of amyloid beta (Abeta)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Abeta plasma levels and Alzheimer's disease (AD) pathology. METHODS: Amyloid beta levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects. RESULTS: Plasma Abeta levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Abeta40 than disease-free vessels. Inactivated platelets contained more Abeta peptides than activated ones. Substantially more Abeta was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Abeta. CONCLUSIONS: Efforts to use plasma levels of Abeta peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Abeta values is also due in part to the ability of Abeta to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Abeta plasma levels. Furthermore, the long-range impact of Abeta immunotherapy on peripheral Abeta sources should also be considered.

Connor DJ, Sabbagh MN. · Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ 85351, USA. · J Alzheimers Dis. · Pubmed #18997299 No free full text.

Abstract: The Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) is the most commonly used primary outcome instrument in clinical trials for treatments of dementia. Variations in forms, administration procedures and scoring rules, along with rater turnover and intra-rater drift may decrease the reliability of the instrument. A survey of possible variations in the ADAS-Cog was administered to 26 volunteer raters at a clinical trials meeting. Results indicate notable protocol variations in the forms used, administration procedures, and scoring rules. Since change over time is used to determine treatment effect in clinical trials, standardizing the instrument's ambiguities and addressing common problems will greatly increase the instrument's reliability and thereby enhance its sensitivity to treatment effects.

Beach TG, White CL, Hladik CL, Sabbagh MN, Connor DJ, Shill HA, Sue LI, Sasse J, Bachalakuri J, Henry-Watson J, Akiyama H, Adler CH, Anonymous00063. · Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. · Acta Neuropathol. · Pubmed #18982334 No free full text.

Abstract: Involvement of the olfactory bulb by Lewy-type alpha-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical alpha-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included alpha-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson's Disease Rating Scale (Spearman R -0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

Sabbagh MN. · The Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ, USA. · Alzheimers Dement. · Pubmed #18631965 links to  free full text

This publication has no abstract.

Shill HA, Adler CH, Sabbagh MN, Connor DJ, Caviness JN, Hentz JG, Beach TG. · Sun Health Research Institute, Sun City, AZ, USA. · Neurology. · Pubmed #18413570 No free full text.

Abstract: OBJECTIVE: To assess pathologic changes in prospectively characterized subjects with essential tremor (ET). METHODS: Subjects enrolled in the Sun Health Research Institute Brain and Body Donation Program were examined annually by a movement disorders neurologist, and semiannually by a behavioral neurologist and neuropsychologist. Twenty-four subjects without a prior diagnosis of dementia or other major movement disorder met clinical criteria for ET and came to autopsy. Subjects with mild cognitive impairment (n = 3) were included. These subjects were compared with 21 controls. Brains were examined postmortem according to standardized protocols for assessment of age-related changes and specific pathologic conditions (e.g., Parkinson disease, Alzheimer disease). RESULTS: Subjects had a mean age of 86.2 years and a mean duration of tremor of 11.1 years. Seven subjects had evidence for cerebellar pathology (Purkinje cell loss, cerebellar cortical sclerosis, and proliferation of Bergmann glia). Pigmented neurons were qualitatively depleted in the locus ceruleus in eight subjects and in the substantia nigra in five subjects. Of these, three had Lewy bodies, one subject had brainstem predominant disease, and two had limbic stage. Three subjects had a nonspecific cerebral tauopathy and another met pathologic criteria for progressive supranuclear palsy. However, when compared with controls, only changes in the locus ceruleus and gliosis of the cerebellum remained significant findings. CONCLUSIONS: This study supports previous findings of heterogenous pathology in essential tremor (ET). There is an increased frequency of cerebellar gliosis and locus ceruleus depletion. We did not find an increased incidence of Lewy bodies in subjects with ET.

Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T. · Satoris, Inc., 2686 Middlefield Road, Suite E, Redwood City, California 94063, USA. · Nat Med. · Pubmed #17934472 No free full text.

Abstract: A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

Sabbagh MN, Lahti T, Connor DJ, Caviness JN, Shill H, Vedders L, Mahant P, Samanta J, Burns RS, Evidente VG, Driver-Dunckley E, Reisberg B, Bircea S, Adler CH. · The Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ 85351, USA. · Dement Geriatr Cogn Disord. · Pubmed #17851237 No free full text.

Abstract: BACKGROUND/AIMS: Previously we have shown that functional declines in Parkinson's disease (PD) and Alzheimer's disease (AD) correlate to global measures of cognitive decline. We now determine if the correlation between cognitive impairment and functional ability in PD is similar to that in AD using individual cognitive measures. METHODS: 93 PD subjects and 124 AD/MCI subjects underwent the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and a neuropsychological battery. RESULTS: In PD subjects, the FAST and GDS correlated significantly with Rey Auditory Verbal Learning Test (AVLT), Controlled Oral Word Association (COWA), Animal Fluency, and Stroop but not with Clock Draw or Judgment Line Orientation (JLO). In AD/MCI subjects, FAST and GDS correlated with all neuropsychological components except Stroop. In the AD/MCI group, the UPDRS significantly correlated with the FAST, GDS, MMSE, and all neuropsychological parameters except the Stroop. In the PD group, the motor UPDRS significantly correlated significantly with FAST, GDS, MMSE and all neuropsychological parameters except Digit Span, Stroop, Clock Draw and JLO. CONCLUSIONS: Similar to AD, functional decline in PD correlates with multiple measures of cognitive impairment. Some differences between PD and AD may be explained by the influence of motor disability and declines in visuospatial function in PD.

Sabbagh MN, Shah F, Reid RT, Sue L, Connor DJ, Peterson LK, Beach TG. · Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun City, AZ 85351, USA. · Arch Neurol. · Pubmed #17172618 links to  free full text

Abstract: BACKGROUND: Neurochemical and pathologic studies show that mild cognitive impairment (MCI) is frequently a transitional state between normal aging and Alzheimer disease (AD). Neuropathologic sample sizes have been limited because relatively few individuals with MCI die before dementia develops. Decreased neocortical nicotinic receptor binding is characteristic of AD but has not been investigated in subjects with MCI. OBJECTIVE: To assess nicotinic receptor binding and pathologic differences in control subjects with no dementia (ND) and in subjects with clinically and pathologically described MCI or Alzheimer disease. DESIGN: This was a clinicopathologic analysis. Subjects with ND had no demonstrable cognitive or functional impairment. Subjects with MCI met Petersen clinical criteria for single- or multiple-domain amnestic MCI and died before the disorder progressed to AD. Subjects with AD met National Institute for Neurological Diseases and Stroke/Alzheimer's Disease and Related Disorders Association clinical criteria for AD. All subjects underwent a complete diagnostic and semiquantitative neuropathologic examination. Data were examined after both clinical and histopathologic classification of subjects. SETTING: Sun Health Research Institute Brain Donation Program, and Arizona Alzheimer Disease Center. PARTICIPANTS: Twenty-one control subjects with ND, 8 subjects with MCI, and 70 subjects with AD, prospectively followed up to autopsy. MAIN OUTCOME MEASURES: Nicotinic acetylcholine receptor binding value, total tangle density, total plaque density, and Braak stage. RESULTS: At the last examination before death, subjects with AD were significantly younger, less educated, and more cognitively and globally impaired compared with subjects with ND. When categorized by clinical diagnosis, MCI was always intermediate between ND and AD. On the whole, MCI was pathologically intermediate between ND and AD for senile plaque density, neurofibrillary tangle density, and Braak stage, but some subjects with MCI lacked neuritic plaques entirely. Binding for nicotinic acetylcholine receptors did not differ between the ND and MCI groups, but it was significantly less in the AD group. CONCLUSIONS: Most MCI may be considered a transitional state between ND and AD clinically and neuropathologically, but in some MCI cases there is lack of neuritic plaques, and, therefore, it cannot be considered early AD. Nicotinic receptor binding seems to be lost during the transition from MCI to AD.

Valla J, Schneider L, Niedzielko T, Coon KD, Caselli R, Sabbagh MN, Ahern GL, Baxter L, Alexander G, Walker DG, Reiman EM. · Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Arizona Alzheimer's Disease Consortium, 350 W. Thomas Road, Phoenix, AZ 85013, USA. · Mitochondrion. · Pubmed #17123871 links to  free full text

Abstract: Mitochondrial abnormalities are found in Alzheimer's disease (AD), but previous reports have not examined at-risk groups. In subjects with AD, mild cognitive impairment (MCI), and non-demented aged controls, platelet and lymphocyte mitochondria were isolated and analyzed for Complexes I, III, and IV of the electron transport chain. Western blots were used to control for differential enrichment of samples. Results demonstrated significant declines in Complexes III and IV in AD, and a significant decline in Complex IV in MCI. This report confirms mitochondrial deficiencies in AD, extends them to MCI, and suggests they are present at the earliest symptomatic stages of disease.

Roher AE, Garami Z, Alexandrov AV, Kokjohn TA, Esh CL, Kalback WM, Vedders LJ, Wilson JR, Sabbagh MN, Beach TG. · Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City AZ 85351, USA. · Neurol Res. · Pubmed #16945221 No free full text.

Abstract: OBJECTIVE: Recent post-mortem studies have reported that the severity of atheromatous deposits in the circle of Willis is significantly greater, relative to non-demented (ND) elderly persons, in subjects with neuropathologically diagnosed Alzheimer's disease (AD). Additionally, the severity of intracranial atherosclerosis correlates significantly with the densities of neuritic plaques and neurofibrillary tangles. In this study, we examine the arteries of the circle of Willis by transcranial Doppler (TCD) ultrasonography. METHODS: TCD was used to measure, in 25 AD patients and 30 ND elderly subjects, mean flow velocities and pulsatility indices in 16 different segments of the circle of Willis. The data were compared with and without adjustment for age, gender and systolic blood pressure. RESULTS: The AD patients had systematically higher pulsatility indices (p<0.005) than the ND group. Incremental increases of pulsatility indices in these segments had odds ratios ranging from 1.8 to 48 for the presence of AD when adjusted for age, gender and systolic blood pressure. The left internal carotid artery siphon and the left posterior cerebral artery were the two vessels that were strongly associated with AD diagnosis. Mean flow velocities were generally lower in patients with AD but the differences did not reach the significance level. DISCUSSION: The pulsatility indices of the arteries of AD patients were generally greater than those of similarly-aged ND subjects. This difference is most likely due to increased arterial wall rigidity imposed by atherosclerotic changes. Atherosclerotic disease of intracranial arteries may be a risk factor for AD.

Baxter LC, Sparks DL, Johnson SC, Lenoski B, Lopez JE, Connor DJ, Sabbagh MN. · Barrow Neurological Institute, Phoenix, AZ 85013, USA. · J Alzheimers Dis. · Pubmed #16914835 No free full text.

Abstract: OBJECTIVE: To examine the relationship between commonly used screening cognitive measures with gray and white matter integrity in patients with mild to moderate AD. BACKGROUND: New neuroimaging techniques, such as voxel-based morphometry (VBM), make it possible to study the relationship between structural brain integrity and cognitive functioning in AD. METHODS: Gray and white matter integrity was evaluated using VBM in fifteen patients with mild to moderate AD. ADAS-Cog and MMSE scores were also performed as part of the baseline assessment for a larger clinical trial in the AD patients. Correlations between cognitive measures and VBM were performed. RESULTS: Both the ADAS-Cog and the MMSE showed a similar relationship with gray matter degeneration, reflecting greater cognitive impairment with decreased gray matter in the left temporal lobe. However, the MMSE score was much more reflective of underlying white matter changes than ADAS-Cog scores, particularly in frontotemporal region. These findings suggest that the ADAS-Cog and MMSE reflect different aspects of the underlying brain changes observed in AD. The ADAS-Cog was more specific to gray matter integrity whereas the MMSE reflected a more global reduction in both gray and white matter. CONCLUSIONS: These results support using neuroimaging markers of neural integrity as an important consideration when evaluating treatment efficacy. Furthermore, whole-brain analyses such as VBM help to evaluate neural systems that are not necessarily targeted by the treatment.