Alzheimer Disease: Connor DJ

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.

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.

Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. · Department of Psychiatry, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. · Am J Geriatr Psychiatry. · Pubmed #19155748 No free full text.

Abstract: OBJECTIVES: Patients with Alzheimer dementia often display both agitated behavior and poor sleep. Given that the disease is often associated with low endogenous levels of melatonin, exogenous melatonin administration may lead to improvements in sleep and agitation. DESIGN: Randomized, placebo-controlled study. SETTING: Nursing homes in San Diego, CA, metropolitan area. PARTICIPANTS: Subjects were patients with probable Alzheimer disease. INTERVENTION: Melatonin (8.5 mg immediate release and 1.5 mg sustained release) (N = 24) or placebo (N = 17) administered at 10:00 P.M. for 10 consecutive nights. The protocol consisted of baseline (3 days), treatment (10 days), and posttreatment (5 days) phases. MEASUREMENTS: Sleep was measured continuously using actigraphy. Agitation was rated using both the Agitated Behavior Rating Scale and the Cohen-Mansfield Agitation Inventory. Treatment effects were examined both across the 24-hr day and separately by nursing shift. RESULTS: There were no significant effects of melatonin, compared with placebo, on sleep, circadian rhythms, or agitation. CONCLUSION:: This study failed to find a beneficial effect of exogenous melatonin, consistent with a number of other studies. The lack of efficacy may be related to the absence of a true treatment effect or to the superphysiologic dose of melatonin used.

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.

Sparks DL, Lemieux SK, Haut MW, Baxter LC, Johnson SC, Sparks LM, Sampath H, Lopez JE, Sabbagh MH, Connor DJ. · Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ, USA. · Cleve Clin J Med. · Pubmed #18540154 links to  free full text

Abstract: Numerous clinical studies suggest a link between elevated cholesterol and increased risk of Alzheimer disease (AD), and the preponderance of data suggests that statin therapy may reduce the risk of AD later in life. The first clinical investigation of statin therapy in patients with AD, the AD Cholesterol-Lowering Treatment (ADCLT) trial, found that atorvastatin 80 mg/day was associated with improvements relative to placebo on some, but not all, cognitive measures after 6 months and 1 year of therapy. We report here findings from a pilot ADCLT substudy showing a nonsignificant reduction in total hippocampal volume with 1 year of atorvastatin therapy compared with placebo, driven by a highly significant reduction in right hippocampal volume with atorvastatin therapy.

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.

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.

Beach TG, Wilson JR, Sue LI, Newell A, Poston M, Cisneros R, Pandya Y, Esh C, Connor DJ, Sabbagh M, Walker DG, Roher AE. · W.H. Civin Laboratory for Neuropathology, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. · Acta Neuropathol. · Pubmed #17021755 No free full text.

Abstract: The role of intracranial atherosclerosis in Alzheimer's disease (AD) has been a subject of debate since the first decade of the last century. The initial "vascular hypothesis" of AD was rejected after a series of mid-twentieth century gross anatomical postmortem studies that showed an inconstant relationship between intracranial atherosclerosis and senile dementia. These early studies did not utilize statistical methods, however, and the investigators did not appear to consider the possibility that intracranial atherosclerosis might have a probabilistic, rather than an absolute, effect on AD risk. Recent studies by three independent groups have found a significant statistical association between postmortem measures of circle of Willis atherosclerosis and AD. The present study was undertaken to further address the validity of this association in a large autopsy series, including cases diagnosed neuropathologically with vascular dementia (VaD) and non-AD dementias. Postmortem gross anatomical grading of circle of Willis atherosclerosis was performed in 397 subjects classified by neuropathological diagnosis, including 92 non-demented elderly controls, 215 with AD, 30 with VaD and 60 with non-AD dementias. Circle of Willis atherosclerosis was more severe in subjects with AD and VaD than in control subjects, while it was equivalent between control subjects and subjects with non-AD dementias. Increasing atherosclerotic grade increased the odds ratios (OR) for the diagnoses of both AD and VaD and also increased the ORs for both increased neuritic plaque density and higher Braak neurofibrillary tangle stage. The significance of these associations was retained after consideration of the effects of age, gender and the apolipoprotein E-epsilon4 allele. The results suggest that the statistical association between intracranial atherosclerosis and AD is not an artifact of diagnostic misclassification or of unequal distribution of the apolipoprotein E-epsilon4 allele.

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.

Sparks DL, Connor DJ, Sabbagh MN, Petersen RB, Lopez J, Browne P. · Sun Health Research Institute, Sun City, AZ 85351, USA. · Acta Neurol Scand Suppl. · Pubmed #16866904 No free full text.

Abstract: CONTEXT: Recent evidence suggests that treatment of mild-to-moderate Alzheimer's disease (AD) with atorvastatin provides significant benefit on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) after 6 months. OBJECTIVE: To determine if benefit on ADAS-cog performance produced by atorvastatin is influenced by severity of cognitive impairment, circulating cholesterol levels, or apolipoprotein E genotype. DESIGN: A double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to atorvastatin calcium or placebo. SETTING: A single-site study at the clinical research center of the Sun Health Research Institute. PARTICIPANTS: Ninety-eight individuals with mild-to-moderate AD (MMSE score of 12-28) provided informed consent, and 67 were randomized. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of many other medications in the treatment of co-morbidities. Participants using cholesterol-lowering medications or being treated for major depression or a psychiatric condition were excluded. INTERVENTION: Once daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo. MAIN OUTCOME MEASURES: A primary outcome measure was change ADAS-cog sub-scale score. Secondary outcome measures included scores on the MMSE, and circulating cholesterol levels. The Apolipoprotein E genotype was established for each participant. RESULTS: A significant positive effect on ADAS-cog performance occurred after 6 months of atorvastatin therapy compared with placebo. This positive effect was more prominent among individuals entering the trial with, (i) higher MMSE scores, (ii) cholesterol levels above 200 mg/dl or (iii) if they harbored an apolipoprotein-E-4 allele compared with participants not responding to atorvastatin treatment. Individuals in the placebo group tended to experience more pronounced deterioration if their cholesterol levels exceeded 200 mg/dl or they harbored an apolipoprotein-E-4 allele. CONCLUSION: Atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment, an individual's apolipoprotein E genotype or whether the patient exhibits elevated cholesterol levels.

Connor DJ, Seward JD, Bauer JA, Golden KS, Salmon DP. · Sun Health Research Institute, Sun City, AZ 85351, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16118528 No free full text.

Abstract: The ability of three different Clock Drawing Test (CDT) scoring systems to detect Dementia of the Alzheimer Type (DAT) was investigated. As part of a neuropsychological battery, fifty DAT Type patients and fifty matched controls drew a clock. Each drawing was scored by three independent raters according to three different scoring systems: the 3-Factor system, the Template system, and the Abbreviated system. The CDT scoring systems were able to detect Dementia of the Alzheimer Type when the disease was moderate to severe, but lacked sensitivity in milder dementia. Animal Fluency was a better single predictor of dementia. Clinicians are advised to interpret the results of the Clock Drawing Test cautiously in an outpatient setting, where milder forms of dementia and low base rates are likely.

Davie JE, Azuma T, Goldinger SD, Connor DJ, Sabbagh MN, Silverberg NB. · Department of Speech and Hearing Science, Arizona State University, Tempe, AZ 85287-0102, USA. · Neuropsychology. · Pubmed #15099149 No free full text.

Abstract: In this study, individuals with mild cognitive impairment (MCI) were tested to see if executive dysfunction impacts their implementation of expectancy biases in a priming task. Young adults, healthy older adults, and individuals with MCI made speed-related decisions to sequentially presented word pairs. The proportion of category related (e.g., apple-fruit) versus coordinate related (apple-pear) pairs was varied to create different expectancy biases. When the proportion of category pairs was high (80%), the control groups showed an expectancy bias: Significant inhibition was observed for coordinate pairs compared with category pairs. The MCI group also demonstrated an expectancy bias but with much larger costs for unexpected targets. The findings suggest that individuals with MCI are inordinately sensitive to expectancy violations, and these findings are discussed in terms of possible executive dysfunction.

Sparks DL, Connor DJ, Browne P, Sabbagh MN, Anonymous00003. · Laboratory of Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ 85351, USA. · J Mol Neurosci. · Pubmed #12212783 No free full text.

Abstract: Elevated circulating cholesterol can have profound effects on the health of an individual. Such excess cholesterol can promote coronary artery disease, production and accumulation of beta-amyloid in the brain, and possibly Alzheimer's disease (AD). In a clinical trial evaluating the benefit of a cholesterol-lowering drug in the treatment of AD, mean cholesterol levels at baseline among individuals participating in the trial were found to be relatively high. Based on this observation we suggest that cholesterol levels should be actively monitored in the elderly, as many individuals with AD are over 65 years of age and therefore excluded by currently accepted guidelines.

Caselli RJ, Beach TG, Sue LI, Connor DJ, Sabbagh MN. · Department of Neurology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, AZ 85259, USA. · Dement Geriatr Cogn Disord. · Pubmed #12145451 No free full text.

Abstract: Dementia with Lewy bodies (DLB) may include both Alzheimer and Lewy body pathology, but has never been reported to cause primary progressive aphasia. We report a 69-year-old woman who died 11 years after presenting with the syndrome of progressive aphasia. Six years after aphasia onset she developed visual hallucinations, and subsequently parkinsonism. Autopsy examination revealed Alzheimer's disease (AD), cortical Lewy bodies, and depigmentation and Lewy bodies in the substantia nigra and locus ceruleus. The aphasia most likely reflected the initial onset of AD, and the psychosis and parkinsonism most likely reflected the subsequent onset of Lewy body pathology. This first reported case of progressive aphasia occurring within the context of AD and Lewy body pathology uniquely illustrates the clinical and pathological nosological relationships between these two disease processes, and demonstrates a limitation of the general term, 'DLB'.