Moderate Probable Alzheimer's Disease Research Articles

Alzheimer's Disease THErapy With NEuroaid (ATHENE): ARandomized Double-Blind Delayed-Start Trial.

Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression. Randomized double-blind placebo-controlled delayed-start study. Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n= 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6months, followed by a further 6months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035). The primary outcome measure was occurrence of serious adverse events (SAEs) at 6months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales. There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference-4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD)-1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences. This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.

Probing gut-brain links in Alzheimer's disease with rifaximin.

Gut‐microbiome‐inflammation interactions have been linked to neurodegeneration in Alzheimer's disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut‐specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open‐label trial, we treated 10 subjects with mild to moderate probable AD dementia (Mini‐Mental Status Examination (MMSE) = 17 ± 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament‐light levels (P < .004) and a significant increase in fecal phylum Firmicutes microbiota. Serum phosphorylated tau (pTau)181 and glial fibrillary acidic protein (GFAP) levels were reduced (effect sizes of −0.41 and −0.48, respectively) but did not reach statistical significance. In addition, there was a nonsignificant downward trend in serum cytokine interleukin (IL)‐6 and IL‐13 levels. Cognition was unchanged. Increases in stool Erysipelatoclostridium were correlated significantly with reductions in serum pTau181 and serum GFAP. Insights from this pilot trial are being used to design a larger placebo‐controlled clinical trial to determine if specific microbial flora/products underlie neurodegeneration, and whether rifaximin is clinically efficacious as a therapeutic.

Cognitive heterogeneity in probable Alzheimer disease: Clinical and neuropathologic features.

To identify heterogeneity in cognitive profiles of patients with probable Alzheimer disease (AD) who have mild to moderate dementia and satisfy inclusion and exclusion criteria for a typical AD clinical trial, and to determine whether cognitive profiles are systematically related to the clinical course and neuropathologic features of the disease. Neuropsychological test data from patients with mild to moderate probable AD (n = 4,711) were obtained from the National Alzheimer's Coordinating Center. Inclusion and exclusion criteria usually used in AD clinical trials were applied. Principal component analysis and model-based clustering were used to identify cognitive profiles in a subset of patients with autopsy-verified AD (n = 800) and validated in the overall (nonautopsy) sample and an independent cohort with similar test data. Relationships between cognitive profile, clinical characteristics, and rate of decline were examined with mixed-effects models. In the autopsy-confirmed sample, 79.6% of patients had a typical AD cognitive profile (greater impairment of episodic memory than other cognitive functions), and 20.4% had an atypical profile (comparable impairment across cognitive domains). Similar results were obtained in the overall (typical 79.8%, atypical 20.2%) and validation (typical 71.8%, atypical 28.2%) samples. Atypicality was associated with younger age, male sex, lower probability of APOE ε4, less severe global dementia, higher depression scores, lower Braak stage at autopsy, and slower cognitive decline. We can reliably identify distinct cognitive profiles among patients with clinically diagnosed probable AD that are associated with tangle pathology and with different rates of decline. This may have implications for clinical trials in AD, especially therapies targeting tau.

A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer's disease.

PF-04447943 is a potent, selective phosphodiesterase 9A (PDE9A) inhibitor that elevates guanoscine 3',5' - cyclic monophosphate (cGMP) in brain and cerebrospinal fluid. PDE9A inhibition enhances synaptic plasticity and improves memory in preclinical cognition models, and prevents decreases in dendritic spine density in transgenic mice that overexpress amyloid precursor protein (APP) leading to high levels of amyloid beta (Aβ) production (Tg2576). This Phase 2 multicenter study was designed to assess the efficacy, safety and pharmacokinetics of PF-04447943 compared with placebo in mild to moderate probable Alzheimer's disease (AD). Subjects in overall good health with Mini Mental State Examination (MMSE) scores of 14-26 were randomized to 12 weeks treatment with PF-04447943 25 mg q12h (n=91) or placebo (n=100). Concomitant acetylcholinesterase inhibitor or memantine use was excluded. The primary outcome was the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog). The Neuropsychiatric Inventory (NPI), Clinical Global Impression-Improvement scale (CGI-I) and standard safety measures were secondary outcomes. Completion rates were similar, 87% PF-04447943 vs 92% placebo. At week 12 the mean (SE) baseline adjusted decrease from baseline in ADAS cog for PF-04447943-treated patients was -1.91 (0.54). Placebo treated patients had a change of -1.60 (0.50). The difference between treatments was -0.31 (90% CI of -1.52, 0.90). Corresponding values for the NPI were -2.86 (0.72) vs -2.70 (0.67) with a treatment difference of -0.16 (90% CI of -1.78, 1.48). Neither these changes nor the distribution of CGI-I scores were statistically significantly different between groups. The incidence of serious adverse events (AEs) was similar between groups with 2 deaths in the placebo group. The PF-04447943 group reported more gastrointestinal AEs including diarrhea (5.5% vs 3%) and nausea (5.5% vs 1%) and had a higher rate of discontinuation due to AEs (6.6% vs 2%). Although generally safe and well-tolerated, 12 weeks PF-04447943 treatment did not improve cognition, behavior, and global change compared with placebo.

Efficacy of increasing donepezil in mild to moderate Alzheimer's disease patients who show a diminished response to 5 mg donepezil: a preliminary study

With the recent approval of several new drugs, pharmacological management of Alzheimer's disease has become more complicated in Japan. The efficacy and safety of increasing the dose of donepezil to 10 mg daily were assessed in an open-label study of patients with mild to moderate Alzheimer's disease who were showing a diminished response to 5 mg daily. The subjects included 27 patients with mild to moderate probable Alzheimer's disease whose primary caregivers had confirmed progression of symptoms during treatment with donepezil 5 mg daily. The dose of donepezil was increased to 10 mg daily, and the Alzheimer's disease assessment scale-cognitive subscale (Japanese version), Neuropsychiatric Inventory, and Zarit caregiver burden interview scores were compared before and after dose escalation. Adverse events were also investigated. Efficacy was evaluated in 24 patients; three dropped out because of adverse reactions. The Alzheimer's disease assessment scale score showed significant improvement after dose escalation of donepezil (P = 0.006). The total score of the Neuropsychiatric Inventory and the Zarit score showed no significant changes. However, the anxiety score of the Neuropsychiatric Inventory showed a significant increase (P = 0.028). Safety assessment revealed that the dropout rate was 11.1% and adverse reactions occurred in 40.7%. Nausea (29.6%) and loss of appetite (22.2%) were common adverse reactions. Because cognitive function showed improvement after increasing the dose of donepezil, the dosage of this drug should probably be adjusted based on the overall severity of Alzheimer's disease as well as the progression of cognitive dysfunction.

Biomarkers of Vascular Risk, Systemic Inflammation, and Microvascular Pathology and Neuropsychiatric Symptoms in Alzheimer's Disease

Numerous serum and plasma based biomarkers of systemic inflammation have been linked to both neuropsychiatric disorders and Alzheimer's disease (AD). The present study investigated the relationship of clinical biomarkers of cardiovascular risk (cholesterol, triglycerides, and homocysteine) and a panel of markers of systemic inflammation (CRP, TNF-α, IL1-ra, IL-7, IL-10, IL-15, IL-18) and microvascular pathology (ICAM-1, VCAM-1) to neuropsychiatric symptoms in a sample with mild AD. Biomarker data was analyzed on a sample of 194 diagnosed with mild to moderate probable AD. The sample was composed of 127 females and 67 males. The presence of neuropsychiatric symptoms was gathered from interview with caretakers/family members using the Neuropsychiatric Inventory. For the total sample, IL-15, VCAM (vascular adhesion molecule), and triglycerides were significantly and negatively related to number of neuropsychiatric symptoms, and total cholesterol and homocysteine were positively related and as a group accounted for 16.1% of the variance. When stratified by gender, different patterns of significant biomarkers were found with relationships more robust for males for both total symptoms and symptom clusters. A combination of biomarkers of systemic inflammation, microvascular pathology, and clinical biomarkers of cardiovascular risk can account for a significant portion of the variance in the occurrence of neuropsychiatric symptoms in AD supporting a vascular and inflammatory component of psychiatric disorders found in AD. Gender differences suggest distinct impact of specific risks with total cholesterol, a measure of cardiovascular risk, being the strongest marker for males and IL-15, a marker of inflammation, being the strongest for females.

Reproducibility of gait variability measures in people with Alzheimer's disease

Gait variability may be especially important to measure in people with Alzheimer's disease (AD) as it is related to risk of falling and may reflect the cognitive demand of walking. Its usefulness as an outcome measure in people with AD is currently limited by the lack of published evaluation of its reproducibility. Therefore measures of temporal and spatial gait variability were recorded using an instrumented mat on two occasions, one week apart in 16 community-dwelling people with mild to moderate probable AD. Data were combined in three ways for analysis: all available strides; all available strides from walks with mean velocity within 10cm/s of each other; and the first 12 strides from the second method. Measures of velocity, stride length and cadence variability were all found to have good reliability using an average of 64 strides from velocity-matched walks (ICC3,1 0.77–0.90) however only stride length variability reached acceptable reliability for a clinical test (ICC3,1 0.9). Estimates of the number of strides required to reach an ICC of 0.9 for velocity, cadence and stride width variability were between 169 and 212. Poor to moderate reliability of gait variability measures was obtained using 12 strides. Minimal detectable change values, calculated to reflect absolute agreement, appear to be feasible and may assist with evaluation of interventions to improve gait. Further research should examine the effects on reproducibility of gait variability measures, of systematic cueing aimed at producing consistent, optimal walking in larger groups with a range of dementia type and severity.

P-455 - Analysis of the effect of galantamine in the treatment of mild to moderate Alzheimer's disease (AD)

Alzheimer's disease is a progressive neurodegenerative disorder in which the patient experiences progressive loss of cognitive and functional abilities and concomitant behavioral disturbances. While all acetylcholinesterase inhibitors enhance brain activity by inhibiting the breakdown of acetylcholine, Galantamine differs from the other cholinesterase inhibitors in that it allosterically modulates nicotinic acetylcholine receptors. Allosteric modulation of presynaptic nicotinic receptors is thought to cause an increase in the release of several neurotransmitters. These actions help to compensate for the decreased release of acetylcholine associated with the loss of cholinergic neurons in AD. Subjects were diagnosed with mild to moderate probable AD based on the criteria set by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association, namely a screening score of 10–24 on the Mini-Mental State Examination (MMSE) and a score of ≥ 18 on 11-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADA - cog11). One hundred subjects received 1 (one) capsule of Galantamine twice per day in the morning and evening for 6 (six) months. The administration of the Galantamine was associated with significant greater cognitive benefits and significant better maintenance of daily activities and was generally safe and has proven better tolerability.

Atorvastatin does not slow cognitive decline in patients with mild to moderate probable Alzheimer's disease who are taking donepezil

Atorvastatin does not slow cognitive decline in patients with mild to moderate probable Alzheimer's disease who are taking donepezil

Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease

There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD. This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks. A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated. In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.

Reduction of SorLA/LR11, a Sorting Protein Limiting β-Amyloid Production, in Alzheimer Disease Cerebrospinal Fluid

The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces beta-amyloid precursor protein trafficking to secretases, notably BACE1 that generates beta-amyloid, the principal component of senile plaques in Alzheimer disease (AD). LR11 protein is reduced in patients with late-onset AD, and LR11 polymorphisms have been associated with late-onset AD. T o detect soluble LR11 and APP in cerebrospinal fluid (CSF) from patients with AD and control subjects, as (like beta-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells. Case-control study. Academic research. Patients with AD and control subjects. We evaluated CSF LR11, beta-amyloid precursor protein, and apolipoprotein E levels by Western blot in lumbar and postmortem CSF samples. LR11 levels were detectable and stable during 6 months in the CSF of patients with AD. LR11 levels were significantly reduced in lumbar samples from patients with mild to moderate probable AD, as well as in ventricular CSF from patients with autopsy-confirmed AD (predominantly Braak stage III-IV). Bivariate analysis with beta-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble beta-amyloid precursor protein but not apolipoprotein E levels. Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote beta-amyloid production or as an index of therapeutic response in late-onset AD.

Increased striatal dopamine (D2/D3) receptor availability and delusions in Alzheimer disease

Dysfunction within corticostriatal dopaminergic neurocircuitry has been implicated in neuropsychiatric symptoms associated with Alzheimer disease (AD). This study aimed to test the hypothesis that the symptom domains delusions and apathy would be associated with striatal dopamine (D2) receptor function in AD. In vivo dopamine (D2/D3) receptor availability was determined with [(11)C]raclopride (RAC) PET in 23 patients with mild and moderate probable AD. Behavioral symptoms were measured using the Neuropsychiatric Inventory and the Apathy Inventory. Imaging data were analyzed using a region-of-interest approach. The potential confounding effects of age, sex, and disease stage were explored using a linear mixed model. Correlational and independent samples comparisons were used to examine the relationship between behavioral and binding potential (BP(ND)) measures. Mean [(11)C]RAC BP(ND) was higher in patients with delusions (n = 7; 5 men) than in patients without delusions (n = 16; 6 men) (p = 0.006). When women were excluded from the analysis, [(11)C]RAC BP(ND) was higher in men with delusions than in men without delusions (p = 0.05). Apathy measures showed no association with [(11)C]RAC BP(ND). Striatal dopamine (D2/D3) receptor availability is increased in Alzheimer disease patients with delusions, to an extent comparable to that observed in drug-naive patients with schizophrenia. Whether this represents up-regulation of dopamine (D2) or possibly dopamine (D3) receptors and how this relates to responsivity of the striatal dopaminergic system merit further exploration.

IC-P2-128: Twelve-month cerebral metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment: Preliminary findings from the Alzheimer's disease neuroimaging initiative

In a small positron emission tomography (PET) study, we previously characterized twelve-month cerebral metabolic rate for glucose (CMRgl) declines in moderate probable Alzheimer's disease (pAD) patients and estimated the number of patients needed to detect disease-modifying treatment effects in a single-center randomized clinical trial (RCT, Alexander et al, 2002). The objectives of this study are to characterize twelve-month CMRgl declines in mild pAD and amnestic mild cognitive impairment (aMCI) patients from the multi-center Alzheimer's Disease Neuroimaging Initiative (ADNI) and estimate the number of mild pAD patients and MCI patients needed to evaluate a putative disease-slowing treatment in twelve-month multi-center RCTs. SPM5 was used to characterize twelve-month declines in 17 mild pAD patients (baseline age 71±12, MMSE 24±2) and 46 aMCI patients (baseline age 66±13, MMSE 27±2). Maximal CMRgl declines were used to estimate the number of mild pAD and aMCI patients needed per group to detect disease-modifying treatment effects in six- or twelve-month multi-center RCTs with 80% power and P≤0.001 uncorrected for multiple comparisons. The pAD patients had twelve-month CMRgl declines in posterior cingulate, precuneus, parietal, temporal and frontal regions and the aMCI patients had twelve-month CMRgl declines in the posterior cingulate, precuneus, parietal and temporal regions. To detect a 20% treatment effect on posterior cingulate CMRgl declines, we estimate the need for 153 mild pAD patients per group and 728 aMCI patients per group in twelve-month RCTs. This study provides preliminary information about twelve-month CMRgl declines in mild pAD and aMCI patients and the number of patients needed to detect disease-modifying treatment effects in a twelve-month multi-center RCT. Future analyses will extend our findings to the entire ADNI cohort, provide power estimates for 6, 12, 18 and 24-month multi-center RCTs using specified search regions versus ROIs, and compare these power estimates to those using clinical ratings, other imaging modalities and other image-analysis techniques.

An aberrant protein complex in CSF as a biomarker of Alzheimer disease

To determine if an aberrant protein complex consisting of prostaglandin-d-synthase (PDS) and transthyretin (TTR) in CSF differentiates between subjects with Alzheimer disease (AD) and normal control (NC) subjects. Western blot analysis and a unique sandwich ELISA were used to quantify levels of complexed PDS/TTR in ventricular CSF of subjects with autopsy-verified diagnoses and in lumbar CSF of living subjects with mild to moderate probable AD and age-matched NC subjects. Ventricular CSF was obtained from short postmortem interval autopsies of 7 NC subjects (4 men/3 women), 12 diseased control (DC) subjects (7 men/5 women), 4 subjects with mild cognitive impairment (MCI) (2 men/2 women), and 8 subjects with late-stage AD (LAD) (4 men/4 women). Lumbar CSF was obtained from 15 subjects with probable AD (5 men/10 women) and 14 age-matched NC subjects (10 men/4 women) and was analyzed in a double-blind fashion. A significant increase in complexed PDS/TTR in ventricular CSF was found in MCI and LAD subjects but not DC subjects compared with NC subjects. Double-blind analysis of complexed PDS/TTR in lumbar CSF showed a significant sixfold increase in levels of the PDS/TTR complex in living probable AD subjects compared with age-matched NC subjects and a 100% sensitivity and 93% specificity in the identification of subjects with AD. After further study of larger numbers of patients, quantifying prostaglandin-d-synthase/transthyretin complex in CSF may be useful in the diagnosis of Alzheimer disease, possibly in the early stages of the disease.

Proteomic identification and early validation of complement 1 inhibitor and pigment epithelium‐derived factor: Two novel biomarkers of Alzheimer's disease in human plasma

Emerging disease modifying therapeutic strategies for Alzheimer's disease (AD) have generated a critical need for biomarkers of early stage disease. Here, we describe the identification and assessment of a number of candidate biomarkers in patients with mild to moderate probable AD. Plasma from 47 probable Alzheimer's patients and 47 matched controls were analysed by proteomics to define a significant number of proteins whose expression appeared to be associated with AD. These were compared to a similar proteomic comparison of a mouse transgenic model of amyloidosis, which showed encouraging overlap with the human data. From these studies a prioritised list of 31 proteins were then analysed by immunoassay and/or functional assay in the same human cohort to verify the changes observed. Eight proteins continued to show significance by either immunoassay or functional assay in the human plasma and these were tested in a further set of 100 probable AD patients and 100 controls from the original cohort. From our data it appeared that two proteins, serpin F1 (pigment epithelium-derived factor) and complement C1 inhibitor are down-regulated in plasma from AD patients.

Adaptação transcultural da escala de avaliação de incapacidade em demência (Disability Assessment For Dementia - DAD)

The original version of the Disability Assessment for Dementia (DAD) was translated into Portuguese and back translated to English. The divergences of translation were identified and discussed, resulting in a version that was used in a preliminary investigation for cross-cultural adaptation. The final version was administered to 29 patients with mild to moderate probable Alzheimer's disease. The correlation coefficients of DAD were 0.929 and 0.932 for the inter-examiner and test-retest evaluations respectively. The reliability indexes were also high (Kappa 0.72 p<0.001 inter-examiners and 0.85 p<0.001 test-retest). The Brazilian version of DAD was easy to administer and had good reliability to assess the functional status of demented patients. It will contribute to the follow-up of these patients in our population. Moreover, it can be used in transcultural studies on functional abilities in dementia.

Retinal Abnormalities in Early Alzheimer’s Disease

There is evidence suggesting that visual disturbances in patients with Alzheimer's Disease (AD) are due to pathologic changes in the retina and optic nerve, as well as to higher cortical impairment. The purpose of this study was to evaluate retinal hemodynamic parameters and to characterize patterns of retinal nerve fiber layer (RNFL) loss in patients with early AD. Nine patients with mild to moderate probable AD (mean Mini Mental State Examination score 24 of a possible 30 (age 74.3 +/- 3.3 years; mean +/- SD) and eight age-matched control subjects (age, 74.3 +/- 5.8 years) were included in this prospective cross-sectional study. Blood column diameter, blood velocity, and blood flow rate were measured in the major superior temporal retinal vein in each subject by using a laser Doppler instrument. Peripapillary RNFL was measured by optical coherence tomography. Patients with AD showed a significant narrowing of the venous blood column diameter (131.7 +/- 10.8 microm) compared with control subjects (148.3 +/- 12.7 microm, P = 0.01), and a significantly reduced venous blood flow rate (9.7 +/- 3.1 microL/min) compared with the control subjects (15.9 +/- 3.7 microL/min, P = 0.002). A significant thinning of the RNFL was found in the superior quadrant in patients with AD (92.2 +/- 21.6 microm) compared with control subjects (113.6 +/- 10.7 microm, P = 0.02). There were no significant differences in the inferior, temporal, or nasal RNFL thicknesses between the groups. Retinal abnormalities in early AD include a specific pattern of RNFL loss, narrow veins, and decreased retinal blood flow in these veins. The results show that AD produces quantifiable abnormalities in the retina.

Effects of donepezil on cortical metabolic response to activation during 18FDG-PET in Alzheimer’s disease: a double-blind cross-over trial

Cholinergic enhancement is among the best established treatments of Alzheimer's disease (AD). The cognitive effects of treatment are thought to be mediated by improvement of neuronal transmission. Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) by measuring cortical metabolic response to activation assesses integrity of neuronal transmission in vivo. To determine the effects of treatment with donepezil, a centrally selective acetylcholinesterase inhibitor, on cortical metabolism in AD using 18FDG-PET. We enrolled 23 patients, 18 of which completed the study, with mild to moderate probable AD (mini-mental status exam scores of 15-28, inclusive) in a double-blind cross over trial of 8 weeks donepezil compared to 8 weeks placebo with repeated double 18FDG-PET examinations during passive audio-visual stimulation. Effects of treatment on cortical metabolic response to stimulation were determined with a linear model on a voxel level using Statistical Parametric Mapping (SPM 99, Wellcome Department of Imaging Neuroscience, London). Effects of treatment on cognitive measures were not different between donepezil and placebo. During passive audio-visual stimulation, patients showed activation in posterior visual and auditory areas and decreased activation in frontal cortex and basal ganglia. Resting state metabolism was increased with donepezil in left prefrontal cortex and decreased in right hippocampus. Cortical response to activation was increased in right hippocampus with donepezil compared to placebo. Donepezil treatment shows a spatially limited functional effect on right hippocampus and left prefrontal cortical metabolism, independently of clinical response to treatment.

Detecting subtle spontaneous language decline in early Alzheimer’s disease with a picture description task

The objective was to collect normative data for a simple and a complex version of a picture description task devised to assess spontaneous speech and writing skills in patients with Alzheimer's disease (AD), and to test whether some aspects of spontaneous language can discriminate between normal and pathological cognitive decline. Two hundred and forty English-speaking healthy volunteers were recruited to participate in this normative study. Thirty patients with a clinical diagnosis of minimal to moderate probable AD were also recruited. Age and education influenced some aspects of spontaneous oral and written language whereas sex had no influence on any of the variables assessed. A high proportion (>70%) of AD patients performed below cut-off on those scales that measured semantic processing skills. Deficits were detected even amongst those in the very early stage of the disease when the complex version of the task was used. Prospective assessment of spontaneous language skills with a picture description task is useful to detect those subtle spontaneous language impairments caused by AD even at an early stage of the disease.

Reduced phospholipid breakdown in Alzheimer’s brains: a 31P spectroscopy study

Abnormalities of membrane phospholipid metabolism have been described in Alzheimer's disease (AD). We investigated, with the aid of (31)P magnetic resonance spectroscopy, the in vivo intracerebral availability of phosphomonoesters (PME) and phosphodiesters (PDE) in patients with AD. Eighteen outpatients with mild or moderate probable AD and 16 nondemented elderly volunteers were assessed with the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) and its cognitive subscale of the CAMDEX schedule (CAMCOG). Scans were performed on a 1.5 T magnetic resonance imager addressing a 40-cm(3) voxel in the left prefrontal cortex. Main outcome measures were mean relative peak areas of PME and PDE, which provide an estimate of membrane phospholipid metabolism. PME resonance and the PME/PDE ratio were increased in AD patients as compared to controls (p<0.05). PME was negatively correlated with global cognitive performance as shown by the Mini-Mental State Examination (r(s)=-0.36, p=0.05) and CAMCOG scores (r(s)=-0.49, p=0.007), as well as with discrete neuropsychological functions, namely, memory (r(s)=-0.53, p=0.004), visual perception (r(s)=-0.54, p=0.003), orientation (r(s)=-0.36, p=0.05), and abstract thinking (r(s)=-0.48, p=0.01). We provide evidence of reduced membrane phospholipid breakdown in the prefrontal cortex of mild and moderately demented AD patients. These abnormalities correlate with neuropsychological deficits that are characteristic of AD.