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Background: Age may affect treatment outcome in trials of mild probable Alzheimer’s disease (AD). Objective: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. Methods: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation (“on”) or sham DBS-f (“off”) for 12 months. Results: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the “on” and “off” groups in the intent to treat (ITT) population. There was a significant age by time interaction with the Alzheimer’s Disease Assessment Scale; ADAS-cog-13 (p = 0.028). Six of the 12 enrolled participants

Background A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. Objectives The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. Methods A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies. Results A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Conclusions Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown. Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer’s disease (AD). Methods: We evaluated active “on” versus sham “off” bilateral DBS directed at the fornix-a major fiber bundle in the brain’s memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01608061","term_id":"NCT01608061"}}NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation. Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the “on” versus “off” stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients

Informant-based assessments of cognition and function are commonly used to differentiate individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) front those who are cognitively normal. However, determining the extent to which informant-based measures correlate to objective neuropsychological tests is important given the widespread use of neuropsychological tests in making clinical diagnoses of aMCI and AD. The aim of the current study is to determine how well the Alzheimer’s Questionnaire (AQ) correlates with objective neuropsychological tests. The study utilized data from 300 individuals participating in a brain and body donation program. Individuals diagnosed with aMCI (n = 83) and AD (n = 67) were matched oil age, gender, and education to a control individual (n = 150). The average age for the entire sample was 83.52 ± 6.51 years with an average education level of 14.57 ± 2.55 years. Results showed that the AQ correlated strongly with the Mini-Mental State Exam (r = −0.71, p < 0.001) and the Mattis Dementia Rating Scale-2 (r = −0.72, p < 0.001), and moderate correlations were noted for the AQ with memory function (Rey Auditory Verbal Learning Test Delayed Recall, r = −0.61, p < 0.001) and executive function (Trails B, r = 0.53, p < 0.001). The findings of this study suggest that the AQ correlates well with several neuropsychological tests and lend further support to the validity of the AQ as a screening instrument for cognitive impairment.

Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease (AD) pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation and dysphasia. Positron emission tomography (PET) imaging using the amyloid ligand 18F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the cerebral cortex, thalamus and striatum, Braak stage II neurofibrillary degeneration and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that AD is the sole cause.

Alzheimer's disease is growing in prevalence worldwide. Though many Western countries have developed programs of surveillance and care around Alzheimer's disease and dementia, certain regions of the world are beginning to recognize the magnitude of the disease burden in the general population. In the Middle East, there is growing awareness of the burden of Alzheimer's disease and how it impacts health economics, care delivery, and research. Here we summarize the proceedings of the 5th International Conference on Alzheimer's Disease in the Middle East. We had speakers from 20 countries updating the audience on progress toward improving healthcare and research related to AD in this region of the world.

The field of Alzheimer's disease (AD) research eagerly awaits the results of a large number of Phase III clinical trials that are underway to investigate the effectiveness of anti-amyloid-β (Aβ) immunotherapy for AD. In this case report, we review the pertinent clinical history, examine the neuropathology, and characterize the Aβ profile of an AD patient who received bapineuzumab immunotherapy. The patient received four bapineuzumab infusions over a 39 week period. During the course of this treatment, there was no remarkable change in cognitive impairment as determined by MMSE scores. Forty-eight days after the fourth bapineuzumab infusion was given, MRI revealed that the patient had developed lacunar infarcts and possible vasogenic edema, probably related to immunotherapy, but a subsequent MRI scan 38 days later demonstrated resolution of vasogenic edema. The patient expired due to acute congestive heart failure complicated by progressive AD and cerebrovascular accident 378 days after the first bapineuzumab infusion and 107 days after the end of therapy. Neuropathological and biochemical analysis did not produce evidence of lasting plaque regression or clearance of Aβ due to immunotherapy. The Aβ species profile of this case was compared with non-immunized AD cases and non-demented controls and found to be similar to non-immunized AD cases. SELDI-TOF mass spectrometric analysis revealed the presence of full-length Aβ₁₋₄₂ and truncated Aβ peptides demonstrating species with and without bapineuzumab specific epitopes. These results suggest that, in this particular case, bapineuzumab immunotherapy neither resulted in detectable clearance of amyloid plaques nor prevented further cognitive impairment.

As the number of patients with Alzheimer disease is expected to grow, finding ways to prevent and lower the risk of Alzheimer disease becomes a crucial matter. Risk factors for developing AD have been identified including health conditions, dietary habits, genetics and heredity, gender, education, age, and lifestyle. Interventions targeted at some of these risk factors may offer opportunities for development of an optimal preventive strategy. Life style habits which include dietary habits and physical activities appear to have positive effect on modifying many risk factors. Studies have shown controversial results when it comes to the relation between the adherence to a Mediterranean diet and /or physical activity and the incidence of Alzheimer disease. Many population-based studies reported the positive association between antioxidants intake (like Vitamin E and C), and polyunsaturated fatty acids whether it is from the diet or supplements on the cognitive performance. Future investigations should aim to determine objectively whether lifestyle modification through diet, exercise, or vitamins/supplements truly exert risk reduction or outright prevention. In this review, life-style habits are reviewed as they pertain to influence on risk of developing AD as well as on cognitive decline. Epidemiological studies and animal studies are reviewed.

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.

Objective To determine the effect of memantine in the treatment of Dementia with Lewy Bodies (DLB). Background While memantine has been used to successfully treat moderate-to-severe Alzheimer's disease (AD) and some non AD dementias, no reports are available regarding the effect of the drug on DLB. Methods We reviewed the charts of 11 subjects with DLB by McKeith Criteria that were prospectively evaluated and treated with memantine (with or without cholinesterase inhibitors (ChEIs)) for varying lengths of time. Results 9 of 11 DLB subjects on memantine were also on ChEIs. Seven of eleven were stable or improved with memantine while the remaining four worsened or responded adversely when exposed to the drug. No adverse effects on motor function were observed. Conclusions Memantine can be used safely in patients with DLB, but its symptomatic effects may be variable.

Objective To characterize the lipid profile in Alzheimer's Disease (AD) and to determine whether it differs from the cardiac risk profile. Background Links between hypercholesterolemia and AD development continue to grow. Presently, limited information exists about the lipid profile characteristics in AD. Methods We examined the lipid profiles (total cholesterol (TC), high-density lipoprotein (HDL), lower-density lipoprotein (LDL), TC/HDL ratio, and triglyceride (TG) levels) of 153 subjects with probable/possible AD (mean age 77.2 +/- 8.6 years, mean MMSE 19.9 +/- 5.6) and 25 non-demented subjects with atherosclerotic heart disease (ASHD) (mean age 73.8 +/- 7.2 years); neither on lipid lowering therapy. Results Subjects with TC > 200 mg/dl composed 69% of AD and 72% of ASHD groups. Mean TC was 218.9 +/- 38.9 mg/dl and 218.5 +/- 9.2 mg/dl for AD and ASHD subjects respectively. AD subjects exhibited significantly higher HDL and lower TG and TC/HDL ratios. MMSE did not correlate with any lipid parameters in AD. Discussion Elevated TC, LDL and TG with normal HDL and TC/HDL ratio characterize the lipid profile in AD, which somewhat overlaps with but may be distinct from the cardiac risk profile. MMSE does not correlate with lipid parameters suggesting no interaction between cholesterol and cognition in AD.

Research on acetylcholinesterase inhibitors (ChEIs) indicates that long term exposure increases the level of nicotinic acetylcholine receptors (nAChRs) but the effects of donepezil on nAChRs are not well studied. Therefore, we investigated the effects of sub-chronic donepezil administration on nAChRs in rats and rat pheochromocytoma PC-12 cells. Male Sprague Dawley rats were administered donepezil (0.7 and 2.4 micromoles/kg), nicotine (2.5 micromoles/kg) or saline subcutaneously twice daily for 14 days, PC-12 cells were incubated with 10(-6) to 10(-4) M donepezil for 72 hours and nAChR levels were determined by receptor binding assay using the nAChR ligands [3H]-epibatidine (EPI) for non-alpha 7 nAChRs and [3H]-methyllyconitine (MLA) for alpha 7 nAChRs. Chronic donepezil administration at 1.4 micromoles/kg/day and 4.8 micromoles/ kg/day significantly increased [3H]-epibatidine binding in the cortex to 126 +/- 1.3% and 127 +/- 3.2% of the saline control animals, respectively. [3H]-MLA binding in the cortex increased to 114 +/- 4.4% and 124 +/- 2.8% of the control group for the high and low dose groups, respectively. Hippocampal [3H]-EPI binding in the low dose and high dose groups significantly increased to 135 +/- 3.6% and 125 +/- 4.6% of the controls, respectively while there were no changes in the level of [3H]-MLA binding. In striatal homogenates, neither [3H]-EPI nor [3H]-MLA binding were significantly effected at either dose of donepezil. In PC-12 cells, [3H]-EPI binding was increased at the non-physiological 10(-4)M concentration only. There was no effect of donepezil on [3H]-MLA binding at any concentration examined. These results indicate that donepezil increases cortical alpha 7 and non-alpha 7 nAChRs, hippocampal non-alpha 7 nAChRs but does not influence striatal nAChR levels. Furthermore, the lack of an effect on the alpha 7-nAChRs in PC-12 cells suggests that the increase in cortical alpha 7 nAChRs may be an indirect effect of increased acetylcholine levels in vivo.

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.

We thank the editorial staff and Dr. Ghosh-Dastidar and colleagues for their commentary on our manuscript “Relationship of Cognitive Measures and Gray and White Matter In Alzheimer’s Disease” [1]. Dr. GhoshDastidar and colleagues have provided an overview of voxel-based morphometry methodology as well as the strengths and limitations of utilizing this technique in investigating MRI features done during clinical studies of various diseases. We agree that the sample size of this study is not sufficient to make general statements about its utility in investigating MRI changes in Alzheimer’s disease. Instead, we hope the findings of this study will provide interest in larger studies that further characterize the underlying neural changes associated with cognitive measures. We hope that we provide an example of how voxel-based morphometry can help answer these basic questions about the commonly used cognitive tests. Another important point that is discussed by GhoshDastidar et al. is the use of a custom template for image registration. It may be true that study-specific custom templates limit our ability to directly compare to other studies, but this technique minimizes mis-registration due to the obvious differences in elderly compared to the MNI composite and other templates. These limitations will likely be resolved with studies such as the Alzheimer’s Disease Neuroimaging Initiative, that will allow the creation of templates from studies of large numbers of elderly subjects. We look forward to seeing more studies of Alzheimer’s disease using VBM as we believe this technology may have an important role in elucidating how the brain adapts to stimuli and disease.