Current Alzheimer Research (v.9, #9)

ERRATUM (-).

Despite the growing interest in cognitive training programs as a potential non-pharmacological approach to slowing cognitive decline in mild cognitive impairment (MCI), there has been little research on the differential effectiveness of training among subtypes of MCI (i.e., amnestic, single non-amnestic, and multi-domain). The current study examined the longitudinal effects of cognitive speed of processing training (SOPT) among older adults with psychometricallydefined MCI from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial. Mixed model ANOVAs examined the effectiveness of SOPT in participants with MCI relative to controls and also compared training effectiveness in MCI subgroups to appropriate controls. A mixed effects model compared SOPT training effects longitudinally across five years relative to controls. A second mixed effects model compared the durability of training gains between the MCI subtypes across 5 years. All subtypes of MCI showed immediate improvement post-training relative to controls, with the single non-amnestic subtype showing the most benefit. Additionally, all subtypes showed similar trajectories across five years. There were no significant changes in performance across time, indicating initial training gains were maintained. These results provide support for the effectiveness and potential durability of SOPT among persons with MCI regardless of subtype. Future research should investigate if SOPT transfers to improvements in the everyday functioning of those with MCI.

The Animal Models of Dementia and Alzheimer’s Disease for Pre-Clinical Testing and Clinical Translation by Akshay Anand, Avijit Banik, Keshav Thakur, Colin L. Masters (1010-1029).
Dementia is a clinical syndrome with abnormal degree of memory loss and impaired ability to recall events from the past often characterized by Alzheimer’s disease. The various strategies to treat dementia need validation of novel compounds in suitable animal models for testing their safety and efficacy. These may include novel anti-amnesic drugs derived from synthetic chemistry or those derived from traditional herbal sources. Multiple approaches have been adopted to create reliable animal models ranging from rodents to non-human primates, where the animals are exposed to a predetermined injury or causing genetic ablation across specific regions of brain suspected to affect learning functions. In this review various animal models for Alzheimer’s disease and treatment strategies in development of anti dementia drugs are discussed and an attempt has been made to provide a comprehensive report of the latest developments in the field.

Enhancement of neurogenesis and stem cell transplantation are potential therapies for neurodegenerative diseases. In Alzheimer’s disease (AD) newborn neural cells and the transplanted cells encounter a diseased brain where the accumulation of toxic amyloid-β (Aβ) peptides disturbs normal functions and interactions of brain cells. In addition, ADlinked mutatations in newborn neurons or autologously transplanted neural progenitor cells (NPCs) are likely to affect the fate of these cells. Here we analyzed the effect of AD-linked APdE9 mutant on NPCs in culture and by isolating NPCs from APdE9 transgenic mice and transplanting them into APdE9 and wild type mouse brain. We show that the brain environment in APdE9 mutant mice reduced astrocytic differentiation but increased the survival and migration of NPCs in vivo. APdE9 mutation of NPCs increased neuronal differentiation also in vitro. Instead extracellular Aβ42 peptide decreased the survival, neuronal differentiation and migration of NPCs in vitro, whereas Aβ40 had an opposite effect. NPC transplantation induced brain neurogenesis, which was not altered in Aβ burdened APdE9 brain or by APdE9 mutant in NPCs. Thus, AD-linked mutations in newborn neural cells or NPCs do not compromise the utilization of enhanced neurogenesis or autologous NPC transplantation as potential therapies. The results suggest that combining the treatments resulting in reduced Aβ42 and enhanced neurogenesis may be one therapeutic approach to be explored in AD.

All Cognitive Systems but Speed and Visuospatial Functions Reduce the Effect of CSF Pathology on Other Systems by Sindre Rolstad, Anne I. Berg, Henrik Zetterberg, Boo Johansson, Anders Wallin (1043-1049).
The concept of reserve can be conceived as differences in the ability to compensate for pathology by recruiting additional or alternative networks. The purpose of this study was to examine whether certain cognitive systems may compensate for the effect of CSF amyloid beta 42 (Aβ42) and total tau (T-tau) on other cognitive systems. Five hundred and nine participants underwent neuropsychological examination and lumbar puncture. Multiple regression was performed with interaction terms to test whether a cognitive system reduced the impact of CSF pathology on other systems. All cognitive systems except speed and visuospatial functions were associated with reduced effects of T-tau and Aβ42 on semantic memory, working memory and visuospatial abilities. The burden of Aβ42 was reduced more often than that of T-tau. Our results suggest that most cognitive systems may be beneficial to maintenance of cognitive performance despite CSF burden. The results support the notion of cognitive reserve.

Measuring Alzheimer Disease Progression with Transition Probabilities: Estimates from NACC-UDS by D. Eldon Spackman, Srikanth Kadiyala, Peter J. Neumann, David L. Veenstra, Sean D. Sullivan (1050-1058).
Objectives: Estimate the probabilities, for Alzheimer's disease (AD) patients, of transitioning between stages of disease severity (mild, moderate, severe, dead) and care settings (community, institutional). Methods: Data were compiled by the National Alzheimer Coordinating Center. The main analyses were limited to 3,852 patients who were 50 years old, diagnosed with possible/probable AD and had at least two center visits. A multinomial logistic model accounting for patient and center level correlation was used to calculate transition probabilities between stages of the Clinical Dementia Rating (CDR). Separately we calculated the probabilities of being institutionalized based on CDR stage. Both analyses controlled for baseline age, time between visits, sex, marital status, whether white, whether Hispanic and number of years of education. Results: The annual probabilities of dying for patients in mild, moderate and severe health states were 5.5%, 21.5% and 48.0%, respectively, while the annual probabilities for institutionalization were 1.2%, 3.4% and 6.6%, respectively. The majority of mild and moderate patients remain in the same health state after one year, 77.4% and 50.1% respectively. Progressing patients are most likely to transition one stage, but 1.3% of mild patients become severe in one year. Some patients revert to lower severity stages, 7% from moderate to mild. Conclusions: Transition probabilities to higher CDR stages and to institutionalization are lower than those published previously, but the probability of death is higher. These results are useful for understanding AD progression and can be used in simulation models to evaluate costs and compare new treatments or policies.

Cerebral vasogenic edema and microhemorrhages are potential safety concerns for compounds intended to treat subjects with Alzheimer’s disease (AD) by targeting amyloid β (Aβ). Ponezumab (PF-04360365) is an investigational anti-Aβ monoclonal antibody. Two hundred female mice (APPK670N;M671L; Tg2576) 16–19 months old received an aglycosylated CHO-derived murine surrogate of ponezumab by intraperitoneal administration once weekly for up to 26 weeks at doses of 0, 10, 30, or 100 mg/kg. Drug exposure and plasma Aβ levels increased with increasing dose. After 26 weeks, the 100 mg/kg group had significantly greater plasma levels of Aβ1-x and Aβx-40 than the vehicle group (p < 0.001). Brain microhemorrhages were identified histologically using hematoxylin and eosin and/or Perls’ Prussian blue iron staining. The incidence in the vehicle group was equal to or higher than those of the treated groups. There was no evidence of vasogenic edema. In summary, intraperitoneal administration of a murine surrogate of ponezumab to aged Tg2576 mice for up to 6 months did not produce any compound-related brain microhemorrhage or other pathologies.

Low 25OH Vitamin D2 Levels Found in Untreated Alzheimer’s Patients, Compared to Acetylcholinesterase-Inhibitor Treated and Controls by Iltaf Shah, Andrea Petroczi, Naji Tabet, Anthony Klugman, Mokhtar Isaac, Declan P. Naughton (1069-1076).
Following contradictory reports, the aim of this study was to apply our highly specific novel assay to delineate the relationship between vitamin D forms and Alzheimer’s disease. The study incorporated patients, both untreated and treated with acetylcholinesterase inhibitors, along with controls. Patients were grouped as A: untreated (n=26) and B: treated with donepezil, rivastigmine or galantamine (n=44). The study included a control Group (C, n=35) with no cognitive impairment. Cognitive function was assessed using the MMSE. Levels of vitamin D forms were measured using liquid chromatography-mass spectrometry (LC-MS/MS) and calcium measurements were conducted using inductively coupled plasma-mass spectrometry (ICP-MS). In the cohort studied, no relationship was observed between MMSE score, calcium and any form of vitamin D. The indisputable finding is that the level of 25hydroxyvitamin D2 (25OHD2) (3.165±6.352 nmol/L, p < 0.001) was significantly lower in the untreated Group (A) compared to the control and treated groups (7.932±9.196 and 12.138±15.682 nmol/L, respectively). In contrast, the levels of the primary forms, vitamin D2 and total vitamin D were the highest for the untreated group. Vitamin D levels, assessed as 25OHD are significantly lower in patients suffering from Alzheimer’s disease arising from extremely low levels of 25OHD2 along with low levels of 25OHD3. Treatment with acetylcholinesterase inhibitors reverses this deficit. Further research is warranted to delineate the mode of action of acetylcholinesterase inhibitors with respect to normalising 25OHD2 levels. These observations resulted in the hypothesis that along with the common functions of vitamin D, different forms have distinct roles in health and disease.

The Role for Oxidative Stress in Aberrant DNA Methylation in Alzheimer’s Disease by Jessica L. Fleming, Christopher J. Phiel, Amanda Ewart Toland (1077-1096).
Alzheimer’s disease (AD) is a common, progressive neurodegenerative disorder without highly effective therapies. The etiology of AD is heterogeneous with amyloid-beta plaques, neurofibrillary tangles, oxidative stress, and aberrant DNA methylation all implicated in the disease pathogenesis. DNA methylation is a well-established process for regulating gene expression and has been found to regulate a growing number of important genes involved in AD development and progression. Additionally, aberrations in one-carbon metabolism are a common finding in AD patients with individuals exhibiting low S-adenosylmethionine and high homocysteine levels as well as low folate and vitamin B. Oxidative stress is considered one of the earliest events in AD pathogenesis and is thought to contribute largely to neuronal cell death. Emerging evidence suggests an interaction exists between oxidative stress and DNA methylation; however, the mechanism(s) remain unclear. This review summarizes known and potential genes implicated in AD that are regulated by DNA methylation and oxidative stress. We also highlight the evidence for the role of oxidative damage contributing to DNA hypomethylation in AD patients through several mechanisms as well as implications for disease understanding and therapeutic development.

Patterns of Gray and White Matter Changes in Individuals at Risk for Alzheimer’s Disease by Heidi I.L. Jacobs, Martin P.J. van Boxtel, Ed H.B.M. Gronenschild, Victoria J. Williams, Saartje Burgmans, Harry B.M. Uylings, Jelle Jolles, Frans R.J. Verhey (1097-1105).
Structural brain changes precede cognitive and clinical symptoms in Alzheimer’s disease (AD). We aimed to examine the gray and white matter tissue changes in individuals with memory decline over a 12-year period, who might be at risk for AD. The participants were selected from the longitudinal Maastricht Aging Study based on their scores on the verbal word learning task. A group with profound memory decline over a 12-year period (n = 20) was identified and matched with a group that did not meet this criterion (n = 20). All of the participants underwent MRI scanning. Diffusion tensor imaging and cortical thickness analyses were performed to investigate the white and gray matter differences respectively. We found decreased white matter integrity in the memory decline group compared to the control group in frontal and parietal brain regions and in several cortico-cortical and cortico-subcortical tracts. Cortical thinning in the memory decline group was found in frontal, parietal, medial temporal and occipital areas. These results showed similarities with the structural brain changes observed in early AD. Thus, not only may cognitive changes be detected years before the clinical diagnosis, but typical gray and white matter changes appear to be present in older people with memory decline as well. This suggests that a combination of cognitive decline and structural brain changes might be an ideal biomarker for AD pathogenesis.

Antipsychotic Use and Mortality Risk in Community-Dwelling Alzheimer’s Disease Patients: Evidence for a Role of Dementia Severity by Virginie Gardette, Maryse Lapeyre-Mestre, Nicola Coley, Christelle Cantet, Jean-Louis Montastruc, Bruno Vellas, Sandrine Andrieu (1106-1116).
Antipsychotics are widely used for the treatment of behavioral and psychological symptoms of dementia (BPSD). Concerns have been raised in the literature over the safety of antipsychotics, with suggestions of an increased risk of mortality. The objective of this study was to determine the all-cause mortality risk associated with antipsychotic use among Alzheimer’s disease (AD) patients. A new-user study was conducted in a multicentric prospective cohort, composed of 534 community-dwelling mild-to-moderate AD patients recruited in 16 French memory centers. A survival analysis using a Cox proportional hazards model assessed hazard ratios (HRs) for death according to either first or second generation antipsychotic use (time-varying variable). Among the 534 patients, 102 new users were identified throughout the 3.5 year-follow-up period and 113 deaths occurred. The main antipsychotics used were risperidone and tiapride. Unadjusted and sociodemographic-adjusted (age, gender, center) analyses suggested an increased risk of death with antipsychotic use (HR: 1.84; 95% CI: [1.09-3.09] and HR: 1.93; 95% CI: [1.15-3.25]) respectively). However, antipsychotic use did not appear to be an independent predictive factor of death when dementia severity (cognitive status) was accounted for during fully adjusted multivariate analyses (HR: 1.12; 95% CI: [0.59-2.12]). Antipsychotic use may be associated with an increased risk of mortality, but to a lesser extent than several other factors which were found to be significant predictors of mortality (age, male gender, cognitive score, recent hospitalisation, medical aid). To date, antipsychotic risks outweigh their benefits in BPSD for which non-pharmacological approaches remain the first-line strategy and should be privileged.