Slower Rate Of Disease Progression Research Articles

Adherence to cognitive and physical exercise engagement: a challenge to successful dementia risk reduction and prevention efforts

With human life expectancy and proportion of older adults increasing, global use of evidence-supported preventative methods to minimize risk of brain-related disabilities such as Alzheimer's disease and other dementias—as well as interventions to slow rate of disease progression—is important. Sustained engagement in cognitive and physical exercise programs may prevent or delay dementia onset as well as maximize health and function of those with dementia. Despite awareness of the importance of cognitive and physical exercise to brain health, exercise program adherence by older adults is extremely challenging. In this Perspective article, we summarize what is known about contributors to exercise program adherence and strategies to promote it. We discuss our viewpoint on knowledge gaps regarding exercise adherence and research that needs to be conducted. We conclude by proposing a multi-dimensional exercise adherence assessment framework that includes portable neurophysiologic technologies to inform initial design and updating of individualized exercise programs that optimize sustained exercise program engagement and, ultimately, maximize brain health in older adults with and without mild cognitive impairment and dementia.

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications.

Iron is essential for all organisms and cells. Diseases of iron imbalance affect billions of patients, including those with iron overload and other forms of iron toxicity. Excess iron load is an adverse prognostic factor for all diseases and can cause serious organ damage and fatalities following chronic red blood cell transfusions in patients of many conditions, including hemoglobinopathies, myelodyspasia, and hematopoietic stem cell transplantation. Similar toxicity of excess body iron load but at a slower rate of disease progression is found in idiopathic haemochromatosis patients. Excess iron deposition in different regions of the brain with suspected toxicity has been identified by MRI T2* and similar methods in many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Based on its role as the major biological catalyst of free radical reactions and the Fenton reaction, iron has also been implicated in all diseases associated with free radical pathology and tissue damage. Furthermore, the recent discovery of ferroptosis, which is a cell death program based on free radical generation by iron and cell membrane lipid oxidation, sparked thousands of investigations and the association of iron with cardiac, kidney, liver, and many other diseases, including cancer and infections. The toxicity implications of iron in a labile, non-protein bound form and its complexes with dietary molecules such as vitamin C and drugs such as doxorubicin and other xenobiotic molecules in relation to carcinogenesis and other forms of toxicity are also discussed. In each case and form of iron toxicity, the mechanistic insights, diagnostic criteria, and molecular interactions are essential for the design of new and effective therapeutic interventions and of future targeted therapeutic strategies. In particular, this approach has been successful for the treatment of most iron loading conditions and especially for the transition of thalassemia from a fatal to a chronic disease due to new therapeutic protocols resulting in the complete elimination of iron overload and of iron toxicity.

Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.

CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS). RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N=45) were randomised 1:1 to receive 30mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively. In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI:-11.9 to 27.3%, p=0.43), total MUNIX score change (18.8, 95% CI:-56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI:-12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio=0.408 (95% Wald CI: 0.166 to 1.001, log-rank p=0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed. CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS. The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.

Hyper-religiosity and visual hallucinations in a patient with frontotemporal dementia carrying a double variant in GRN gene

Introduction: Hyper-religiosity has been reported in patients affected by frontotemporal dementia (FTD) with asymmetrical, predominantly right-sided frontotemporal atrophy. Case report: We report a FTD patient carrying a double genetic variant (p.Cys139Arg and c.*78C > T) in the progranulin (GRN) gene who showed an unusual clinical phenotype characterized by hyper-religiosity behavior and visual hallucinations with exclusively religious content. Noteworthy, this patient exhibited a slow clinical and radiological rate of disease progression and a predominantly left-sided frontotemporal atrophy. Discussion and conclusion: The simultaneous presence of these GRN variants in our FTD patient with predominant atrophy in the left (dominant) hemisphere could determine the unusual phenotype with hyper-religiosity and visual hallucinations with exclusively religious content and influence the slow rate of disease progression.

Role of Circulating T Follicular Helper Cells and Stem-Like Memory CD4+ T Cells in the Pathogenesis of HIV-2 Infection and Disease Progression.

CD4+ T cells are critical players in the host adaptive immune response. Emerging evidence suggests that certain CD4+ T cell subsets contribute significantly to the production of neutralizing antibodies and help in the control of virus replication. Circulating T follicular helper cells (Tfh) constitute a key T cell subset that triggers the adaptive immune response and stimulates the production of neutralizing antibodies (NAbs). T cells having stem cell-like property, called stem-like memory T cells (Tscm), constitute another important subset of T cells that play a critical role in slowing the rate of disease progression through the differentiation and expansion of different types of memory cell subsets. However, the role of these immune cell subsets in T cell homeostasis, CD4+ T cell proliferation, and progression of disease, particularly in HIV-2 infection, has not yet been elucidated. The present study involved a detailed evaluation of the different CD4+ T cell subsets in HIV-2 infected persons with a view to understanding the role of these immune cell subsets in the better control of virus replication and delayed disease progression that is characteristic of HIV-2 infection. We observed elevated levels of CD4+ Tfh and CD4+ Tscm cells along with memory and effector T cell abundance in HIV-2 infected individuals. We also found increased frequencies of CXCR5+ CD8+ T cells and CD8+ Tscm cells, as well as memory B cells that are responsible for NAb development in HIV-2 infected persons. Interestingly, we found that the frequency of memory CD4+ T cells as well as memory B cells correlated significantly with neutralizing antibody titers in HIV-2 infected persons. These observations point to a more robust CD4+ T cell response that supports B cell differentiation, antibody production, and CD8+ T cell development in HIV-2 infected persons and contributes to better control of the virus and slower rate of disease progression in these individuals.

The relative efficiency of time-to-progression and continuous measures of cognition in presymptomatic Alzheimer's disease

IntroductionClinical trials on preclinical Alzheimer’s disease are challenging because of the slow rate of disease progression. We use a simulation study to demonstrate that models of repeated cognitive assessments detect treatment effects more efficiently than models of time to progression. MethodsMultivariate continuous data are simulated from a Bayesian joint mixed-effects model fit to data from the Alzheimer’s Disease Neuroimaging Initiative. Simulated progression events are algorithmically derived from the continuous assessments using a random forest model fit to the same data. ResultsWe find that power is approximately doubled with models of repeated continuous outcomes compared with the time-to-progression analysis. The simulations also demonstrate that a plausible informative missing data pattern can induce a bias that inflates treatment effects, yet 5% type I error is maintained. DiscussionGiven the relative inefficiency of time to progression, it should be avoided as a primary analysis approach in clinical trials of preclinical Alzheimer’s disease.

Electrical impedance myography in facioscapulohumeral muscular dystrophy: A 1‐year follow‐up study

Electrical impedance myography (EIM) is a noninvasive technique for measuring muscle composition and a potential physiological biomarker for facioscapulohumeral muscular dystrophy (FSHD). Thirty-two participants with genetically confirmed and clinically affected FSHD underwent EIM in 7 muscles bilaterally. Correlations between EIM and baseline clinical measures were used to select EIM variables of interest in FSHD, and EIM and clinical measures were followed for 1 year. There were no significant changes in the EIM variables. Although 50-kHZ reactance correlated the strongest with clinical measures at baseline, the 50-211-kHZ phase ratio demonstrated lower within-subject 12-month variability, potentially offering sample size savings for FSHD clinical trial planning. EIM did not identify significant disease progression over 12 months. It is currently unclear whether this is because of limitations of the technology or the slow rate of disease progression in this cohort of FSHD patients over this period of time. Muscle Nerve 58: 213-218, 2018.

Activation of autophagy in peripheral blood mononuclear cells in amyotrophic lateral sclerosis

Introduction. Accumulation of intracellular protein aggregates is one of the key processes in pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is a complex process during which cell components and organelles are transferred inside lysosomes and are degraded. Autophagy disturbance was found to take place in various neurodegenerative diseases. Autophagy alteration can be observed not only in the central nervous system but also in peripheral blood mononuclear cells (PBMCs). Protein LC3 is the key marker of autophagy. Objective. To determine protein LC3 concentration in PBMCs of ALS patients and to analyze the relationship between this parameter and clinical characteristics of the disease. Materials and methods. The study involved 66 patients with definite ALS and 15 healthy volunteers. Past medical history was elicited in all patients; neurological examination and the pulmonary function test were performed. PBMCs were isolated from blood of patients and healthy volunteers. The cells were lysed and subjected to Western blot analysis using anti-LC3 antibodies. Results. The LC3-I level in PBMCs of ALS patients was increased compared to that in the control group (p<0.001). The LC3-I/LC3-II level was elevated in patients with the lumbosacral form of ALS (stage II ALS and the slow rate of disease progression). The tendency towards increased LC3-II level was observed for the bulbar form and stage III ALS. Conclusions. The results demonstrated for the first time that PBMCs of ALS patients tend to exhibit a higher level of autophagy activity compared to healthy volunteers.

Preproinsulin specific CD8 + T cells in subjects with latent autoimmune diabetes show lower frequency and different pathophysiological characteristics than those with type 1 diabetes

Latent autoimmune diabetes in adults (LADA) resembles type 1 diabetes (T1D) in disease presentation except that its onset is slow. We compared pathophysiological characteristics of CD8+ T cells recognizing preproinsulin (PPI) derived epitopes in both disease groups using MHC-I dextramers (DMRs) in peripheral blood and after in-vitro stimulation with PPI. Subjects with T1D harbored higher frequency of DMR+ CD8+ T cells with relatively higher frequency of effector T cell subsets. Following stimulation with PPI, an increase in DMR+ CD8+ T cells, particularly the central-memory subset was observed in T1D group, whereas no significant change in DMR+ CD8+ T cell subsets was observed in LADA group. Intracellular expression of Granzyme-B and Perforin in DMR+ CD8+ T cells was comparable in both the groups. In conclusion, lower frequency and inferior proliferative potential on account of a relatively restrained central-memory subset of PPI specific CD8+ T cells are associated with slow rate of disease progression in LADA.

Slow progression of exudative age related macular degeneration associated with hypertrophy of the retinal pigment epithelium.

Choroidal neovascular (CNV) lesions in younger patients are often accompanied by the appearance of a surrounding ring of pigment that is associated with disease regression or slowed disease progression. In older patients with age-related macular degeneration (AMD), however, hypertrophy of the retinal pigment epithelium (RPE) is known to occur but has not previously been reported to be associated with CNV regression. This report describes the clinical course of a case series of AMD patients with pigment hypertrophy adjacent to CNV associated with stabilization of the CNV lesion. A retrospective analysis of exudative AMD patients seen by a single retina specialist over a 7-year period. Retrospective analysis of 955 exudative AMD patients revealed pigment hypertrophy associated with CNV in 33 patients. A ring of pigment surrounded CNV in 6 of these. Three representative patients are presented to illustrate the decrease in macular edema, reduced fluorescein leakage and slowed CNV progression that was associated with a pigment ring around CNV in AMD. Pigment hypertrophy was associated with blocked fluorescein leakage and exudative AMD patients with a complete pigment ring maintained stable visual acuity, macular edema, fluorescein leakage and CNV lesion size without treatment for intervals of up to 21 months. We report slowed disease progression in AMD patients who develop pigment around CNV. The slow rate of disease progression in the AMD patient subgroup having a pigment ring is a factor to consider in determining the treatment interval for exudative AMD patients.

Women with Chronic Hepatitis C Virus Infection

The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited.

Characteristics, Pathophysiology and Clinical Management of Weight Loss in Huntington’s Disease

SUMMARY Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. Clinically, the disease is characterized by motor impairment, cognitive deterioration and behavioral disturbances. Unintended weight loss is also a hallmark of the disease and frequently leads to general weakening and a decline in the quality of life of HD patients. Moreover, a higher BMI has been associated with a slower rate of disease progression. In this review, the authors first delineate the characteristics of weight loss in both HD patients and genetic models of the disease. Subsequently, they discuss the pathophysiological processes underlying weight loss in HD and highlight the implications for management and care of HD patients with, or at risk of, unintended weight loss.

Nutritional and Metabolic Support in Adults With Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable, degenerative, neuromuscular condition. Nutritional and metabolic support is an integral component of care for patients with ALS because those capable of maintaining a normal nutrition status exhibit a slower rate of disease progression. Although there are multiple barriers to maintaining a normal nutrition status, the multidisciplinary team approach can facilitate early identification of symptoms, early intervention, and better outcomes for these patients. Barriers that patients often encounter include dysphagia, hypermetabolism, hypometabolism, upper extremity weakness, early satiety, constipation, depression, and loss of appetite. The role of the registered dietitian in the multidisciplinary ALS clinic is to intervene by providing a high standard of nutrition support. Further research into other facets of nutrition for ALS could lead to new interventions to slow weight loss and provide evidence-based guidelines for nutrition professionals. Areas for further research include the use of appetite stimulants, dietary supplements, delayed gastric motility, diet composition, metabolic rate, and the development of a standard equation for estimation of caloric needs in ALS.

Inhibition of HIV-1 Disease Progression by Contemporaneous HIV-2 Infection

BackgroundProgressive immune dysfunction and the acquired immunodeficiency syndrome (AIDS) develop in most persons with untreated infection with human immunodeficiency virus type 1 (HIV-1) but in only approximately 20 to 30% of persons infected with HIV type 2 (HIV-2); among persons infected with both types, the natural history of disease progression is poorly understood.MethodsWe analyzed data from 223 participants who were infected with HIV-1 after enrollment (with either HIV-1 infection alone or HIV-1 and HIV-2 infection) in a cohort with a long follow-up duration (approximately 20 years), according to whether HIV-2 infection occurred first, the time to the development of AIDS (time to AIDS), CD4+ and CD8+ T-cell counts, and measures of viral evolution.ResultsThe median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with dual infection and 68 months (95% CI, 60 to 76) in participants infected with HIV-1 only (P=0.003). CD4+ T-cell levels were higher and CD8+ T-cell levels increased at a lower rate among participants with dual infection, reflecting slower disease progression. Participants with dual infection with HIV-2 infection preceding HIV-1 infection had the longest time to AIDS and highest levels of CD4+ T-cell counts. HIV-1 genetic diversity was significantly lower in participants with dual infections than in those with HIV-1 infection alone at similar time points after infection.ConclusionsOur results suggest that HIV-1 disease progression is inhibited by concomitant HIV-2 infection and that dual infection is associated with slower disease progression. The slower rate of disease progression was most evident in participants with dual infection in whom HIV-2 infection preceded HIV-1 infection. These findings could have implications for the development of HIV-1 vaccines and therapeutics. (Funded by the Swedish International Development Cooperation Agency–Swedish Agency for Research Cooperation with Developing Countries and others.)

D-Serine Production, Degradation, and Transport in ALS: Critical Role of Methodology

In mammalian systems, D-serine is perhaps the most biologically active D-amino acid described to date. D-serine is a coagonist at the NMDA-receptor, and receptor activation is dependent on D-serine binding. Because D-serine binding dramatically increases receptor affinity for glutamate, it can produce excitotoxicity without any change in glutamate per se. D-serine is twofold higher in the spinal cords of mSOD1 (G93A) ALS mice, and the deletion of serine racemase (SR), the enzyme that produces D-serine, results in an earlier onset of symptoms, but with a much slower rate of disease progression. Localization studies within the brain suggest that mSOD1 and subsequent glial activation could contribute to the alterations in SR and D-serine seen in ALS. By also degrading both D-serine and L-serine, SR appears to be a prime bidirectional regulator of free serine levels in vivo. Therefore, accurate and reproducible measurements of D-serine are critical to understanding its regulation by SR. Several methods for measuring D-serine have been employed, and significant issues related to validation and standardization remain unresolved. Further insights into the intracellular transport and tissue-specific compartmentalization of D-serine within the CNS will aid in the understanding of the role of D-serine in the pathogenesis of ALS.

Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis as a system failure is a concept supported by the finding of consistent extramotor as well as motor cerebral pathology. The functional correlates of the structural changes detected using advanced magnetic resonance imaging techniques such as diffusion tensor imaging and voxel-based morphometry have not been extensively studied. A group of 25 patients with amyotrophic lateral sclerosis was compared to healthy control subjects using a multi-modal neuroimaging approach comprising T(1)-weighted, diffusion-weighted and resting-state functional magnetic resonance imaging. Using probabilistic tractography, a grey matter connection network was defined based upon the prominent corticospinal tract and corpus callosum involvement demonstrated by white matter tract-based spatial statistics. This 'amyotrophic lateral sclerosis-specific' network included motor, premotor and supplementary motor cortices, pars opercularis and motor-related thalamic nuclei. A novel analysis protocol, using this disease-specific grey matter network as an input for a dual-regression analysis, was then used to assess changes in functional connectivity directly associated with this network. A spatial pattern of increased functional connectivity spanning sensorimotor, premotor, prefrontal and thalamic regions was found. A composite of structural and functional magnetic resonance imaging measures also allowed the qualitative discrimination of patients from controls. An integrated structural and functional connectivity approach therefore identified apparently dichotomous processes characterizing the amyotrophic lateral sclerosis cerebral network failure, in which there was increased functional connectivity within regions of decreased structural connectivity. Patients with slower rates of disease progression showed connectivity measures with values closer to healthy controls, raising the possibility that functional connectivity increases might not simply represent a physiological compensation to reduced structural integrity. One alternative possibility is that increased functional connectivity reflects a progressive loss of inhibitory cortical influence as part of amyotrophic lateral sclerosis pathogenesis, which might then have relevance to future therapeutic strategies.

Strategies to quantify unspliced and multiply spliced mRNA expression in HIV-2 infection

HIV-2 infection is associated with a slower rate of disease progression with limited impact on the survival of the majority of infected adults, and much lower plasma viral load than HIV-1. In spite of the major differences in viremia, the quantitative assessment of HIV-2 proviral load documented levels similar to those observed in HIV-1 infected individuals, suggesting an equivalent number of circulating infected cells in both infections. It remains unclear whether this apparent paradox results from a contribution of latent/quiescent viruses or from transcriptional and/or post-transcriptional control of HIV-2 replication. In order to investigate these possibilities, a one-step and two-step reverse transcription quantitative real-time PCR based methods (RT-qPCR) for gag and tat mRNA HIV-2 transcripts were developed. These methods were validated and compared to assess the expression of HIV-2 gag and tat transcripts in parallel with proviral DNA and viral production. The results suggest that the two-step approach may allow a better detection of low level gag and tat mRNA HIV-2 transcripts.

American association for the study of liver diseases endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis

American association for the study of liver diseases endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis

Viral Genetic Determinants of Nonprogressive HIV Type 1 Subtype C Infection in Antiretroviral Drug-Naive Children

Characterization of HIV-1 from slow progressors is important to facilitate vaccine and antiviral drug development. To identify virus attenuations that may contribute to slower rates of disease progression, the full-length viral genomes from primary isolates of six slow progressing HIV-positive children were sequenced. Proviral DNA was extracted from cocultured peripheral blood mononuclear cells and used to PCR amplify, sequence, and extensively analyze the near full-length genomes and LTR regions. All primary HIV-1 isolates were HIV-1 subtype C throughout their genome, and amino acid (AA) sequence analysis revealed open reading frames for all genes. However, all isolates had at least one unusual gene/protein. For example, isolate LT5 had a 2AA insertion in the Vpr mitochondriotoxic domain. Isolate LT21 contained an additional 5AA in the C-terminus of tat exon 2, while integrase in isolate LT39 had an additional 4AA at the C-terminus. Rev from isolates LT45 and LT46 did not have the characteristic subtype C 16AA truncation, and in addition, had a further 3AA. Furthermore, altered functional domains were noted in several isolates, such as the cAMP-dependent kinase PKA phosphorylation site in Nef (LT5), a Vpr mutation involved in decreased proapoptotic activity (all isolates), and the Nef ExxxLL motif involved in the interaction with AP-1 and AP-2 (LT46). The slower HIV-1 disease progression in these six children may be attributed to altered protein functions. For example, LT46 Nef is unable to bind AP-1 and AP-2 and therefore is inactive on CD4 endocytosis. The biological relevance of these findings requires further investigation.

A disease progression meta-analysis model for cognitive deterioration in patients with Alzheimer's disease

Previously, efforts have been made by various authors to evaluate disease progression in Alzheimer's disease (AD), utilizing patient data from individual clinical studies or pooled patient data across studies. In this analysis, we conducted a systematic review of public data sources from 1990 to 2008 of all available studies of acetylcholinesterase (AChE) inhibitors, as well as clinical studies evaluating the rate of deterioration in AD patients (e.g. Vitamin E study). The unique aspect of this analysis is that we have developed a model to describe the longitudinal response in ADAS-cog (change from baseline) in patients with mild-to-moderate AD and estimate disease progression in both placebo-treated and AChE inhibitor-treated patients. A total of 52 trials, with data from 19,972 patients and 84,441 individual observations, were identified. From these, we obtained 576 mean change in ADAS-cog scores from baseline values, spanning 12 weeks to 3 years of treatment. The model described the rate of disease progression, the placebo effect observed, and the symptomatic effect of AChE inhibitors. Baseline ADAS-cog, MMSE, age and publication year were tested as covariates. Disease progression in patients with mild-to-moderate AD across all available and relevant literature sources was estimated as 5.5 points per year (95% CI: 4.9-6.1) with baseline ADAS-cog of 25. An Emax-over time model best described the symptomatic drug effect for AChE inhibitors. Baseline ADAS-cog was a significant covariate on disease progression in that greater baseline impairment was associated with faster cognitive decline. The model was not able to describe any effect of baseline age, likely due to the narrow distribution of mean age (literature-level analysis). There was no significant impact of publication year in the model. Baseline ADAS-cog was a significant covariate on disease progression, and describes, or at least explains, the different rates of deterioration observed in mild versus moderate stages of AD. There was no significant impact of publication year in the model, suggesting a slower rate of disease progression has not been observed in more recent trials. Differences from various previous analyses may be due to differences in underlying disease severity in the datasets used.