Arch Neurol. Author manuscript; available in PMC 2013 May 22.

Published in final edited form as: Arch Neurol. 2012 July; 69(7): 836–841.

Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures

Dr Douglas R. Galasko, MD, Dr Elaine Peskind, MD, Dr Christopher M. Clark, MD, Dr Joseph F. Quinn, MD, Dr John M. Ringman, MD, Dr Gregory A. Jicha, MD, PhD, Dr Carl Cotman, PhD, Ms Barbara Cottrell, BS, Dr Thomas J. Montine, MD, PhD, Dr Ronald G. Thomas, PhD, and Dr Paul Aisen, MD

Abstract

Objective

To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers.

Design

Double-blind, placebo-controlled clinical trial.

Setting

Academic medical centers.

Participants

Subjects with mild to moderate Alzheimer disease.

Intervention

Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo.

Main Outcome Measures

Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale).

Results

Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau₁₈₁ levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups.

Conclusions

Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted.

Citation

clinicaltrials.gov Identifier: NCT00117403
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661272/

PMCID: PMC3661272 NIHMSID: NIHMS446574

National Center for Biotechnology Information, U.S. National Library of Medicine

Asia Pac Psychiatry. 2012 Nov 29. doi: 10.1111/appy.12015. [Epub ahead of print]

Physical activity program preferences and perspectives of older adults with and without cognitive impairment.

Chong TW, Doyle CJ, Cyarto EV, Cox KL, Ellis KA, Ames D, Lautenschlager NT; AIBL Research Group.

Source

Melbourne Health/North Western Aged Persons Mental Health Program, Bundoora Extended Care Centre, Melbourne, Australia; Department of Psychiatry, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia.

Abstract

INTRODUCTION:

There is increasing evidence to support the benefits of physical activity on cognition in older adults. This paper describes (i) the attitudes, beliefs and barriers towards physical activity of older adults with and without cognitive impairment and (ii) their opinion of the attributes of the ideal physical activity program.

METHODS:

Thematic analysis of focus groups and individual interviews with 50 older adults with no cognitive impairment, subjective memory complaints, mild cognitive impairment and Alzheimer’s disease was performed.

RESULTS:

Consistent with previous research in cognitively intact older adults, most participants, irrespective of cognitive status, had a positive attitude towards physical activity and believed it was beneficial both generally and for cognition. There was a preference for physical activity programs to be suggested by advertising and general practitioners (GPs), undertaken in a group setting, and beliefs that they should be tailored to individual’s needs and preferences, and should be affordable according to their income. Participants with cognitive impairment cited specific barriers including “memory” and “lack of companion” as well as preferring “accessible” settings and “simple/light/safe” activities.

DISCUSSION:

These findings provide useful data, particularly from participants with cognitive impairment, with whom there has been little research to date. This could contribute to efforts to translate the growing research evidence of the benefits of physical activity for brain health into effective community programs.

Citation

http://www.ncbi.nlm.nih.gov/pubmed/23857923

PMID: 23857923 PubMed - as supplied by publisherCopyright © 2012 Wiley Publishing Asia Pty Ltd.

Dear Readers:

Gantenerumab is a Hoffmann-La Roche monoclonal antibody for the treatment of Alzheimer’s disease. The drug has passed Phase 1 and Phase 2 testing and is currently in Phase 3 testing (Last verified: May 2013). Phase 3 studies are intended to gather more information about the safety and effectiveness of a drug by studying different populations and different dosages and by using the drug in combination with other drugs.

To read about the gantenerumab clinical trial, go here: http://www.clinicaltrials.gov/show/NCT00531804

This Phase 3 study will evaluate the effect of gantenerumab on cognition and functioning and the safety and pharmacokinetics in patients with Alzheimer’s Disease. Patients will receive injections of either gantenerumab or a placebo. Patients will undergo positron emission tomography (PET) scanning to assess brain amyloid. The anticipated time on study treatment is 104 weeks, with an option for an additional two years of treatment.

I found some videos produced by Susanne Ostrowitzki, MD; Dennis Deptula, PhD; Lennart Thurfjell, PhD; et. al. in their study, Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab, (Arch Neurol. 2012;69(2):198-207. doi:10.1001/archneurol.2011.1538.)

If you are interested in seeing how gantenerumab treatment resulted in a reduction in brain amyloid level, take a look at these fascinating videos. Citations are listed below.

Gantenerumab is a drug to watch.

~ Jennifer

• Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab 1 Running Time: (00:48)

• Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab 2 Running Time: (00:47)

• Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab 3 Running Time: (00:47)

Citation

Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab

Susanne Ostrowitzki, MD; Dennis Deptula, PhD; Lennart Thurfjell, PhD; Frederik Barkhof, MD; Bernd Bohrmann, PhD; David J. Brooks, MD, DSc; William E. Klunk, MD; Elizabeth Ashford, BSc; Kisook Yoo, PhD; Zhi-Xin Xu, MD; Hansruedi Loetscher, PhD; Luca Santarelli, MD

Arch Neurol. 2012;69(2):198-207. doi:10.1001/archneurol.2011.1538.

JAMA Neurology

© 2013 American Medical Association.

BMC Neurosci. 2013 Apr 5;14:44. doi: 10.1186/1471-2202-14-44.

Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice.

Sivilia S, Lorenzini L, Giuliani A, Gusciglio M, Fernandez M, Baldassarro VA, Mangano C, Ferraro L, Pietrini V, Baroc MF, Viscomi AR,Ottonello S, Villetti G, Imbimbo BP, Calzà L, Giardino L.

Source

Department of Veterinary Medicine, University of Bologna, Bologna, Italy.

Abstract

BACKGROUND:

Alzheimer disease is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The pathological hallmarks includes extracellular amyloid plaques and intraneuronal neurofibrillary tangles, but the primary cause is only partially understood. Thus, there is growing interest in developing agents that might target multiple mechanisms leading to neuronal degeneration. CHF5074 is a nonsteroidal anti-inflammatory derivative that has been shown to behave as a γ-secretase modulator in vitro and to inhibit plaque deposition and to reverse memory deficit in vivo in transgenic mouse models of Alzheimer’s disease (AD). In the present study, the effects of a long-term (13-month) treatment with CHF5074 on indicators of brain functionality and neurodegeneration in transgenic AD mice (Tg2576) have been assessed and compared with those induced by a prototypical γ-secretase inhibitor (DAPT).

RESULTS:

To this end, plaque-free, 6-month-old Tg2576 mice and wild-type littermates were fed with a diet containing CHF5074 (125 and 375 ppm/day), DAPT (375 ppm/day) or vehicle for 13 months. The measured indicators included object recognition memory, amyloid burden, brain oligomeric and plasma Aβ levels, intraneuronal Aβ, dendritic spine density/morphology, neuronal cyclin A positivity and activated microglia. Tg2576 mice fed with standard diet displayed an impairment of recognition memory. This deficit was completely reverted by the higher dose of CHF5074, while no effects were observed in DAPT-treated mice. Similarly, amyloid plaque burden, microglia activation and aberrant cell cycle events were significantly affected by CHF5074, but not DAPT, treatment. Both CHF5074 and DAPT reduced intraneuronal Aβ content, also increasing Aβ40 and Aβ42 plasma levels.

CONCLUSIONS:

This comparative analysis revealed a profoundly diverse range of clinically relevant effects differentiating the multifunctional anti-inflammatory derivative CHF5074 from the γ-secretase inhibitor DAPT and highlighted unique mechanisms and potential targets that may be crucial for neuroprotection in mouse models of AD.

Citation

http://www.ncbi.nlm.nih.gov/pubmed/23560952
National Center for Biotechnology Information, U.S. National Library of Medicine

Int J Prev Med. 2013 May;4(Suppl 2):S205-10.

The effect of pioglitazone on the Alzheimer’s disease-induced apoptosis in human umbilical vein endothelial cells.

Dehghani L, Meamar R, Askari G, Khorvash F, Shaygannejad V, Pour AF, Javanmard SH.

Source

Department of Medical science, Najaf Abad Branch, Islamic Azad University, Isfahan, Iran.

Abstract

BACKGROUND

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and nowadays the role of endothelial cell (EC) injury has been proposed in pathological process in AD. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist has anti-inflammatory properties through activation in glial cells and improves vascular function and prevent atherosclerotic disease progression. The aim of this study is evaluation of pioglitazone effects as a drug of PPAR-γ agonist on endothelial apoptosis induced by sera from AD patients.

METHODS

Human umbilical vein endothelial cells (HUVECs) were treated with sera from AD patients (n = 10) and sera from controls (n = 10). Apoptosis was identified by annexin V-propidium iodide staining and cell death detection kit. Apoptosis was evaluated after and before adding of 10 μM pioglitazone on EC. Nitrite (NO2 (-)) levels were determined in the culture supernatants.

RESULTS

Induced apoptosis by the serum of patients was inhibited markedly when pioglitazone used before treating HUVECs with the sera of AD. Also, the measurement of nitrite concentration showed significantly greater levels of dissolved NO2/NO3 metabolite in the culture media of HUVECs treated by sera of AD patients (P < 0.05), while the rate of nitric oxide significantly decreased when pioglitazone exists in culture media.

CONCLUSION

Further studies are justified to investigate the novel role of the PPARs in the prevention of the neuronal and endothelial damage in neurological disorder and present a new therapeutic approach for Alzheimer’s patients.

Citation

http://www.ncbi.nlm.nih.gov/pubmed/23776725
National Center for Biotechnology Information, U.S. National Library of Medicine

Cold Spring Harb Perspect Med. 2012 April; 2(4): a006171.

doi: 10.1101/cshperspect.a006171

PMCID: PMC3312395

The Neuropsychological Profile of Alzheimer Disease

Sandra Weintraub,¹ Alissa H. Wicklund,¹ and David P. Salmon²

Abstract

Neuropsychological assessment has featured prominently over the past 30 years in the characterization of dementia associated with Alzheimer disease (AD). Clinical neuropsychological methods have identified the earliest, most definitive cognitive and behavioral symptoms of illness, contributing to the identification, staging, and tracking of disease. With increasing public awareness of dementia, disease detection has moved to earlier stages of illness, at a time when deficits are both behaviorally and pathologically selective. For reasons that are not well understood, early AD pathology frequently targets large-scale neuroanatomical networks for episodic memory before other networks that subserve language, attention, executive functions, and visuospatial abilities. This chapter reviews the pathognomonic neuropsychological features of AD dementia and how these differ from “normal,” age-related cognitive decline and from other neurodegenerative diseases that cause dementia, including cortical Lewy body disease, frontotemporal lobar degeneration, and cerebrovascular disease.

Over the past 30 years, neuropsychological assessment has featured centrally in characterizing the dementia associated with Alzheimer disease (AD), identifying the most salient and earliest cognitive and behavioral symptoms and contributing to the staging and tracking of disease (Flicker et al. 1984; Morris et al. 1989; Storandt and Hill 1989; Storandt 1991; Welsh et al. 1991, 1992; Locascio et al. 1995; Albert 1996;Storandt et al. 1998; see also Salmon and Bondi 2009). As research has increasingly focused on earlier stages of illness, it has become clear that biological markers of AD can precede cognitive and behavioral symptoms by years. It has also become clear that the early symptoms of AD represent the selective targeting by disease of specific, “large-scale” neuroanatomical networks, with clinical deficits consistent with the anatomical locus of impact (Weintraub and Mesulam 1993, 1996, 2009;Seeley et al. 2009). In the usual case, AD pathology is initially selective for limbic regions that subserve episodic memory, which leads to a circumscribed memory deficit in the early stages of the disease (Braak and Braak 1991; Jack et al. 1997; de Toledo-Morrell et al. 2000). It is only as pathology progresses to other neocortical regions over time (Braak and Braak 1996a,b; Braak et al. 1999; Jack et al. 2000) that additional cognitive symptoms emerge and the full dementia syndrome becomes apparent.

These discoveries have prompted a revision of the established research diagnostic criteria for AD dementia that had served so well since 1984 (McKhann et al. 1984). The new criteria define not only the dementia of AD (McKhann et al. 2011) but also incorporate a fuller spectrum of cognitive aging, including an intermediate stage of mild cognitive impairment (MCI) that precedes the dementia (Albert et al. 2011). A third, even earlier, stage of “preclinical AD” has also been identified (Sperling et al. 2011). This prodromal period is characterized by the presence of biomarkers, such as brain amyloid deposition and CSF tau and amyloid, that can be detected in vivo in asymptomatic individuals years before the onset of cognitive decline (Perrin et al. 2009; Sperling et al. 2009; Jack et al. 2010). At present, the recommended use of biomarkers to detect AD applies mainly to research. Thus, neuropsychological assessment continues to provide reliable symptom markers of AD that are critical for early diagnosis. The present article describes the profile of neuropsychological deficits associated with the dementia of AD and contrasts it with cognitive changes that occur in “normal” aging and in other forms of neurodegenerative disease that cause dementia.

NEUROPSYCHOLOGICAL DEFICITS IN ALZHEIMER DISEASE

Episodic Memory

The earliest neurofibrillary changes that are part of the pathology of AD usually occur in medial temporal lobe structures (e.g., hippocampus, entorhinal cortex; see Braak and Braak 1991), interrupting the neural network critical for episodic memory function. Thus, it is not surprising that a deficit in the ability to learn and remember new information (i.e., anterograde amnesia) is the clinical hallmark of AD pathology. However, the amyloid pathology that likely occurs years prior to the onset of symptoms (Morris et al. 1996; Reiman et al. 1996; Moonis et al. 2005; Mintun et al. 2006; Becker et al. 2010; De Meyer et al. 2010) is not particularly abundant in medial temporal lobe, but instead in the regions comprising the “default mode network” (Buckner et al. 2005; Sperling et al. 2009). These changes in the default mode network, comprised of a set of functionally interconnected cortical areas (posterior cingulate, inferior parietal lobule, lateral temporal neocortex, ventromedial and dorsomedial prefrontal cortex) that project heavily to medial temporal lobe structures (Buckner et al. 2008), presage cell death in the hippocampus by years.

Numerous studies have shown that patients with AD are impaired on episodic memory tests that use a variety of cognitive procedures (e.g., free recall, recognition, paired-associate learning) across virtually all modalities (e.g., auditory, visual, olfaction) (for review, see Salmon 2000). Evidence from many of these studies suggests that the episodic memory deficit of AD patients is due in large part to ineffective consolidation or storage of new information. Early studies that characterized the episodic memory deficit in AD used word list learning tasks such as those from the Consortium to Establish a Registry for Alzheimer Disease (CERAD) (Welsh et al. 1991) and the California Verbal Learning Test (CVLT) (Delis et al. 1991). These studies consistently showed that AD patients rapidly forget information over time and are equally impaired (relative to age-matched controls) on recognition and free recall components of the tasks. This pattern of performance is consistent with impaired consolidation rather than ineffective retrieval of new information (Delis et al. 1991).

Indices of rapid forgetting have important clinical utility for the early detection and differential diagnosis of AD. Welsh and colleagues (1991), for example, found that the amount of information recalled after a 10-min delay on the CERAD word list learning task differentiated very early AD patients from healthy elderly controls with better than 90% accuracy. This measure was superior in this regard to other measures derived from this task, including immediate recall on each of three learning trials, recognition memory score, and the number of intrusion errors produced throughout the test. Other studies have shown that measures of rapid forgetting can differentiate mildly demented AD patients from healthy elderly controls with ∼85%–90% accuracy (Flicker et al. 1984; Butters et al. 1988; Knopman and Ryberg 1989; Morris et al. 1991; Welsh et al. 1991; Tröster et al. 1993). Additional mechanisms contributing to episodic memory impairment in AD include increased sensitivity to interference due to decreased inhibitory processes leading to the production of intrusion errors (Fuld et al. 1982; Jacobs et al. 1990; Delis et al. 1991), and defective use of semantic information to bolster encoding (see Martin et al. 1985; Dalla Barba and Wong 1995; Dalla Barba and Goldblum 1996).

A number of prospective longitudinal studies of cognitive function in nondemented older adults have shown that a subtle decline in episodic memory often occurs before the emergence of the obvious cognitive and behavioral changes required for a clinical diagnosis of AD (Bondi et al. 1994; Jacobs et al. 1995; Linn et al. 1995; Grober and Kawas 1997; Howieson et al. 1997; Small et al. 2000; Backman et al. 2001; Kawas et al. 2003). Some of these studies suggest that memory performance may be poor, but stable, a number of years before the development of the dementia syndrome, and then declines rapidly in the period immediately preceding the AD dementia diagnosis. Small et al. (2000) and Backman et al. (2001), for example, found that episodic memory was mildly impaired 6 yr before dementia onset, but changed little over the next 3 yr. Chen et al. (2001) and Lange et al. (2002) showed a significant and steady decline in episodic memory on delayed recall conditions of word list and story memory tests beginning ∼3 yr before the dementia diagnosis in individuals who were either initially asymptomatic or met criteria for MCI at enrollment in these longitudinal studies. Taken together, these studies suggest that an abrupt decline in memory in an elderly individual might better predict the imminent onset of dementia than poor but stable memory ability. These and similar findings led to the development of formal criteria for amnestic MCI (see Petersen et al. 2001), a predementia condition in elderly individuals, which is characterized by subjective and objective memory impairment that occurs in the face of relatively preserved general cognition and functional abilities (for reviews, see Collie and Maruff 2000;Albert and Blacker 2006).

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Neurology 10.1212/WNL.0b013e31829c5e8a

July 3, 2013, doi: 10.1212/WNL.0b013e31829c5e8a

Life-span cognitive activity, neuropathologic burden, and cognitive aging

Robert S. Wilson, PhD, Patricia A. Boyle, PhD, Lei Yu, PhD, Lisa L. Barnes, PhD, Julie A. Schneider, MD and David A. Bennett, MD

Citation

Accepted in final form March 14, 2013.

© 2013 American Academy of Neurology

Geriatr Psychol Neuropsychiatr Vieil. 2013 Mar 1;11(1):99-109.

Musical long-term memory throughout the progression of Alzheimer disease.

Groussard M, Mauger C, Platel H.

Source

Inserm, U1077, Caen, France, UMR-S1077, Université de Caen Basse-Normandie, Caen, France, UMR-S1077, École pratique des hautes études, Caen, France, U1077, CHU de Caen, Caen, France, Service d’explorations fonctionnelles, CHU de Caen, Caen, France.

Abstract

In Alzheimer patients with a solid musical background, isolated case-reports have reported the maintenance of remarkable musical abilities despite clear difficulties in their verbal memory and linguistic functions. These reports have encouraged a number of scientists to undertake more systematic studies which would allow a rigorous approach to the analysis of musical memory in Alzheimer patients with no formal musical background.

Although restricted in number, the latest data are controversial regarding preserved musical capacities in Alzheimerpatients. Our current review of the literature addresses this topic and advances the hypothesis that the processes of musical memory are function of illness progression.

In the earlier stages, the majority of evaluations concerned musical episodic memory and suggested a dysfunction of this memory whereas in the moderate and severe stages, musical semantic memory and implicit learning are the majority of investigations and seemed more resistant to Alzheimer disease.

In summary, our current review bring to understand the memory circuits involved and highlight the necessity to adapted the investigational tools employed to conform with the severity of the signs and symptoms of progressive Alzheimer disease in order to demonstrate the preserved musical capacities.

Citation

PMID: 23508326 PubMed - as supplied by publisher

http://www.ncbi.nlm.nih.gov/pubmed/23508326

National Center for Biotechnology Information, U.S. National Library of Medicine