Alzheimer Disease: Jacova C

Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. · INSERM U610, Hôpital de la Salpêtrière, Paris, France. · Lancet Neurol. · Pubmed #17616482 No free full text.

Abstract: The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

Feldman HH, Jacova C. · Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. · Can J Neurol Sci. · Pubmed #17469689 No free full text.

Abstract: Prevention in Alzheimer's disease and other dementias (AD/dementia) is defined on the basis of clinical states and their expressed symptoms. Primary prevention refers to delaying the development of the full-blown state of clinically expressed disease in normal individuals. Current primary prevention research is driven by evidence of AD/dementia protective factors that have emerged from epidemiological studies. The first randomized controlled trials (RCTs) of primary AD/dementia prevention have been designed to test the efficacy and safety of NSAIDs, hormonal therapy, antihypertensive drugs and antioxidants. The experience of these trials has indicated safety concerns as a key issue and highlighted significant design challenges in this type of research. These trials have required large sample sizes and unsustainable costs. There should be consideration given in future trials to enriching study samples with risk factors to increase progression rates to AD/dementia. Innovative strategies will also be needed to recruit and retain subjects given the long follow-up periods, modest perceived benefit and the potential for the risk-benefit ratio to change during the trial. It is foreseeable that regulatory authorities will be presented with primary prevention RCTs for approval and labelling, and that criteria to evaluate such evidence still need to be developed.

Burns A, O'Brien J, Anonymous00334, Auriacombe S, Ballard C, Broich K, Bullock R, Feldman H, Ford G, Knapp M, McCaddon A, Iliffe S, Jacova C, Jones R, Lennon S, McKeith I, Orgogozo JM, Purandare N, Richardson M, Ritchie C, Thomas A, Warner J, Wilcock G, Wilkinson D, Anonymous00335. · University of Manchester, Manchester, UK. · J Psychopharmacol. · Pubmed #17060346 No free full text.

Abstract: The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review the evidence on the drug treatment for dementia. The level of evidence (types) was rated using a standard system: Types 1a and 1b (evidence from meta-analysis of randomised controlled trials or at least one controlled trial respectively); types 2a and 2b (one well-designed study or one other type of quasi experimental study respectively); type 3 (non-experimental descriptive studies); and type 4 (expert opinion). There is type 1a evidence for cholinesterase inhibitors (donepezil, rivastigmine and galantamine) for mild to moderate Alzheimer's disease; memantine for moderate to severe Alzheimer's disease; and for the use of bright light therapy and aromatherapy. There is type 1a evidence of no effect of anti inflammatory drugs or statins. There is conflicting evidence regarding oestrogens, with type 2a evidence of a protective effect of oestrogens but 1b evidence of a harmful effect. Type 1a evidence for any effect of B12 and folate will be forthcoming when current trials report. There is type 1b evidence for gingko biloba in producing a modest benefit of cognitive function; cholinesterase inhibitors for the treatment of people with Lewy body disease (particularly neuropsychiatric symptoms); cholinesterase inhibitors and memantine in treatment cognitive impairment associated with vascular dementia; and the effect of metal collating agents (although these should not be prescribed until more data on safety and efficacy are available). There is type 1b evidence to show that neither cholinesterase inhibitors nor vitamin E reduce the risk of developing Alzheimer's disease in people with mild cognitive impairment; and there is no evidence that there is any intervention that can prevent the onset of dementia. There is type 1b evidence for the beneficial effects of adding memantine to cholinesterase inhibitors, and type 2b evidence of positive switching outcomes from one cholinesterase inhibitor to another. There is type 2a evidence for a positive effect of reminiscence therapy, and type 2a evidence that cognitive training does not work. There is type 3 evidence to support the use of psychological interventions in dementia. There is type 2 evidence that a clinical diagnosis of dementia can be made accurately and that brain imaging increases that accuracy.Although the consensus statement dealt largely with medication, the role of dementia care in secondary services (geriatric medicine and old age psychiatry) and primary care, along with health economics, was discussed. There is ample evidence that there are effective treatments for people with dementia, and Alzheimer's disease in particular. Patients, their carers, and clinicians deserve to be optimistic in a field which often attracts therapeutic nihilism.

Feldman HH, Jacova C. · Division of Neurology, Dept. of Medicine, Clinic for Alzheimer Disease and Related Disorders, University of British Columbia, S192-2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. · Am J Geriatr Psychiatry. · Pubmed #16085780 No free full text.

Abstract: Mild cognitive impairment (MCI) describes a state of cognitive functioning that is below defined norms, yet falls short of dementia in severity. It exists across a cognitive continuum with borders that are difficult to define precisely. Within our "graying" western societies, its prevalence increases with age. A number of subtypes of MCI, including age-associated memory impairment (AAMI), age-associated cognitive decline (AACD), amnestic MCI (MCIa), and cognitive impairment not dementia (CIND) have contributed to our understanding of MCI. Recent efforts have been directed at developing a uniform diagnostic classification for MCI that reflects the maturation of knowledge about this state. There is considerable etiological and clinical heterogeneity within MCI; however, there is a unifying increased risk of progression to dementia. The diagnostic process for MCI involves assessment of multiple cognitive domains, with particular attention to episodic and semantic memory, while neuroimaging with structural MRI and PET both add to the diagnostic and prognostic evaluation of MCI. Although there are no pharmacological treatments at present that are capable of delaying the long-term progression of MCI to dementia, there is some evidence of short-term symptomatic benefits with acetylcholinesterase inhibitors. MCI is an important clinical problem, which clinicians can expect to face with increasing frequency. The essentials of management include a thorough assessment directed at etiological determination and counseling and judicious use of available therapeutics.

Jacova C, Kertesz A, Blair M, Fisk JD, Feldman HH. · Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. · Alzheimers Dement. · Pubmed #19595951 No free full text.

Abstract: This evidence-based review examines the utility of brief cognitive tests and neuropsychological testing (NPT) in the detection and diagnosis of mild cognitive impairment (MCI) and dementia. All patients presenting with cognitive complaints are recommended to have a brief screening test administered to document the presence and severity of memory/cognitive deficits. There is fair evidence to support the use of a range of new screening tests that can detect MCI and mild dementia with higher sensitivity (>/=80%) than the Mini-Mental State Exam (MMSE). NPT should be part of a clinically integrative approach to the diagnosis and differential diagnosis of dementia. It should be applied selectively to address specific clinical and diagnostic issues including: 1) The distinction between normal cognitive functioning in the aged, MCI and early dementia: there is fair evidence that NPT can document the presence of specific diagnostic criteria and provide additional useful information on the pattern of memory/cognitive impairment. 2) The evaluation of risk for Alzheimer disease (AD) or other types of dementia in persons with MCI: there is fair evidence that NPT measures or profiles can predict progression to dementia (predictive accuracy ranges from approximately 80 to 100%, sensitivities from 53 to 80%, and specificities from 67 to 99%). 3) Differential diagnosis: There is fair evidence that NPT can complement clinical history and neuroimaging in determining the dementia etiology. Different dementia types have distinguishable NPT profiles though these may be stage-dependent, and increased sensitivity may be at the expense of specificity. 4) When NPT is part of a comprehensive assessment, which also entails clinical interviews and consideration of other clinical data, there is good evidence that it can contribute to management decisions in MCI and dementia, including the determination of retained and impaired cognitive abilities, their functional and vocational impact, and opportunities for cognitive rehabilitation.

Feldman HH, Jacova C. · Division of Neurology, University of British Columbia Hospital, Vancouver, BC, Canada. · Nat Clin Pract Neurol. · Pubmed #19190589 No free full text.

Abstract: Identification of both the initial and the sustained clinical benefits achieved with symptomatic treatments for Alzheimer disease (AD) is a challenge. This commentary addresses a report by Wattmo et al. on 3-year follow-up of a cohort of patients with AD who were treated with donepezil. The investigators developed predictive regression models that can accurately calculate group mean Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) scores. They determined that patients with mild to moderate AD have a mean 5-7-month cognitive improvement with donepezil treatment, with greater benefit in more-advanced disease. While these results are encouraging, this study has important limitations. Although the predictive models work well for determining group means, the authors note that they do not predict individual patient responses, which vary greatly. Additionally, the study had a drop-out rate of 62%, which might elicit survivorship bias and overestimation of treatment benefit. We remind clinicians that small improvements in cognition matter most when a concurrent measurable benefit is seen in daily function.

Hsiung GY, Alipour S, Jacova C, Grand J, Gauthier S, Black SE, Bouchard RW, Kertesz A, Loy-English I, Hogan DB, Rockwood K, Feldman HH. · Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. · Dement Geriatr Cogn Disord. · Pubmed #18417973 links to  free full text

Abstract: BACKGROUND: Patients with cognitive impairment no dementia (CIND) are at an increased risk of progression to Alzheimer's disease (AD). Whether subtle impairments in functional or social abilities at the CIND stage can predict progression to AD is not yet fully determined. We evaluated whether impairments on the Disability Assessment for Dementia (DAD) and Functional Rating Scale (FRS) can predict progression to AD. METHODS: We examined 70 patients with CIND from the ACCORD cohort having complete DAD and FRS baseline and 2-year follow-up data. MANCOVA adjusted for age, sex, education and baseline MMSE score compared the baseline and 2-year change in DAD and FRS scores in CIND patients who progressed to AD versus non-progressors. RESULTS: There were no significant differences between CIND progressors and non-progressors in baseline total DAD or FRS scores. FRS domain analysis revealed that greater impairment in social/occupational functioning significantly predicted progression, while there were no predictive DAD domains. In progressors, both DAD and FRS scores significantly declined over time with the largest changes in instrumental activities of daily living (IADL). CONCLUSION: While changes in IADL characterize the progression from CIND to AD, impairment in complex social-cognitive competency significantly predicts risk of progression and may mark early AD.

Jacova C, Peters KR, Beattie BL, Wong E, Riddehough A, Foti D, Scheltens P, Li DK, Feldman HH. · Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. · Dement Geriatr Cogn Disord. · Pubmed #18264009 No free full text.

Abstract: BACKGROUND/AIMS: Cognitive impairment no dementia (CIND) describes individuals whose cognitive functioning falls below normal but who do not meet dementia criteria. An important goal within CIND is to identify subgroups that will predictably progress to Alzheimer disease. CIND with amnestic deficits has been associated with high risk of Alzheimer disease but has until now been investigated on a retrospective basis. In this study a prospectively defined amnestic CIND group was characterized on a detailed neuropsychological test battery and on structural magnetic resonance imaging (MRI) measures. METHODS: Amnestic CIND was defined as meeting at least 1 but not all DSM-IV-TR criteria for dementia, scoring > or =1 SD below norms on Rey Auditory Verbal Learning Test delayed recall, having a Clinical Dementia Rating score of 0.5 and a Mini-Mental State Exam score > or =24. This cross-sectional study compared subjects meeting these criteria (n = 25) to age- and education-matched controls (n = 26). The neuropsychological battery included memory and nonmemory measures that were analyzed as continuous variables and dichotomized into impaired (> or =1 SD below controls) versus nonimpaired. MRI scans were evaluated with a global-brain volumetric measure [brain fractional ratio (BFR)] and with visually based medial temporal lobe atrophy (MTA) ratings. RESULTS: Amnestic CIND had neuropsychological impairment in the episodic memory domain and also in nonmemory domains. There were 80% of CIND subjects with multidomain impairment. The most clear-cut nonmemory impairment was in the verbal ability domain, with 64% of subjects affected and a moderate effect size (d = 0.7). On MRI, BFR was lower (74.5 +/- 4.6 vs. 75.5 +/- 4.4) and MTA higher (72 vs. 38% with MTA > or =1) in CIND than in control subjects. BFR correlated with MTA (r = -0.45) and with a composite memory score (r = 0.296). CONCLUSION: A prospective amnestic CIND grouping appears to identify individuals with a multidomain pattern of neuropsychological impairment and with both medial temporal lobe and global brain atrophy.

Jacova C, Hsiung GY, Feldman HH. · Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. · Neurology. · Pubmed #17101929 No free full text.

Abstract: The success of prevention trials of Alzheimer disease and other dementias (AD/dementia) hinges on their ability to recruit and retain at-risk study populations. Losing subjects is a threat to the power to detect a treatment effect and, potentially, to the validity of these studies. Observational cohort studies accumulate data around participant outcomes that can help to inform the design of future prevention trials. Our objectives were to investigate the rates of refusal and dropout within observational cohort studies and to evaluate their characteristics and impact. This study examined data from the Canadian Cohort Study of Cognitive Impairment and Related Dementias (ACCORD), a 2-year observational cohort study of patients newly referred to dementia clinics. The sample included 124 Not Cognitively Impaired (NCI) and 342 Cognitively Impaired Not Demented (CIND) subjects. Subjects who refused initial neuropsychological (NP) testing were compared to those who completed NP testing and subjects who dropped out to those who attended follow-up. Refusal was common, with 40% of subjects not completing neuropsychological testing at baseline. Dropout was also substantial, with 55% lost to the 2-year follow-up. Subjects who refused NP testing were significantly older and less educated. CIND refusers had lower cognitive and functional scores at entry and a 2-year progression rate to dementia twice as high as that of non-refusers. CIND dropouts also had lower baseline cognitive and functional scores. These observations suggest that dropouts and refusals in prevention trials include those subjects who are at high risk for progression to AD/dementia. Targeted strategies to retain these individuals within prevention studies will be needed to achieve sufficient study power and validity.