Alzheimer Disease: Scheltens P

Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B, Anonymous00263. · Memory Disorders Research Group, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Denmark. · Eur J Neurol. · Pubmed #17222085 No free full text.

Abstract: The aim of this international guideline on dementia was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with dementia. It covers major aspects of diagnostic evaluation and treatment, with particular emphasis on the type of patient often referred to the specialist physician. The main focus is Alzheimer's disease, but many of the recommendations apply to dementia disorders in general. The task force working group considered and classified evidence from original research reports, meta-analysis, and systematic reviews, published before January 2006. The evidence was classified and consensus recommendations graded according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. The recommendations for clinical diagnosis, blood tests, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, genetic testing, tissue biopsy, disclosure of diagnosis, treatment of Alzheimer's disease, and counselling and support for caregivers were all revised when compared with the previous EFNS guideline. New recommendations were added for the treatment of vascular dementia, Parkinson's disease dementia, and dementia with Lewy bodies, for monitoring treatment, for treatment of behavioural and psychological symptoms in dementia, and for legal issues. The specialist physician plays an important role together with primary care physicians in the multidisciplinary dementia teams, which have been established throughout Europe. This guideline may contribute to the definition of the role of the specialist physician in providing dementia health care.

Scheltens P. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #17878189 No free full text.

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Hack CE, Scheltens P. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #15377678 links to  free full text

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van de Pol L, Scheltens P. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #15026488 links to  free full text

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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.

van der Flier WM, Barkhof F, Scheltens P. · Department of Neurology and Alzheimer Center, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Ann N Y Acad Sci. · Pubmed #17413024 No free full text.

Abstract: Atrophy and cerebrovascular disease are the two most important magnetic resonance imaging (MRI) characteristics in the evaluation of dementia. On MRI, atrophy is the primary hallmark of neurodegenerative dementias including Alzheimer's disease (AD), while vascular dementia is characterized by the presence of ischemic vascular damage, such as territorial infarcts, lacunes, and white matter hyperintensities. Evidence is accumulating that vascular factors play an important role in the development of cognitive decline at old age and clinical AD. In the present article we present results of four recent MRI studies suggesting the additional involvement of small vessel disease in neurodegenerative disorders. Atrophy in the medial temporal lobe, as typically observed in AD, and small vessel disease often coincide. In terms of clinical significance, their effects may even be synergistic. The strict distinction between AD and vascular dementia is often artificial, as most patients suffer from both disorders to some extent. For the future, we see an important role for MRI in identifying those different compartments, regardless of clinical classification. Treatment could be directed by (and evaluated through) MRI patterns, rather than a diagnostic label.

Scheltens P, Barkhof F. · Dept. Neurology and Alzheimer Center. VU University Medical Center. · J Nutr Health Aging. · Pubmed #16554946 No free full text.

Abstract: In the past clinical trials in dementia, symptomatic or disease modifycing in nature, relied mostly on clinical/neuropsychological endpoints. In the recent past much effort has been put into incorporating imaging, notably MRI, into trials in order to provide a surrogate marker for progression and measure a disease modifying effect, and to provide more insight into the homogeneity, or absence of, the included sample. In the following review an update will be given on the current thinking on how and when MRI should be used in the design of a clinical trial in Alzheimer's disease and mild cognitive impairment, with particular emphasis on trials focusing on disease modification.

de Leeuw FE, van Norden AG, van der Flier WM, Olde Rikkert MG, Scheltens P. · Universitair Medisch Centrum St Radboud, Huispostnummer 326, Postbus gIoI, 6500 HB Nijmegen. · Ned Tijdschr Geneeskd. · Pubmed #16398165 No free full text.

Abstract: There is increasing evidence that vascular risk factors including hypertension, high cholesterol, hyperhomocysteinaemia and diabetes mellitus are connected to the risk of Alzheimer's disease (AD). The risk of AD may be reduced by the treatment of hypertension prior to onset of cognitive impairment. One small randomised clinical trial has provided some evidence of beneficial effects on cognition of cholesterol-lowering drugs such as the statins in patients with AD. Treatment of hypertension, hyperhomocysteinaemia and diabetes mellitus with the aim of halting the progression of cognitive decline in AD is still under study and results are awaited. For the time being findings from the trials carried out thus far should be interpreted with care due to methodological shortcomings, both in study design and execution. In order to investigate the role of vascular risk factors both in the aetiology and treatment of AD, large prospective randomised trials with long-term follow-up of AD patients who have been diagnosed using revised uniform diagnostic criteria that take the heterogeneity of the disease into account, are necessary.

Scarpini E, Galimberti D, Guidi I, Bresolin N, Scheltens P. · Dept. of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy. · J Neurol Sci. · Pubmed #16249006 No free full text.

Abstract: Language disturbances are common features occurring in different neurodegenerative diseases, including Alzheimer's disease (AD) and the Frontotemporal Lobar Degeneration (FTLD) variants Primary Progressive Aphasia (PPA) and Semantic Dementia (SD). Despite AD and FTLD are supposed to have a different pathophysiology, PPA has been demonstrated to have in some cases an AD pathological component. The syndromic and etiological heterogeneity is crucial for the differential diagnosis and consequently for a therapeutical approach. Here, the case of a patient with progressive isolated language disturbances is presented, and further discussed on the basis of current diagnostic criteria and available guidelines for treatment.

Wiltfang J, Lewczuk P, Riederer P, Grünblatt E, Hock C, Scheltens P, Hampel H, Vanderstichele H, Iqbal K, Galasko D, Lannfelt L, Otto M, Esselmann H, Henkel AW, Kornhuber J, Blennow K. · Molecular Neurobiology Lab, Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. · World J Biol Psychiatry. · Pubmed #16156480 No free full text.

Abstract: Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Bastos Leite AJ, Scheltens P, Barkhof F. · Department of Radiology, Vrije Universiteit (VU) Medical Center, Amsterdam, the Netherlands. · Top Magn Reson Imaging. · Pubmed #16041289 No free full text.

Abstract: The number of elderly people is increasing rapidly and, therefore, an increase in neurodegenerative and cerebrovascular disorders causing dementia is expected. Alzheimer disease (AD) is the most common cause of dementia. Vascular dementia, dementia with Lewy bodies, and frontotemporal dementia are the most frequent causes after AD, but a large proportion of patients have a combination of degenerative and vascular brain pathology. Characteristic magnetic resonance (MR) imaging findings can contribute to the identification of different diseases causing dementia. The MR imaging protocol should include axial T2-weighted images (T2-WI), axial fluid-attenuated inversion recovery (FLAIR) or proton density-weighted images, and axial gradient-echo T2*-weighted images, for the detection of cerebrovascular pathology. Structural neuroimaging in dementia is focused on detection of brain atrophy, especially in the medial temporal lobe, for which coronal high resolution T1-weighted images perpendicular to the long axis of the temporal lobe are extremely important. Single photon emission computed tomography and positron emission tomography may have added value in the diagnosis of dementia and may become more important in the future, due to the development of radioligands for in vivo detection of AD pathology. New functional MR techniques and serial volumetric imaging studies to identify subtle brain abnormalities may also provide surrogate markers for pathologic processes that occur in diseases causing dementia and, in conjunction with clinical evaluation, may enable a more rigorous and early diagnosis, approaching the accuracy of neuropathology.

Rombouts S, Scheltens P. · Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. · Curr Alzheimer Res. · Pubmed #15974906 No free full text.

Abstract: Conventionally, Alzheimer's disease (AD) and other dementias are diagnosed using clinical assessment, neuropsychology and also structural neuroimaging, showing neuronal degeneration starting in the hippocampal regions. However, there is an increasing need for a new method that is more sensitive to early AD identification than currently possible. A new promising technique that may be used for this is to measure local brain activation using functional magnetic resonance imaging (fMRI), since functional loss predates structural loss of brain tissue. A new method to apply fMRI is to study connectivity between brain regions during a resting state without application of a task. Recent data suggest that connectivity within memory systems during such a resting state is associated with the level of memory function. Here we explain how we will study healthy elderly controls, patients with a mild cognitive impairment (MCI, considered to be a transitional stage between normal condition and AD), and AD patients using resting state connectivity fMRI. If resting state connectivity is sensitive to cognitive decline, this will be of great importance for noninvasive dementia research, offering a tool to easily study functional networks in the brain without the requirement of a memory task, and perhaps offering a tool sensitive for early diagnostics.

van Straaten EC, Scheltens P, Barkhof F. · Department of Neurology and Alzheimer Center, VU Medical Center, Amsterdam, The Netherlands. · J Neurol Sci. · Pubmed #15537511 No free full text.

Abstract: Neuroimaging is necessary to demonstrate cerebrovascular disease (CVD) and is therefore an important examination in vascular dementia (VaD) and vascular cognitive impairment (VCI). MRI is preferred over CT because multiple planes and sequences are needed to assess various types of pathology in relevant regions. These protocols allow differentiation of VaD from other forms of dementia and sometimes identify specific underlying disorders. Different diagnostic criteria for VaD exist but the NINDS-AIREN criteria are widely used in controlled clinical trials in VaD. These criteria have relatively low sensitivity but are highly specific and include radiological requirements. The radiological criteria have poor interobserver agreement. In general, the radiological portion of the diagnostic criteria for VaD needs revision and refinement to include bone fide cases of VaD not currently accepted by imaging rules, and for the early detection of patients with VCI.

Nestor PJ, Scheltens P, Hodges JR. · University Neurology Unit, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK. · Nat Med. · Pubmed #15298007 No free full text.

Abstract: The combination of an aging population and the promise, possibly in the near future, of disease-modifying therapies have made the characterization of the early stages of Alzheimer's disease (AD) a topic of major research interest. In this article we review recent progress in our understanding of the evolution of early AD with particular reference to the symptomatic pre-dementia stage designated 'mild cognitive impairment', emphasizing work on the early cognitive profile and associated neuroimaging studies.

Scheltens P, Fox N, Barkhof F, De Carli C. · Department of Neurology and Alzheimer Centre, Vrije Universiteit Medical Centre, Amsterdam, Netherlands. · Lancet Neurol. · Pubmed #12849541 No free full text.

Abstract: Neuroimaging is increasingly used to aid diagnosis in dementia. The traditional view that imaging is important solely as means of excluding treatable causes of dementia is maintained by many guidelines. These conditions however, account for a tiny proportion (<1%) of all causes of dementia. Over the past few years it has been recognised that a more accurate diagnosis and prognosis is important for patients and their families. The different pathological processes that produce cerebral dysfunction at a cellular level also produce macroscopic effects that can be detected in vivo with imaging. Clinically useful measures that distinguish between neurodegenerative disorders at an early stage are still awaited. The most likely future use of structural imaging will be the identification of patients at risk for Alzheimer's disease or with preclinical Alzheimer's disease. For magnetic resonance imaging (MRI) this will mean focusing on those areas that are affected earliest in the disease; ie, entorhinal cortex and hippocampus, using high resolution structural MRI or sophisticated brain mapping techniques. Imaging research is also likely to focus on measuring progression and detecting therapeutic effect. As such, MRI is already become an indispensable tool in clinical trials in dementia.

van Dijk KR, Scherder EJ, Scheltens P, Sergeant JA. · Department of Clinical Neuropsychology, Vrije Universiteit, Amsterdam, The Netherlands. · Rev Neurosci. · Pubmed #12405228 No free full text.

Abstract: An extensive search through nine electronic bibliographic databases (PubMed, Cochrane Library, Web of Science, ERIC, PsychINFO, Psyndex, Cinahl, Biological Abstracts, Rehabdata) was performed in order to review the effects of Transcutaneous Electrical Nerve Stimulation (TENS) on non-pain related cognitive and behavioural functioning. Eight studies were identified on neglect due to stroke, six studies on Alzheimer's disease (AD), one study on aging, and two studies on coma due to traumatic brain injury. The results of the various studies revealed that TENS has a variety of effects. These consist of enhancement of somatosensory functioning, visuo-spatial abilities and postural control in neglect, improved memory, affective behaviour and rest-activity rhythm in AD and acceleration of awakening in coma. Effectiveness of TENS is discussed in relation to various stimulation parameters: duration, frequency, pulse width and intensity. It is argued that arousal may underlie the beneficial influence of TENS in various conditions. Finally, suggestions are offered for future research.

Mulder C, Scheltens P, Visser JJ, van Kamp GJ, Schutgens RB. · Department of Clinical Chemistry, University Hospital Vrije Universiteit, Amsterdam, The Netherlands. · Ann Clin Biochem. · Pubmed #11026514 No free full text.

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Scheltens P, Korf ES. · Department of Neurology, Academisch Ziekenhuis VU, Amsterdam, The Netherlands. · Curr Opin Neurol. · Pubmed #10970055 No free full text.

Abstract: This paper reviews the use of neuroimaging in the diagnosis of dementia, especially Alzheimer's disease. Computed tomography is still used to determine reversible causes of dementia; however, without clinical symptoms these causes are hard to find and computed tomography scanning is only cost-effective in a defined group of patients. Using magnetic resonance imaging, atrophy of the medial temporal lobe can be assessed volumetrically and visually, with a high correlation between the two methods. Medial temporal lobe atrophy is highly predictive of Alzheimer's disease, and correlates with neuropsychological performance and postmortem histologically measured volume. Cerebral volume changes over time seem to differentiate Alzheimer's disease and mild cognitive impairment progressing to Alzheimer's disease from controls with high accuracy. Studies of the corpus callosum in dementia indicate a cortico-cortical disconnection caused by atrophy. Of the new techniques, functional magnetic resonance imaging seems the most promising. This technique can possibly play a role in predicting Alzheimer's disease in patients with mild cognitive impairment. The use of single-photon emission computed tomography and positron emission tomography in (early) differential diagnoses seems limited. Lower regional cerebral blood flow is related to the severity of dementia and survival. Iodine-123 iodobenzamide single-photon emission computed tomography in dementia with Lewy bodies seems promising. Current and future positron emission tomography studies concentrate on memory function and receptor imaging. The focus in neuroimaging, especially magnetic resonance imaging, has shifted to early diagnosis and monitoring of the disease course, with a special interest in predicting dementia in patients with mild cognitive impairment.

Waldemar G, Dubois B, Emre M, Scheltens P, Tariska P, Rossor M. · Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark. · Eur J Neurol. · Pubmed #10809933 No free full text.

Abstract: In 1998 a task force to develop guidelines for diagnostic evaluation and treatment of dementia was initiated by the European Federation of Neurological Societies (EFNS) scientist panel on dementia. The aims of the task force were to provide evidence-based recommendations and to highlight the role of the neurologist in the management of patients with Alzheimer's disease and other disorders associated with dementia. We based our recommendations on a review of available evidence-based guidelines supplemented with further literature reviews. The recommendations were derived from consensus meetings and relate to individual patient management, as there are inadequate data on the cost-effectiveness of different diagnostic evaluations and treatments for dementia. Their specific applications will depend upon available resources. The particular contributions of the neurologist include: early identification and differential diagnosis of rare and common brain disorders causing cognitive and behavioural symptoms, referral for and interpretation of ancillary investigations, and identification and treatment of vascular and other concurrent diseases. A review of the management of dementia in Europe revealed considerable variation. In some countries neurologists have taken the lead in the management of patients with dementia, while in other countries the neurologist is rarely involved. We recommend that neurologists should have a clear role in the management of dementia in the whole of Europe. They should be involved in the diagnostic evaluation of dementia and facilitate the development of multidisciplinary teams for evaluation and management of patients with cognitive disturbances. The increasing role of neurology in the management of patients with dementia has important implications for training and education.

Leys D, Erkinjuntti T, Desmond DW, Schmidt R, Englund E, Pasquier F, Parnetti L, Ghika J, Kalaria RN, Chabriat H, Scheltens P, Bogousslavsky J. · University of Lille, France. · Alzheimer Dis Assoc Disord. · Pubmed #10609680 No free full text.

Abstract: Although vascular dementia (VaD) is the second most frequent cause of dementia after Alzheimer disease (AD), the concept remains controversial in terms of delineation. The objective of this review is to investigate, from available literature, the role of cerebral infarcts in the pathogenesis of VaD and to identify areas of interest that need further evaluation and research. The incidence of new onset dementia is increased after stroke. Stroke subtypes, total volume of cerebral infarction and functional tissue loss, and location of the lesions are probably the major determinants of VaD. Any cause of stroke can lead to VaD. In some circumstances the causal relation between stroke and dementia is clear: (1) in young patients who are unlikely to have associated Alzheimer pathology; (2) when the cognitive functioning was normal before stroke, impaired immediately after, and does not worsen over time; (3) when the lesions are located in strategic areas; and (4) when a well-defined vasculopathy known to cause dementia is proven. However, several issues remain unsolved in VaD: lack of specificity of the diagnostic criteria; influence of white matter changes and associated Alzheimer pathology; influence of preexisting cognitive status; possibility of having VaD without stroke and the clinical relevance of silent infarcts to VaD; and best therapeutic strategy to be used to prevent VaD and to prevent stroke in patients with VaD. These questions form the basis for proposals for future research.

Scheltens P. · Department of Neurology, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands. · J Neurol. · Pubmed #9987709 No free full text.

Abstract: The use of neuroimaging is reviewed in the diagnosis of dementia, especially Alzheimer's disease (AD). Computed tomography (CT) may be used to exclude other causes of dementia than AD. The finding of cortical or subcortical atrophy on CT or magnetic resonance imaging (MRI) itself does not indicate AD. Hippocampal atrophy on CT/MRI provides a useful early marker, although further longitudinal and neuropathological study is required. CT- and MRI-based measurements of hippocampal atrophy show promise in providing useful diagnostic information for discriminating patients with probable AD from normal elderly individuals. Using a standardized imaging protocol, including some assessment of hippocampal atrophy, can save costs since patients with suspected AD must undergo a cross-sectional imaging study to exclude other (treatable) causes of dementia. Combining an assessment of hippocampal atrophy with cerebral blood flow measurements by single photon emission computed tomography is not warranted either from a clinical or from an economic point of view.

Staekenborg SS, van der Flier WM, van Straaten EC, Lane R, Barkhof F, Scheltens P. · Department of Neurology and Alzheimer Centre, Vrije University Medical Centre, Amsterdam, The Netherlands. · Stroke. · Pubmed #18096841 links to  free full text

Abstract: BACKGROUND AND PURPOSE: The aim of this study was to describe the prevalence of a number of neurological signs in a large population of patients with vascular dementia (VaD) and to compare the relative frequency of specific neurological signs dependent on type of cerebrovascular disease. METHODS: Seven hundred six patients with VaD (NINDS-AIREN) were included from a large multicenter clinical trial (registration number NCT00099216). At baseline neurological examination, the presence of 16 neurological signs was assessed. Based on MRI, patients were classified as having large vessel VaD (18%; large territorial or strategical infarcts on MRI), small vessel VaD (74%; white matter hyperintensities [WMH], multiple lacunes, bilateral thalamic lesions on MRI), or a combination of both (8%). RESULTS: A median number of 4.5 signs per patient was presented (maximum 16). Reflex asymmetry was the most prevalent symptom (49%), hemianopia was most seldom presented (10%). Measures of small vessel disease were associated with an increased prevalence of dysarthria, dysphagia, parkinsonian gait disorder, rigidity, and hypokinesia and as well to hemimotor dysfunction. By contrast, in the presence of a cerebral infarct, aphasia, hemianopia, hemimotor dysfunction, hemisensory dysfunction, reflex asymmetry, and hemiplegic gait disorder were more often observed. CONCLUSIONS: The specific neurological signs demonstrated by patients with VaD differ according to type of imaged cerebrovascular disease. Even in people who meet restrictive VaD criteria, small vessel disease is often seen with more subtle signs, including extrapyramidal signs, whereas large vessel disease is more often related to lateralized sensorimotor changes and aphasia.

Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, del Ser T, Inzitari D, Orgogozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. · Division of Neurology, University of British Columbia Hospital, Vancouver, Canada. · Lancet Neurol. · Pubmed #17509485 No free full text.

Abstract: OBJECTIVE: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. METHODS: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

Scherder E, Knol D, van Tol MJ, van Someren E, Deijen JB, Swaab D, Scheltens P. · Institute of Human Movement Sciences, University of Groningen, Groningen, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #16912480 No free full text.

Abstract: OBJECTIVE: In a previous study, low-frequency (0.5 Hz) cranial electrostimulation (CES) neither improved the rest-activity rhythm nor reduced the level of salivary cortisol in patients with probable Alzheimer's disease (AD). To investigate whether the frequency of CES was responsible for these negative findings, we set out to examine the effects of high-frequency CES on the rest-activity rhythm and salivary cortisol of patients with probable AD. We hypothesized that a decreased level of cortisol would parallel a positive effect of high-frequency CES on nocturnal restlessness in AD patients. METHODS: Twenty AD patients were randomly assigned to an experimental group (n = 10) and a control group (n = 10). The experimental group was treated with high-frequency CES, the control group received sham stimulation, for 30 min a day, during 6 weeks. The rest-activity rhythm was assessed by actigraphy. Level of cortisol was measured by means of salivette tubes. RESULTS: The rest-activity rhythm and the level of salivary cortisol did not react positively to high-frequency CES. In contrast, both groups showed an increase in the level of cortisol after the 6-week treatment period. CONCLUSIONS: High-frequency CES appeared to be ineffective in AD patients.

Visser PJ, Scheltens P, Verhey FR. · Department of Psychiatry, University Hospital Maastricht and Alzheimer Centre Limburg, Maastricht, Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #16170074 links to  free full text

Abstract: BACKGROUND: Drugs effective in Alzheimer-type dementia have been tested in subjects with mild cognitive impairment (MCI) because these are supposed to have Alzheimer's disease in the predementia stage. OBJECTIVES: To investigate whether MCI criteria used in these drug trials can accurately diagnose subjects with predementia Alzheimer's disease. METHODS: MCI criteria of the Gal-Int 11 study, InDDEx study, ADCS memory impairment study, ampakine CX 516 study, piracetam study, and Merck rofecoxib study were applied retrospectively in a cohort of 150 non-demented subjects from a memory clinic. Forty two had progressed to Alzheimer type dementia during a five year follow up period and were considered to have predementia Alzheimer's disease at baseline. Outcome measures were the odds ratio, sensitivity, specificity, and positive and negative predictive value. RESULTS: The odds ratio of the MCI criteria for predementia Alzheimer's disease varied between 0.84 and 11. Sensitivity varied between 0.46 and 0.83 and positive predictive value between 0.43 and 0.76. None of the criteria combined a high sensitivity with a high positive predictive value. Exclusion criteria for depression led to an increase in positive predictive value and specificity at the cost of sensitivity. In subjects older than 65 years the positive predictive value was higher than in younger subjects. CONCLUSIONS: The diagnostic accuracy of MCI criteria used in trials for predementia Alzheimer's disease is low to moderate. Their use may lead to inclusion of many patients who do not have predementia Alzheimer's disease or to exclusion of many who do. Subjects with moderately severe depression should not be excluded from trials in order not to reduce the sensitivity.