Alzheimer Disease: Waldemar G

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.

Waldemar G. · No affiliation provided · Ugeskr Laeger. · Pubmed #17032602 No free full text.

This publication has no abstract.

Wahlund LO, Almkvist O, Blennow K, Engedahl K, Johansson A, Waldemar G, Wolf H. · Department of Neurobiology, Caring Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden. · Top Magn Reson Imaging. · Pubmed #17088692 No free full text.

Abstract: BACKGROUND: The diagnostic utility of magnetic resonance imaging in dementia workups has increased recently. The basic use is to exclude space-occupying processes in the brain. However, magnetic resonance imaging offers major opportunities for studying atrophy of specific brain areas. A great interest has been put in whether atrophy in the medial temporal lobe can serve as an early diagnostic marker for Alzheimer disease. METHODS AND RESULTS: In this evaluation, we used evidence-based techniques and reviewed more than 400 articles that address this issue. Our main finding is that a variety of methods in studying brain areas were used, and this made it difficult to extract conclusive information in a systematic way. CONCLUSION: However, we were able to conclude that atrophy of the hippocampus can distinguish patients with Alzheimer disease from healthy subjects, but there was a lack of evidence because of insufficient studies concerning the usefulness of medial temporal lobe atrophy as a diagnostic marker in a more general setting.

Phung TK, Andersen K, Kessing LV, Waldemar G. · H:S Righospitalet, Hukommelsesklinikken, Neurocentret, Neurologisk Klinik. · Ugeskr Laeger. · Pubmed #17032603 No free full text.

Abstract: Emerging knowledge about modifiable risk factors for dementia has given rise to interventions that can potentially prevent or delay the onset of dementia and the possible target periods for intervention extend from prenatal period to old age. Factors during early life such as nutrition, education, and parental socioeconomic status can influence the development of dementia later in life. From mid to late life, a physically, socially, and intellectually active lifestyle is associated with reduced risk for dementia. Moreover, modification of cardiovascular risk factors during this period can potentially reduce risk for dementia.

Czarna JM, Waldemar G, Heegaard NH. · Statens Serum Institut, Autoimmunafdelingen, og H:S Rigshospitalet, Hukommelsesklinikken, Neurologisk Afdeling. · Ugeskr Laeger. · Pubmed #16522291 No free full text.

Abstract: It is estimated that approximately 40,000 people in Denmark suffer from Alzheimer's disease (AD), a neurodegenerative dementia. Symptomatic treatment now exists which can temporarily inhibit the loss of brain function. Unfortunately, AD is difficult to diagnose, especially early in the disease course, and a definite diagnosis is possible only post-mortem. To develop improved diagnostic methods, several biomarkers have been examined for their ability to differentiate AD from normal aging and other dementias. Their measurement in blood samples has not yet been developed, but analyses may now be routinely performed using cerebrospinal fluid (CSF). The CSF biomarkers include amyloid-beta 1-42 (Abeta1-42), which is decreased in AD patients, as well as total tau (t-tau) and hyperphosphorylated tau (p-tau), which are elevated. While a decreased Abeta1-42 level in CSF has no independent value in the diagnostic differentiation, t-tau and p-tau add more specificity to the differentiation of AD from other dementias while retaining a reasonable degree of sensitivity.

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.

Stokholm J, Vogel A, Gade A, Waldemar G. · Memory Disorders Research Unit, Neuroscience Center, Copenhagen University Hospital, Rigshospitalet, Denmark. · Dement Geriatr Cogn Disord. · Pubmed #16682794 No free full text.

Abstract: BACKGROUND/AIMS: The presence of executive impairment in mild Alzheimer's disease (AD) has primarily been demonstrated by means of group comparison. Whether executive dysfunction is a common feature of mild AD or only present in a subgroup of patients remains unclear. The aim of this study was to describe the frequency of impairment on a set of internationally well-known executive tests in patients with very mild AD. METHODS: Thirty-six patients with very mild AD (MMSE scores above 23) and 32 healthy control subjects were administered a battery of 7 executive tests: Trail Making part B, Stroop Interference Test, modified Wisconsin Card Sorting Test (WCST), category- and letter-based verbal fluency, a design fluency task and the Similarities subtest from WAIS. Impairment was defined as a score of 2 SD or more below control means. RESULTS: Executive impairment on at least 1 measure was seen in 76% of the patients, and 50% were impaired on 2 or more tests. Trail Making B and Stroop Interference Test were impaired in more than 40%, whereas only few patients were impaired on Similarities, WCST and design fluency. A wide variation of executive test profiles was seen among the patients. CONCLUSION: Executive impairments are common in early AD and not just a feature characteristic of a subgroup of patients. Complex attentional skills are more frequently affected than other executive functions. There is, however, considerable heterogeneity among AD patients in the pattern of executive dysfunction.

Wimo A, Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wetterholm AL, Mastey V, Haglund A, Zhang R, Miceli R, Chin W, Subbiah P, Anonymous00005. · Department of Family Medicine, Umeå University, Umeå, Sweden. · Dement Geriatr Cogn Disord. · Pubmed #12457078 No free full text.

Abstract: The costs and consequences of donepezil versus placebo treatment in patients with mild to moderate Alzheimer's disease (AD) were evaluated as part of a 1-year prospective, double-blind, randomized, multinational clinical trial. Patients received either donepezil (n = 142; 5 mg/day for 28 days followed by 10 mg/day according to the clinician's judgement) or placebo (n = 144). Unit costs were assessed in 1999 Swedish kronas (SEK) and converted to US dollars (USD). Donepezil-treated patients gained functional benefits relative to placebo on the Progressive Deterioration Scale (p = 0.042) and Instrumental Activities of Daily Living scale (p = 0.025) at week 52. Caregivers of donepezil-treated patients spent an average of 400 h less annually providing care than caregivers of placebo-treated patients. Mean annual healthcare costs were SEK 137,752 (USD 16,438) per patient for the donepezil group and SEK 135,314 (USD 16,147) in the placebo group. With the average annual cost of donepezil at SEK 10,723 (USD 1,280) per patient, the SEK 2,438 (USD 291) cost difference represented a 77% cost offset. When caregiver time and healthcare costs were included, mean annual costs were SEK 209,244 (USD 24,969) per patient in the donepezil group and SEK 218,434 (USD 26,066) in the placebo group, a total saving associated with donepezil treatment of SEK 9,190 (USD 1,097) per patient [95% CI of SEK -43,959 (USD -5,246), SEK 25,581 (USD 3,053); p = 0.6]. The positive effects on the efficacy outcome measures combined with no additional costs from a societal perspective indicate that donepezil is a cost-effective treatment, representing an improved strategy for the management of patients with AD.

Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm AL, Zhang R, Haglund A, Subbiah P, Anonymous00311. · Karolinska Institutet, Alzheimer's Disease Research Center, Division of Geriatric Medicine, Huddinge Hospital B, Stockholm, Sweden. · Neurology. · Pubmed #11502918 No free full text.

Abstract: OBJECTIVE: To evaluate the long-term clinical efficacy and safety of donepezil versus placebo over 1 year in patients with mild to moderate AD. METHODS: Patients (n = 286; mean age, 72.5 years) with possible or probable AD from five Northern European countries were randomized to receive either donepezil (n = 142; 5 mg/day for 28 days, followed by 10 mg/day) or placebo (n = 144) for 1 year. RESULTS: The study was completed by 66.9% of the donepezil- and 67.4% of the placebo-treated patients. The benefit of donepezil over placebo was demonstrated by the Gottfries-Bråne-Steen (a global assessment for rating dementia symptoms) total score at weeks 24, 36, and 52 (p < 0.05) and at the study end point (week 52, last observation carried forward; p = 0.054). Advantages of donepezil over placebo were also observed in cognition and activities of daily living (ADL) assessed by the Mini-Mental State Examination at weeks 24, 36, and 52, and the end point (p < 0.02) and by the Progressive Deterioration Scale at week 52 and the end point (p < 0.05). Adverse events (AE) were recorded for 81.7% of donepezil- and 75.7% of placebo-treated patients, with 7% of donepezil- and 6.3% of placebo-treated patients discontinuing because of AE. Treatment response to donepezil was not predicted by APOE genotype or sex in this population. CONCLUSION: As the first 1-year, multinational, double-blinded, placebo-controlled study of a cholinesterase inhibitor in AD, these data support donepezil as a well tolerated and effective long-term treatment for patients with AD, with benefits over placebo on global assessment, cognition, and ADL.

Stokholm J, Vogel A, Johannsen P, Waldemar G. · Memory Disorders Research Group, The Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Dement Geriatr Cogn Disord. · Pubmed #19299896 No free full text.

Abstract: BACKGROUND: Addenbrooke's Cognitive Examination (ACE) is a cognitive screening test developed to detect dementia. It has been validated in several countries. Validation studies have predominantly included patients with various degrees of dementia and healthy controls. OBJECTIVE: The aim of this study was to evaluate the Danish version of ACE as a screening test for early dementia in an outpatient memory clinic. Further, we wanted to investigate the ability of the ACE to discriminate patients with early Alzheimer's disease (AD) from patients with depression. METHOD: 78 patients with mild AD (MMSE >or=20), 30 non-demented patients diagnosed with depression (originally referred for evaluation of cognitive symptoms), and 63 healthy volunteers, all between 60 and 85 years of age, were included. All patients were given the ACE as a supplement to the standard diagnostic work-up. RESULTS: The cut-off points for optimal trade-off between sensitivity and specificity for ACE were 85/86 (sensitivity 0.99, specificity 0.94). When these cut-off points were applied to the group of depressive patients, the specificity dropped to 0.64, indicating a great overlap in individual test scores for demented and depressed patients. CONCLUSION: The optimal cut-off points for ACE found in this Danish study were close to what is reported in most other European studies. The great overlap in ACE scores for demented and depressed patients emphasize that test scores must be interpreted with great caution when used in diagnostic work-up.

Schüz J, Waldemar G, Olsen JH, Johansen C. · Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. · PLoS One. · Pubmed #19194493 links to  free full text

Abstract: The aim of this study was to investigate a possible link between cellular telephone use and risks for various diseases of the central nervous system (CNS). We conducted a large nationwide cohort study of 420 095 persons whose first cellular telephone subscription was between 1982 and 1995, who were followed through 2003 for hospital contacts for a diagnosis of a CNS disorder. Standardized hospitalization ratios (SHRs) were derived by dividing the number of hospital contacts in the cohort by the number expected in the Danish population. The SHRs were increased by 10-20% for migraine and vertigo. No associations were seen for amyotrophic lateral sclerosis, multiple sclerosis or epilepsy in women. SHRs decreased by 30-40% were observed for dementia (Alzheimer disease, vascular and other dementia), Parkinson disease and epilepsy among men. In analyses restricted to subscribers of 10 years or more, the SHRs remained similarly increased for migraine and vertigo and similarly decreased for Alzheimer disease and other dementia and epilepsy (in men); the other SHRs were close to unity. In conclusion, the excesses of migraine and vertigo observed in this first study on cellular telephones and CNS disease deserve further attention. An interplay of a healthy cohort effect and reversed causation bias due to prodromal symptoms impedes detection of a possible association with dementia and Parkinson disease. Identification of the factors that result in a healthy cohort might be of interest for elucidation of the etiology of these diseases.

Sørensen LV, Waldorff FB, Waldemar G. · Department of Neurology, Memory Disorder Research Group, Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Denmark. · Aging Ment Health. · Pubmed #18791891 No free full text.

Abstract: OBJECTIVES: The aim of this qualitative study was to identify and analyse the participants' experienced outcome of an intensive structured psychosocial intervention programme with tailored counselling, education and support groups for home-living patients with mild Alzheimer's disease and their spousal caregivers. METHOD: Data were collected by semi-structured in-depth interviews conducted separately with each person in 10 couples before the intervention and 1-3 months after completed intervention. For the analysis, a template organizing style of interpretation was used. RESULTS: The analysis revealed that patients found support groups relevant: they found it stimulating to be with peers, it supported their self-esteem, and it supported them in finding new ways of managing everyday life and social relations. During and after the intervention, caregivers were better able to cope with the challenges their partner's disease involved, and they were able to face everyday life and social relations with more serenity and competence. After the intervention, both patients and caregivers sought suitable support groups they could join as a permanent activity and caregivers sought permanent counselling. CONCLUSION: Early tailored counselling and support may improve patients' and caregivers' opportunities to adapt to the challenges of Alzheimer's disease and to maintain well-being.

Lindquist SG, Hasholt L, Bahl JM, Heegaard NH, Andersen BB, Nørremølle A, Stokholm J, Schwartz M, Batbayli M, Laursen H, Pardossi-Piquard R, Chen F, St George-Hyslop P, Waldemar G, Nielsen JE. · Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · Eur J Neurol. · Pubmed #18727676 No free full text.

Abstract: BACKGROUND: Mutations in the Presenilin 2 gene (PSEN2) are rare causes of Alzheimer's disease (AD). Pathogenic mutations in the genes associated with autosomal dominant inherited AD have been shown to alter processing of the amyloid precursor protein (APP) resulting in a relative increase of the amount of Abeta42 peptide. METHODS AND RESULTS: We present a patient with neuropathologically confirmed early-onset AD characterized by profound language impairment. The patient was heterozygous for a novel missense mutation in exon 11 of the PSEN2 gene leading to a predicted amino acid substitution from valine to methionine in position 393, a conserved residue. However, in vitro expression of PSEN2 V393M cDNA did not result in detectable increase of the secreted Abeta42/40 peptide ratio. The mutation was not found in 384 control individuals tested. CONCLUSIONS: The possible pathogenic nature of the mutation is not clarified. We discuss the limitations of functional PSEN2 studies and the challenges associated with genetic counselling of family members at risk.

Frisoni GB, Henneman WJ, Weiner MW, Scheltens P, Vellas B, Reynish E, Hudecova J, Hampel H, Burger K, Blennow K, Waldemar G, Johannsen P, Wahlund LO, Zito G, Rossini PM, Winblad B, Barkhof F, Anonymous00039. · IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. · Alzheimers Dement. · Pubmed #18631976 links to  free full text

Abstract: BACKGROUND: In North America, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has established a platform to track the brain changes of Alzheimer's disease. A pilot study has been carried out in Europe to test the feasibility of the adoption of the ADNI platform (pilot E-ADNI). METHODS: Seven academic sites of the European Alzheimer's Disease Consortium (EADC) enrolled 19 patients with mild cognitive impairment (MCI), 22 with AD, and 18 older healthy persons by using the ADNI clinical and neuropsychological battery. ADNI compliant magnetic resonance imaging (MRI) scans, cerebrospinal fluid, and blood samples were shipped to central repositories. Medial temporal atrophy (MTA) and white matter hyperintensities (WMH) were assessed by a single rater by using visual rating scales. RESULTS: Recruitment rate was 3.5 subjects per month per site. The cognitive, behavioral, and neuropsychological features of the European subjects were very similar to their U.S. counterparts. Three-dimensional T1-weighted MRI sequences were successfully performed on all subjects, and cerebrospinal fluid samples were obtained from 77%, 68%, and 83% of AD patients, MCI patients, and controls, respectively. Mean MTA score showed a significant increase from controls (left, right: 0.4, 0.3) to MCI patients (0.9, 0.8) to AD patients (2.3, 2.0), whereas mean WMH score did not differ among the three diagnostic groups (between 0.7 and 0.9). The distribution of both MRI markers was comparable to matched US-ADNI subjects. CONCLUSIONS: Academic EADC centers can adopt the ADNI platform to enroll MCI and AD patients and older controls with global cognitive and structural imaging features remarkably similar to those of the US-ADNI.

Brandt C, Bahl JC, Heegaard NH, Waldemar G, Johannsen P. · Memory Clinic, Section 6702, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Dement Geriatr Cogn Disord. · Pubmed #18536519 No free full text.

Abstract: AIM: Assays for cerebrospinal fluid (CSF) levels of total tau, phospho-tau protein and beta-amyloid 1-42 have been available for some years. The aim of the study was to assess the usability of these biomarkers in a mixed population of tertiary dementia referral patients in a university-based memory clinic. METHODS: 147 consecutive patients with a lumbar puncture as a part of their clinical workup were studied. A retrospective diagnosis was established based on consensus criteria without the knowledge of the CSF results. RESULTS: When diagnosing Alzheimer's disease (AD) compared to other diagnoses, the sensitivity of a single abnormal value was between 33 and 66%. The specificity was high except when discriminating AD from amnestic mild cognitive impairment. Two or more abnormal markers further increased the specificity and decreased the sensitivity. CONCLUSION: In a tertiary setting, abnormal CSF biomarker results may be of a diagnostic value - whereas normal results do not exclude neurodegenerative disease.

Olde Rikkert MG, van der Vorm A, Burns A, Dekkers W, Robert P, Sartorius N, Selmes J, Stoppe G, Vernooij-Dassen M, Waldemar G. · Department of Geriatrics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. · Am J Alzheimers Dis Other Demen. · Pubmed #18509105 No free full text.

Abstract: In this article, the authors describe how the European Dementia Consensus Network developed a consensus on research ethics in dementia, taking into account the questions posed by the era of genetic research and its new research methods. The consensus process started with a Delphi procedure to analyze relevant stakeholders' positions by describing their statements on the possibilities and limitations of research into genetic determinants of Alzheimer disease and to describe and analyze the moral desirability of genetic research on Alzheimer disease. The conclusions drawn from the Delphi procedure fuelled the development of the consensus statement, which is presented in this paper. The consensus statement aims to stimulate ethically acceptable research in the field of dementia and the protection of vulnerable elderly patients with dementia from application of inadequate research methods or designs.

Gouw AA, van der Flier WM, Fazekas F, van Straaten EC, Pantoni L, Poggesi A, Inzitari D, Erkinjuntti T, Wahlund LO, Waldemar G, Schmidt R, Scheltens P, Barkhof F, Anonymous00402. · Department of Neurology, Alzheimer Center and Image Analysis Center, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Stroke. · Pubmed #18323505 links to  free full text

Abstract: BACKGROUND AND PURPOSE: We studied the natural course of white matter hyperintensities (WMH) and lacunes, the main MRI representatives of small vessel disease, over time and evaluated possible predictors for their development. METHODS: Baseline and repeat MRI (3-year follow-up) were collected within the multicenter, multinational Leukoaraiosis and Disability study (n=396). Baseline WMH were scored on MRI by the Fazekas scale and the Scheltens scale. WMH progression was assessed using the modified Rotterdam Progression scale (absence/presence of progression in 9 brain regions). Baseline and new lacunes were counted per region. WMH and lacunes at baseline and vascular risk factors were evaluated as predictors of WMH progression and new lacunes. RESULTS: WMH progressed (mean+/-SD=1.9+/-1.8) mostly in the subcortical white matter, where WMH was also most prevalent at baseline. The majority of new lacunes, which were found in 19% of the subjects (maximum=9), also appeared in the subcortical white matter, mainly of the frontal lobes, whereas most baseline lacunes were located in the basal ganglia. Baseline WMH and lacunes predicted both WMH progression and new lacunes. Furthermore, previous stroke, diabetes, and blood glucose were risk factors for WMH progression. Male sex, hypertension, systolic blood pressure, previous stroke, body mass index, high-density lipoprotein, and triglyceride levels were risk factors for new lacunes. CONCLUSIONS: WMH and lacunes progressed over time, predominantly in the subcortical white matter. Progression was observed especially in subjects with considerable WMH and lacunes at baseline. Moreover, the presence of vascular risk factors at baseline predicted WMH progression and new lacunes over a 3-year period.

Lindquist SG, Holm IE, Schwartz M, Law I, Stokholm J, Batbayli M, Waldemar G, Nielsen JE. · Memory Disorders Research Group, The Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Eur J Neurol. · Pubmed #18284428 No free full text.

Abstract: We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre-symptomatic and affected family members underwent multidisciplinary (clinical, molecular, neuroimaging and neuropathological) examinations. Treatment with memantine in a family member with early symptoms, based on the clinical phenotype and the lack of specific treatment, appears to stabilize the disease course and increase the glucose metabolism in cortical and subcortical areas, as determined by serial [F(18)]FDG-PET scanning before and after initiation of treatment. Neuropathological examination of a second affected and mutation-positive family member showed moderate atrophy of the temporal lobes including the hippocampi. Microscopy revealed abundant numbers of tau-positive neurofibrillary tangles in all cortical areas and in some brainstem nuclei corresponding to a diagnosis of frontotemporal lobe degeneration on the basis of a MAPT mutation. The clinical and genetic heterogeneity of autosomal dominant inherited dementia must be taken into account in the genetic counselling and genetic testing of families with autosomal dominantly inherited dementia in general.

Lindquist SG, Nielsen JE, Stokholm J, Schwartz M, Batbayli M, Ballegaard M, Erdal J, Krabbe K, Waldemar G. · Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. · J Neurol Sci. · Pubmed #18187157 No free full text.

Abstract: BACKGROUND: Approximately 1% of all cases of Alzheimer's disease are inherited autosomal dominantly, and to date, three causative genes have been found, the Presenilin 1 (PSEN1) gene, the Presenilin 2 (PSEN2) gene and the Amyloid precursor protein (APP) gene. We describe atypical phenotypic features in a family with a pathogenic APP gene mutation and discuss possible explanations for these atypical features. METHODS AND RESULTS: We report a family with a history of dementia compatible with autosomal dominant transmission. The disease course in the proband was not typical for Alzheimer's disease as the diagnosis was preceded by 8 years of an isolated amnesia. Further, the proband had epilepsy with complex partial seizures and central degenerative autonomic failure as determined by clinical physiology. Sequencing the three known causative Alzheimer genes revealed a pathogenic missense mutation, APP Thr714Ala (the Iranian mutation). CONCLUSIONS: The atypical clinical phenotype with long prodromal phase, autonomic failure and seizures in this new proband with the APP Thr714Ala mutation illustrates the clinical heterogeneity in families with identical pathogenic mutations.

Simonsen AH, McGuire J, Podust VN, Hagnelius NO, Nilsson TK, Kapaki E, Vassilopoulos D, Waldemar G. · Biomarker Discovery Center Facility, Ciphergen Biosystems Inc., Copenhagen, Denmark. · Dement Geriatr Cogn Disord. · Pubmed #17971664 No free full text.

Abstract: BACKGROUND: An early and accurate diagnosis of Alzheimer's disease (AD) is important in order to initiate symptomatic treatment with currently approved drugs and will be of even greater importance with the advent of disease-modifying compounds. METHODS: Protein profiles of human cerebrospinal fluid samples from patients with AD (n = 85), frontotemporal dementia (n = 20), and healthy controls (n = 32) were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to verify previously discovered biomarkers. RESULTS: We verified 15 protein biomarkers that were able to differentiate between AD and controls, and 7 of these 15 markers also differentiated AD from FTD. CONCLUSION: A panel of cerebrospinal fluid protein markers was verified by a proteomics technology which may potentially improve the accuracy of the AD diagnosis.

Høgh P, Teller AS, Hasselbalch S, Waldemar G. · Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Neuroscience Centre, Copenhagen, Denmark. · Dement Geriatr Cogn Disord. · Pubmed #17952007 No free full text.

Abstract: BACKGROUND: The aim of this study was to assess the accuracy of visual image rating as compared to parametric analysis of regional cerebral blood flow (rCBF) measured with SPECT in patients referred to a memory clinic for diagnostic evaluation of cognitive symptoms. METHODS: SPECT with (99m)Tc-HMPAO was used to determine rCBF in 47 patients and 26 healthy control subjects. The 47 patients (30 F/17 M) had a mean age of 74.6 years (range = 62-88) and mild or questionable dementia with an MMSE score of 24.8 (range = 20-30). Two experienced image readers blinded to the classifications and identity of subjects performed visual rating in consensus and the global and regional CBF patterns were evaluated and graded according to severity of hypoperfusion. Correlation coefficients were calculated using results from the parametric analyses as gold standard. RESULTS: The sensitivity and specificity of global visual rating (normal vs. abnormal SPECT) was 92 and 86%, respectively, yielding an overall accuracy of 89% for visual rating compared to parametric analysis. The correlation between visual rating and parametric analysis was highly significant (p < 0.001). CONCLUSION: Visual rating is a valid method for analyzing SPECT images in patients with mild or questionable dementia.

Sørensen LV, Waldorff FB, Waldemar G. · Memory Disorder Research Group, Department of Neurology, Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, 2082, Blegdamsvej 9, DK 2100 Copenhagen, Denmark. · Arch Gerontol Geriatr. · Pubmed #17936382 No free full text.

Abstract: The purpose of this study was to investigate social participation in home-living patients with mild Alzheimer's disease (AD) and to identify predictors for low social participation. The study was based on baseline data from 330 home-living patients with mild AD who participated in The Danish Alzheimer Intervention Study (DAISY). Proxy-obtained information from primary caregiver assessed patients' social participation. The result showed that low social participation was present in mild AD. Significant independent predictors of low social participation were impairment in activities of daily living (ADL) and neuropsychiatric symptoms. The findings from this study add to the literature that social impairment is present even in the mild stage of AD. The findings underscore the importance of assessing social participation in mild AD as soon as few ADL skills are lost.

Ylikoski R, Jokinen H, Andersen P, Salonen O, Madureira S, Ferro J, Barkhof F, van der Flier W, Schmidt R, Fazekas F, Scheltens P, Waldemar G, Salvadori E, Pantoni L, Inzitari D, Erkinjuntti T, Anonymous00192. · Memory Research Unit, Department of Neurology, University of Helsinki, Helsinki, Finland. · Dement Geriatr Cogn Disord. · Pubmed #17565216 No free full text.

Abstract: BACKGROUND/AIMS: The Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) is a widely used rating instrument. The Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog) includes additional tests reflecting mental speed and executive functions. The objective of this study was to compare the results of the two scales among subjects with various degrees of white matter hyperintensities (WMHs). METHODS: In the multicentre, multinational Leukoaraiosis and Disability in the Elderly (LADIS) study, 616 non-disabled subjects between the ages of 65 and 84 were examined using MRI, the ADAS-cog and VADAS-cog. The WMH rating from the MRI divided the patients into groups of mild (n = 280), moderate (n = 187) and severe (n = 149) degrees of change. RESULTS: Covariance analysis controlling for the effect of age and education revealed that the ADAS-cog differentiated only the mild and severe WMH groups, while the differences between all three groups were highly significant with the VADAS-cog. CONCLUSIONS: The VADAS-cog significantly differentiated between all the white matter groups. In comparison, the ADAS-cog differentiated only severe changes. Accordingly, the VADAS-cog may be a more sensitive endpoint in studies of patients with white matter load and vascular burden of the brain.

Verdelho A, Madureira S, Ferro JM, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Hennerici M, O'Brien J, Pantoni L, Salvadori E, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, Anonymous00184. · Neurology Department, Centro de Estudos Egas Moniz, Santa Maria Hospital, Lisbon, Portugal. · J Neurol Neurosurg Psychiatry. · Pubmed #17470472 No free full text.

Abstract: BACKGROUND AND PURPOSE: Age related white matter changes (ARWMC) are frequent in non-demented old subjects and are associated with impaired cognitive function. Our aim was to study the influence of vascular risk factors and ARWMC on the neuropsychological performance of an independent elderly population, to see if vascular risk factors impair cognition in addition to the effects of ARWMC. METHODS: Independent subjects, aged 65-84 years, with any degree of ARWMC were assessed using a comprehensive neuropsychological battery including the Mini-Mental State Examination (MMSE), VADAS-Cog (Alzheimer's disease assessment scale) and the Stroop and Trail Making test. Vascular risk factors were recorded and ARWMC (measured by MRI) were graded into three classes. The impact of vascular risk factors and ARWMC on neuropsychological performance was assessed by linear regression analyses, with adjustment for age and education. RESULTS: 638 patients (74.1 (5) years old, 55% women) were included. Patients with severe ARWMC performed significantly worse on global tests of cognition, executive functions, speed and motor control, attention, naming and visuoconstructional praxis. Diabetes interfered with tests of executive function, attention, speed and motor control, memory and naming. Arterial hypertension and stroke influenced executive functions and attention. The effect of these vascular risk factors was independent of the severity of ARWMC, age and education. CONCLUSION: ARWMC is related to worse performance in executive function, attention and speed. Diabetes, hypertension and previous stroke influenced neuropsychological performance, independently of the severity of ARWMC, stressing the need to control vascular risk factors in order to prevent cognitive decline in the elderly.

Simonsen AH, McGuire J, Hansson O, Zetterberg H, Podust VN, Davies HA, Waldemar G, Minthon L, Blennow K. · Biomarker Discovery Center Facility, Ciphergen Biosystems, Inc., 2100 Copenhagen O, Denmark. · Arch Neurol. · Pubmed #17353378 links to  free full text

Abstract: OBJECTIVE: To use proteomic analysis of cerebrospinal fluid to discover novel proteins and peptides able to differentiate between patients with stable mild cognitive impairment (MCI) and those who will progress to Alzheimer disease (AD). DESIGN: Baseline cerebrospinal fluid samples from patients with MCI and healthy controls were profiled using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. SETTING: Memory disorder clinic. PARTICIPANTS: Patients with MCI (n = 113), of whom 56 were cognitively stable and 57 progressed to AD with dementia during a 4- to 6-year follow-up, as well as 28 healthy controls who were followed up for 3 years. Main Outcome Measure During follow-up, 57 patients progressed to AD and 56 patients had stable MCI. Cerebrospinal fluid from these 2 groups of patients was compared using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. RESULTS: We identified a panel of 17 potential biomarkers that could distinguish between patients with stable MCI and patients with MCI who progressed to AD. We have positively identified and characterized 5 of the potential biomarkers. CONCLUSIONS: Proteomic profiling of cerebrospinal fluid provided a novel panel of 17 potential biomarkers for prediction of MCI progression to AD. The 5 identified biomarkers are relevant to the pathogenesis of AD and could help gain an understanding of the molecular pathways in which they may function.