Alzheimer Disease: Erkinjuntti T

O'Brien J, Reisberg B, Erkinjuntti T. · No affiliation provided · Int Psychogeriatr. · Pubmed #16191210 No free full text.

This publication has no abstract.

Erkinjuntti T, Gauthier S. · Memory Research Unit, Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. · Front Neurol Neurosci. · Pubmed #19182465 No free full text.

Abstract: Vascular cognitive impairment (VCI) is the modern term related to vascular burden of the brain,reflecting all encompassing effects of cerebrovascular disease (CVD) on cognition. VCI include all levels of cognitive decline from mild deficits in one or more cognitive domains to a broad dementia-like syndrome. VCI incorporates the complex interactions between vascular risk factors, CVD etiologies and cellular changes within the brain and cognition. Vascular risk factors towards VCI include,e.g. arterial hypertension, high cholesterol, and diabetes. VCI includes the common poststroke dementia and vascular dementia (VaD). The main subtypes of VaD include the cortical VaD or multi-infarct dementia also referred as poststroke VaD and subcortical ischemic vascular disease and dementia or small vessel dementia. Traditional vascular risk factors and stroke are also independent factors for the clinical presentation of Alzheimer's disease. In addition to these vascular factors, CVD/strokes, infarcts and white matter lesions may trigger and modify progression of Alzheimer's disease.Whilst CVD is preventable and treatable, it clearly is a major factor in the prevalence of cognitive impairment in the elderly worldwide.

Geldmacher DS, Frolich L, Doody RS, Erkinjuntti T, Vellas B, Jones RW, Banerjee S, Lin P, Sano M. · Memory Disorders Program, Department of Neurology, University of Virginia, Box 800394, Charlottesville, Virginia 22908, USA. · J Nutr Health Aging. · Pubmed #17066215 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive degenerative disease that warrants active management to delay or slow progression of its symptoms. The symptoms of AD encompass behavior and daily function as well as cognition, so clinicians should take a global view in the assessment of treatment success. Because there is currently no cure for AD, one cannot expect an initial cognitive improvement observed in the first few months of therapy to be sustained indefinitely. However, one should expect that the patient who is treated early and persistently with medication for AD will show less evidence of behavioral, functional, and cognitive deterioration over a period of time than one would expect in the absence of pharmacotherapy. Thus, treatment success includes not only short-term improvement of symptoms but also less decline over the long term. Determination of treatment success therefore also requires awareness of the typical progression of untreated AD. In this article we review the natural history of AD and evidence for the effectiveness of the treatments indicated for AD: donepezil, galantamine, rivastigmine, and memantine.

Erkinjuntti T, Román G, Gauthier S. · Helsinki University Central Hospital, Finland. · Neurol Res. · Pubmed #15265282 No free full text.

Abstract: Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. Also, CVD frequently contributes to cognitive loss in patients with Alzheimer's disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil, galantamine, and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior and activities of daily living.

Erkinjuntti T. · Memory Research Unit, Department of Neurology, University of Helsinki, Finland. · J Neural Transm Suppl. · Pubmed #12597611 No free full text.

Abstract: Vascular dementias (VaDs) are the second most common cause of dementia. Cerebrovascular disease (CVD) and stroke relates to high risk of cognitive impairment, but also relate to Alzheimer's disease (AD): Vascular cognitive impairment (VCI) and dementias extend beyond the traditional multi-infarct dementia. Pathophysiology of VaD incorporates interactions between vascular etiologies (CVD and vascular risk-factors), changes in the brain (infarcts, white matter lesions, atrophy), host factors (age, education) and cognition. Variation in defining the cognitive syndrome, in vascular etiologies, and allowable brain changes in current criteria have resulted in variable estimates of prevalence, of groups of subjects, and of the types and distribution of putative causal brain lesions. Should new criteria be developed? Ideally in constructing new criteria the diagnostic elements should be tested with prospective studies with clinical-pathological correlation: replace dogma with data. Meanwhile focus on more homogenous subtypes of VaD, and on imaging criteria could be a solution. Subcortical ischemic vascular disease and dementia (SIVD) incorporate small vessel disease as the chief vascular etiology, lacunar infarct and ischaemic white matter lesions as primary type of brain lesions, subcortical location as the primary location of lesions, and subcortical syndrome as the primary clinical manifestation. It incorporates two clinical entities "Binswanger's disease" and "the lacunar state". AD with VaD (mixed dementia) has been underestimated as a prevalent cause in the older population. In addition to simple co-existence, VaD and AD have closer interaction: several vascular risk factors and vascular brain changes relate to clinical manifestation of AD, and they share also common pathogenetic mechanisms. Vascular cognitive impairment (VCI) is a category aiming to replace the "Alzhemerized" dementia concept in the setting of CVD, and substitute it with a spectrum that includes subtle cognitive deficits of vascular origin, post-stroke dementia, and the complex group of the vascular dementias. As far there is no standard treatment for VaDs, and still little is known on the primary prevention (brain at risk for CVD) and secondary prevention (CVD brain at risk for VCI/VaD). There is no standard symptomatic treatment for VaD. Recently symptomatic cholinergic treatment has shown promise in AD with VaD, as well as probable VaD. Future focus should be directed to the distinct etiological and pathological factors: the vascular and the AD burden of the brain.

Erkinjuntti T, Rockwood K. · Department of Neurology, University of Helsinki, Helsinki, Finland. · Semin Clin Neuropsychiatry. · Pubmed #12567331 No free full text.

Abstract: Vascular dementia (VaD) is a term used to describe a particular constellation of cognitive and functional impairment, and is now generally seen as a subset of the larger syndrome of vascular cognitive impairment (VCI). The latter is seen as cognitive impairment in the face of cerebrovascular disease. VCI can be classified clinically by whether patients meet criteria for dementia, and whether the syndrome is distinct or overlaps with primary neurodegenerative diseases, such as Alzheimer's disease. This clinical classification can be further classified by neuroimaging, with subgroups that show cortical infarction, subcortical infarction and white matter changes, each alone or in combination. Understood in this way, VCI is likely the most common form of cognitive impairment in the population. Attempts to treat VaD had varying degrees of success, but it now appears that many forms of VCI might be preventable, especially with good control of vascular risk factors in middle age.

Erkinjuntti T. · Memory Research Unit, Department of Clinical Neurosciences, Helsinki University Central Hospital, P.O. Box 300, 00029 Hyks, Finland. · J Neurol Sci. · Pubmed #12417370 No free full text.

Abstract: Vascular dementia (VaD) has a great deal of overlap (in terms of features and symptoms) with Alzheimer's disease (AD). Mixed dementia, or AD with concomitant cerebrovascular disease (AD with CVD), is increasingly being recognized as a distinct clinical condition that occurs with substantial frequency. The robust evidence for the effectiveness of cholinergic treatments such as galantamine (Reminyl) in AD suggests its potential use in the treatment of dementias related to CVD, and preclinical evidence supports this rationale. Galantamine, which has a unique dual cholinergic mode of action, may be of particular benefit in VaD and AD with CVD. For example, behavioral symptoms, which can be more severe in VaD than in AD and are important determinants of the impact of dementia, may be especially benefited by galantamine. This results from its potential to modulate systems involving other neurotransmitters such as 5-HT (serotonin) and dopamine, which affect mood and emotional balance. The results of a recent landmark clinical trial with galantamine in patients with VaD, or AD with CVD, indicate that galantamine produces benefits across a broad range of symptoms of dementia in both patient populations. Significant cognitive improvements over 6 months, long-term maintenance of cognition for at least 12 months, and global benefits, as well as efficacy in both behavioral and functional symptoms, indicate efficacy with galantamine that is so far unsurpassed by any other drug treatment for dementia. Galantamine therefore has potential to benefit a wide range of patients with dementia in the clinic.

Partanen K, Laakso M, Erkinjuntti T, Soininen H. · KYS:n Kliinisen radiologian Osasto PL 1777, 70211 Kuopio. · Duodecim. · Pubmed #11989015 No free full text.

This publication has no abstract.

Erkinjuntti T. · Department of Clinical Neurosciences, Helsinki University Central Hospital, Helsinki, Finland. · Int J Clin Pract Suppl. · Pubmed #11406922 No free full text.

Abstract: Vascular dementia (VaD) describes dementia arising from cerebrovascular disease (CVD) and ischaemic brain injury, and relates to a number of different vascular mechanisms and clinical manifestations. The characterisation of brain lesions by neuroimaging analysis, and the study of their relation to clinical deficits such as cognitive and functional decline, are critical to the concept and treatment of VaD, and form an important part of widely used diagnostic criteria for this dementia type. For instance, the extent to which pathological brain lesions cause, compound or coexist with cognitive impairment is a major determinant of other clinical deficits, their nature and the rate of disease progression. Through numerous neuroimaging and epidemiological studies, VaD is now seen to encompass a heterogeneous group of clinical syndromes such as multiple-infarct (cortical) dementia, small-vessel (subcortical) dementia and, less commonly, dementia associated with strategic infarcts. Due to a large number of similarities in clinical symptoms, pathophysiological mechanisms, associated risk factors and neurochemical deficits between VaD and Alzheimer's disease, patients with coexistent Alzheimer's disease and CVD ('mixed' dementia) represent another important, but previously underestimated subgroup. This article reviews the clinical symptoms and neuroimaging findings most commonly observed in patients with VaD. Increased familiarity with the clinical picture of VaD should offer more hope of defining realistic treatment aims for future pharmacotherapy.

Gauthier S, Rockwood K, Gélinas I, Sykes L, Teunisse S, Orgogozo JM, Erkinjuntti T, Erzigkeit H, Gleeson M, Kittner B, Pontecorvo M, Feldman H, Whitehouse P. · McGill Centre for Studies in Aging, Verdun, Quebec, Canada. · Alzheimer Dis Assoc Disord. · Pubmed #10609694 No free full text.

Abstract: Decline in functional abilities is a major component of the dementia syndrome. The definition of dementia in the International Classification of Diseases (10th rev.) requires a cognitive impairment sufficient to impair personal activities of daily living (ADL). The Diagnostic and Statistical Manual of Mental Disorders (4th ed.) also requires cognitive deficits sufficiently severe to cause impairment in occupational or social functioning and must represent a decline from a higher level of functioning. However, the term disability is more appropriate than impairment to describe a loss in activities, as opposed to a loss of elementary functions, and is consistent with World Health Organization definitions of impairment, disability, and handicap. There is no doubt that ADL outcomes are required in therapeutic drug studies on vascular dementia, and there is a good rationale and some evidence for the use of ADL scales developed for therapeutic research in Alzheimer disease, favoring scales devoid of items sensitive to physical disabilities. Similarly, ADL-related clinical milestones could be used for longer-term studies aiming predominantly at slowing progression of disease in both early and later stages of dementia. Slower decline in ADL and delay in reaching ADL-related clinical milestones should be considered as valid outcomes by regulatory bodies in the process of dementia drug approval.

Gorelick PB, Erkinjuntti T, Hofman A, Rocca WA, Skoog I, Winblad B. · Department of Neurological Sciences, Rush Medical College, Chicago, Illinois, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10609692 No free full text.

Abstract: Stroke is an important public health problem worldwide. Those at high risk of stroke may be at high risk of cognitive impairment and dementia after stroke. Modifiable cardiovascular risk factors in midlife including hypertension, alcohol use, cigarette smoking, and certain dietary factors may be important targets for prevention of vascular causes of cognitive impairment. These same types of factors may also be associated with Alzheimer disease. Better control of cardiovascular disease risk factors might lead to delay or prevention of vascular dementia and Alzheimer disease.

Rockwood K, Bowler J, Erkinjuntti T, Hachinski V, Wallin A. · Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. · Alzheimer Dis Assoc Disord. · Pubmed #10609683 No free full text.

Abstract: The challenge of describing subgroups is particularly important in vascular dementia, which, in contrast to more stereotypic processes affecting cognitive function, is better thought of as several syndromes rather than as a disease. Many current diagnostic descriptions lack a strong empiric basis. Some of the categories now in use suffer from a priori assumptions about causality and pattern associations, which themselves have not been validated. The so-called mixed dementia syndrome may have been underrepresented in our estimation of dementia subtypes, in comparison with so-called pure vascular causes. Within the vascular syndrome, whether seen in isolation or in combination with other causes of dementia, the relative contributions of white matter changes as compared with multiple cortical strokes needs to be clarified. It remains a matter of controversy as to whether prolonged or chronic intermittent cerebral ischemia is a statistically important part of the dementia. The variable relation between clinical presentation and neuroimaging localization has important consequences for understanding the pathophysiology of cognitive impairment arising from vascular causes. Recent data also suggest that we should focus away from both the Alzheimer disease model of dementia and the multi-infarct model of vascular dementia. There are important opportunities available to clinicians from many disciplines to collaborate in precise clinical descriptions of large numbers of patients to advance our understanding of the spectrum of vascular cognitive impairment.

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.

Desmond DW, Erkinjuntti T, Sano M, Cummings JL, Bowler JV, Pasquier F, Moroney JT, Ferris SH, Stern Y, Sachdev PS, Hachinski VC. · Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, New York, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10609678 No free full text.

Abstract: Dementia is common among patients with cerebrovascular disease, particularly in a setting of one or more clinically evident strokes. Prior cohort and case studies have suggested that the cognitive syndrome of vascular dementia is characterized by predominant executive dysfunction, in contrast to the deficits in memory and language function that are typical of patients with Alzheimer disease. The course of cognitive decline may also differ between those dementia subtypes, with many, but not all, patients with vascular dementia exhibiting a stepwise course of decline caused by recurrent stroke and most patients with Alzheimer disease exhibiting a gradually progressive course of decline. The findings of prior studies of the cognitive syndrome of vascular dementia must be interpreted with caution, however, because of (1) possible inaccuracies in the determination of the dementia subtype and the loss of precision that might result from pooling heterogeneous subgroups of patients with vascular dementia, (2) difficulties inherent in identifying a pattern of strengths and weaknesses in patients who are required to have memory impairment and other deficits to meet operationalized criteria for dementia, and (3) the use of limited test batteries whose psychometric properties are incompletely understood. Specific questions that should be addressed by future studies are discussed.

Erkinjuntti T, Skoog I, Lane R, Andrews C. · Department of Neurology, Helsinki University Central Hospital, Hyks, Finland. · Int J Clin Pract. · Pubmed #14686563 No free full text.

Abstract: Alzheimer's disease patients with hypertension or other vascular risk factors have been shown to receive greater symptomatic benefits than patients with strictly Alzheimer's disease following short-term treatment with rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase. We evaluated the long-term efficacy of rivastigmine in Alzheimer's disease patients with or without hypertension. Subjects in a 26-week placebo-controlled trial of rivastigmine entered an open-label extension study for 104 weeks. Efficacy measures included the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Progressive Deterioration Scale (PDS) and Global Deterioration Scale (GDS). Subjects were stratified by the presence or absence of hypertension at baseline. At 104 weeks, there was a trend for hypertensive patients from the original rivastigmine 6-12 mg/day group (early starters), who received rivastigmine for the full 104 weeks) to have better ADAS-cog scores than the original placebo group (late starters), who received open-label rivastigmine for the last 78 weeks only). Significant treatment differences were observed in the hypertensive subgroup on the PDS and GDS. In non-hypertensive patients, changes from baseline at week 104 were similar in 'early' and 'late' starters of rivastigmine treatment. The additional apparent benefits on disease progression detected in patients with hypertension and Alzheimer's disease may be linked to drug effects on cerebrovascular factors. These findings may have an important influence on the way cholinesterase inhibitors are prescribed.

Kurz AF, Erkinjuntti T, Small GW, Lilienfeld S, Damaraju CR. · Department of Psychiatry and Psychotherapy, Technische Universitaet Munchen, Munich, Germany. · Eur J Neurol. · Pubmed #14641507 No free full text.

Abstract: The relationship between cholinergic dysfunction and cognitive and functional impairment in patients with vascular dementia (VaD) and Alzheimer's disease (AD) with cerebrovascular disease (CVD) suggests a potential role for cholinomimetic therapy. Initial studies of galantamine demonstrated cognitive, behavioral, and functional benefits in these populations. 326 patients with VaD or AD with CVD who completed an initial 12-month trial were treated with galantamine 24 mg/day in a 24-month, open-label extension. This interim analysis was performed at month 12 of the open-label extension (248 completed the trial). Galantamine (up to 24 months total) was well tolerated in both groups. The most frequently reported adverse events, characteristic of older dementia patients, included depression, agitation, and insomnia. Gastrointestinal adverse events were less common than initially, indicating declining incidence with long-term therapy. Patients taking galantamine for the entire study demonstrated the least cognitive decline on AD Assessment Scale-cog/11: 2.7 points vs. 3.1 points in those given placebo initially (P < 0.001 and P = 0.003, respectively). The long-term benefits of galantamine were evident in both groups; cognitive baseline levels were maintained for approximately 21 months in VaD patients and for 12 months in patients with AD with CVD. Long-term (up to 24 months) galantamine therapy in patients with VaD and AD with CVD is well tolerated and associated with prolonged maintenance of cognitive function.

Bullock R, Erkinjuntti T, Lilienfeld S, Anonymous00005. · Kingshill Research Centre, Victoria Hospital, Swindon, UK. · Dement Geriatr Cogn Disord. · Pubmed #14560062 No free full text.

Abstract: We evaluated the long-term cognitive effects and safety of galantamine 24 mg/day in patients with Alzheimer's disease plus cerebrovascular disease (AD + CVD or mixed dementia). Subgroup analysis was performed of patients with AD + CVD who participated in a 6-month, multicenter, randomized, double-blind, parallel-group study and a 6-month, open-label, active-treatment extension. METHOD: Two hundred and eighty-five patients with AD + CVD were randomized to receive either placebo (n = 97) or galantamine 24 mg/day (n = 188) for 6 months. Two hundred and thirty-eight (84%) patients continued with the open-label phase of the study (86 from the placebo group, 152 from the galantamine group) and were treated with galantamine 24 mg/day. The primary efficacy measure was cognitive performance as assessed using the eleven-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog/11). Standard safety evaluations and adverse-event monitoring were performed throughout the 12-month study period. Patients with AD + CVD treated with galantamine experienced statistically and clinically significant improvement in cognition at month 6 (mean change in ADAS-cog/11 score -1.1; p < or = 0.05 vs. baseline) and maintained their cognitive function for the entire 12-month study (mean change in ADAS-cog/11 score +0.1). In contrast, the cognitive function deteriorated among those in the placebo group (mean change in ADAS-cog/11 at month 6 +2.0; p < or = 0.001 vs. baseline). Patients with AD + CVD who were switched from placebo to galantamine for the open-label phase of the trial did show improvement in cognitive function; however, they never attained the same cognitive level as patients who had been treated with galantamine for the entire 12 months [mean (+/- SE) ADAS-cog/11 scores in the placebo/galantamine group 25.7 +/- 1.32 and 24.2 +/- 1.57 at months 6 and 12, respectively, and in the galantamine/galantamine group 21.5 +/- 0.87 and 22.2 +/- 1.06 at months 6 and 12, respectively]. The results of this subgroup analysis indicate that galantamine is effective for long-term maintenance of the cognitive function in patients with AD + CVD and is safe and well tolerated in this patient population.

Small G, Erkinjuntti T, Kurz A, Lilienfeld S. · Department of Psychiatry and Biobehavioral Sciences and Neuropsychiatric Institute, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90024, USA. · CNS Drugs. · Pubmed #12962529 No free full text.

Abstract: INTRODUCTION: Alzheimer's disease and vascular dementia are the two most common types of dementia, with significant overlap of clinical symptoms and pathology. Previous results from a 6-month, double-blind, placebo-controlled, international, multicentre study of the cholinomimetic galantamine in patients with probable vascular dementia or mixed dementia (Alzheimer's disease with cerebrovascular disease) showed significant cognitive, behavioural and functional benefits in these patients. Furthermore, results of a 6-month, open-label extension of this study confirmed that patients with vascular dementia or Alzheimer's disease with cerebrovascular disease may benefit from galantamine therapy for at least 1 year. The objective of the current analysis was to determine if the long-term cognitive benefits of galantamine seen in the above-mentioned study are influenced by dementia type (probable vascular dementia vs Alzheimer's disease with cerebrovascular disease). STUDY DESIGN: A post hoc sub-analysis of a 6-month, multicentre, randomised, double-blind, placebo-controlled study and a subsequent 6-month, open-label extension. PATIENTS AND METHODS: Patients diagnosed with probable vascular dementia or Alzheimer's disease with cerebrovascular disease were treated with galantamine (Reminyl) 24 mg/day for 12 months (6 months double-blind and 6 months open-label) or placebo for 6 months (double-blind) followed by galantamine 24 mg/day for 6 months (open-label). Changes in scores on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog/11) were assessed at months 6, 7.5 and 12. Mean changes from baseline were analysed. RESULTS: Patients with probable vascular dementia treated with galantamine for 6 or 12 months showed significant improvements in ADAS-cog/11 scores versus baseline, which were maintained at the end of the 12-month study. Patients who had Alzheimer's disease with cerebrovascular disease continuously treated with galantamine maintained the cognitive abilities seen at baseline for at least 12 months. Additionally, patients who had Alzheimer's disease with cerebrovascular disease who were switched from placebo to open-label galantamine therapy for 6 months demonstrated cognitive benefits, but these benefits were significantly less than those observed in patients treated with galantamine continuously for the 12-month period. Galantamine was well tolerated throughout the entire 12-month study. CONCLUSIONS: These findings suggest that the drug is efficacious for such common forms of dementia as vascular dementia and Alzheimer's disease with cerebrovascular disease. Moreover, some patients benefit from galantamine therapy that is initiated early, soon after diagnosis, and continued for at least 1 year.

Erkinjuntti T, Kurz A, Small GW, Bullock R, Lilienfeld S, Damaraju CV, Anonymous00331. · Department of Clinical Neurosciences, Helsinki University Central Hospital, Helsinki, Finland. · Clin Ther. · Pubmed #12860497 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) are the most common types of dementia worldwide. Galantamine, an acetylcholinesterase inhibitor and allosteric nicotinic modulator, has shown broad clinical benefits in patients with mild to moderate dementia due to AD, probable VaD, or AD with cerebrovascular disease (CVD)-so-called mixed dementia. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profiles of galantamine 24 mg/d in patients with VaD or AD with CVD over the longer term (>6 months). METHODS: This was an open-label extension of a 6-month double-blind study of galantamine. Patients who had been randomized to receive galantamine 24 mg/d or placebo in the double-blind phase were eligible to continue open-label treatment with galantamine 24 mg/d for 6 months. The primary efficacy end point was change in cognition, based on scores on the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11). Secondary measures included changes in functional ability (as measured on the Disability Assessment for Dementia [DAD]) and behavior (as measured on the Neuropsychiatric Inventory [NPI]). Safety and tolerability were also monitored. RESULTS: Four hundred fifty-nine patients (240 men, 219 women; mean [SE] age, 75.2 [0.33] years) entered the open-label phase. Of these patients, 195 (42.5%) had a diagnosis of probable VaD, and 238 (51.9%) had a diagnosis of AD with CVD; the remainder had an inconclusive diagnosis. At month 12 of the study, improvements from baseline (the start of the double-blind phase) in ADAS-cog/11 scores were observed in both the group that received placebo during the double-blind phase (placebo/galantamine group: -0.3 point; 95% CI, -1.64 to 1.06) and the group that received galantamine during the double-blind phase (galantamine/galantamine group: -0.9 point; 95% CI, -1.73 to 0.03). Improvement in functional ability was demonstrated by statistically significant mean (SE) changes from baseline in DAD score in both the placebo/galantamine group (-7.4 [1.68]; P < or = 0.001) and the galantamine/galantamine group (-3.6 [1.33]; P < or = 0.01). There was no significant change in mean (SE) NPI scores in either group (0.2 [0.98] and 0.1 [0.70], respectively). Galantamine treatment was well tolerated. CONCLUSIONS: In these patients with VaD and AD with CVD, galantamine treatment produced similar sustained benefits in terms of maintenance of or improvement in cognition (ADAS-cog/11), functional ability (DAD), and behavior (NPI) after 12 months.

Erkinjuntti T, Skoog I, Lane R, Andrews C. · Department of Neurology, Helsinki University Central Hospital, Hyks, Finland. · Int J Clin Pract. · Pubmed #12510954 No free full text.

Abstract: Rivastigmine has demonstrated significant benefits in patients with mild to moderate Alzheimer's disease (AD). We aimed to confirm whether rivastigmine was effective in patients with or without concurrent vascular risk factors (VRF), as previously suggested. We chose to stratify the 725 patients involved in an international dose-ranging study according to the presence of arterial hypertension (a marker of VRF) at baseline. Efficacy in each subgroup was assessed using the ADAS-cog, a measure of cognitive performance, the Progressive Deterioration Scale (PDS) and the Clinician's Interview-Based Impression of Change (CIBIC) with caregiver input. Patients receiving rivastigmine 6-12 mg/day showed better outcomes on the ADAS-cog than those receiving placebo, in both the hypertensive and non-hypertensive subgroups. Hypertensive patients receiving rivastigmine 6-12 mg/day also showed improvement over those receiving 1-4 mg/day (p = 0.023). Rivastigmine 6-12 mg/day also provided better outcomes than placebo on the PDS in the hypertensive (p = 0.031) and non-hypertensive (p = 0.035) subgroups. All patients receiving rivastigmine 6-12 mg/day had superior CIBIC-plus scores than those receiving placebo. There was a trend for lower incidences of nausea and vomiting in rivastigmine-treated patients with hypertension than in those without hypertension. No cardiac adverse events or drug-drug interactions were reported. Our data support the hypothesis that rivastigmine provides benefits to patients with or without hypertension, and contribute to the evidence that particular benefits may be observed in those with vascular risk factors.

Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. · Department of Clinical Neurosciences, Helsinki University Central Hospital, Helsinki, Finland. · Lancet. · Pubmed #11965273 No free full text.

Abstract: BACKGROUND: Vascular dementia is the second commonest form of dementia, and vascular factors contribute to the development of dementia in many patients with Alzheimer's disease. Galantamine amplifies the acetylcholine response by inhibiting acetylcholinesterase and modulating nicotinic receptors. It has shown broad, sustained benefits in patients with Alzheimer's disease. We investigated the effects of galantamine in patients with a diagnosis of probable vascular dementia or Alzheimer's disease combined with cerebrovascular disease. METHODS: Eligible patients were randomly assigned galantamine 24 mg/day (n=396) or placebo (n=196) in a multicentre, double-blind, 6-month trial. Primary endpoints were cognition (Alzheimer's disease assessment scale, cognitive subscale [ADAS-cog]) and global functioning (clinician's interview-based impression of change plus caregiver input [CIBIC-plus]). Secondary endpoints included assessments of activities of daily living and behavioural symptoms. Patients were monitored for adverse events. Analyses were on the basis of observed case or last observation carried forward. FINDINGS: Galantamine showed greater efficacy than placebo on ADAS-cog (galantamine change -1.7 [SE 0.4] vs placebo 1.0 [0.5]; treatment effect 2.7 points; p<0.0001) and CIBIC-plus (213 [74%] vs 95 [59%] patients remained stable or improved, p=0.0001). Activities of daily living and behavioural symptoms were also significantly improved compared with placebo (p=0.002 and p=0.016, respectively). Galantamine was well tolerated. INTERPRETATION: Galantamine showed a therapeutic effect on all key areas of cognitive and non-cognitive abilities in this group of dementia patients.

Kittner B, De Deyn PP, Erkinjuntti T. · European/Canadian Propentofylline Study Group, Aventis Pharmaceuticals, Bridgewater, New Jersey 08807, USA. · Ann N Y Acad Sci. · Pubmed #10818549 No free full text.

This publication has no abstract.

Pekkonen E, Jääskeläinen IP, Hietanen M, Huotilainen M, Näätänen R, Ilmoniemi RJ, Erkinjuntti T. · Department of Neurology, Helsinki University Central Hospital, Finland. · Clin Neurophysiol. · Pubmed #10576491 No free full text.

Abstract: OBJECTIVE: To study whether preconscious auditory processing is deteriorated in patients with Alzheimer's disease (AD) having mild to moderate cognitive symptoms. To investigate whether auditory processing correlates with the impairment of the higher cortical functions. METHODS: P50m and N100m responses elicited by a sequence of repetitive tones were recorded with a whole-head magnetometer from 22 patients with probable AD and from 18 healthy age-matched controls. In addition, an extensive neuropsychological test battery assessing main cognitive domains was administered to all subjects. RESULTS: The patients with AD had significantly delayed N100m responses in the left hemisphere that correlated with the impairment of the language functions. CONCLUSIONS: N100m auditory responses measured with magnetoencephalography may be useful in evaluating the severity and progression of the cortical dysfunction in dementia.

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.

Erkinjuntti T, Gauthier S, Bullock R, Kurz A, Hammond G, Schwalen S, Zhu Y, Brashear R. · Memory Research Unit, Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. · J Psychopharmacol. · Pubmed #18308781 No free full text.

Abstract: Alzheimer's disease combined with cerebrovascular disease (AD with CVD) is associated with progressive decline, with CVD impacting AD onset and severity of progression. Subjects with confirmed diagnosis of AD with CVD were treated with galantamine during a six-month, randomized, placebo-controlled trial (N = 285). Responder analyses were performed for cognitive, behavioural and functional outcome measures. Galantamine treatment resulted in significantly greater cognitive and functional improvements compared with placebo at six months, and a significantly higher percentage of treatment responders. The proportion of responders demonstrating improved or maintained cognition on the 11-item AD assessment scale-cognitive subscale (ADAS-cog/11) was 60.5% for galantamine versus 46.0% for placebo (P = 0.013). The proportion of patients responding by at least four-points on the ADAS-cog/11 was significantly greater for the galantamine group compared with placebo (33.6% versus 17.2%; P = 0.003). Seventy-five percent of galantamine-treated subjects improved or remained stable as assessed by CIBIC-plus compared with 53.6% on placebo (P = 0.0006). Significantly higher responder rates were observed with galantamine for behaviour (64.9% versus 56.6%; P = 0.024), and numerically favourable responder rates were seen with galantamine for activities of daily living. Treatment-emergent adverse events were generally related with the gastrointestinal system (nausea 20% versus 10%; vomiting 12% versus 5%; galantamine and placebo groups, respectively). Three deaths occurred during double-blind treatment: 2 of 188 subjects receiving galantamine, and 1 of 97 subjects receiving placebo. These findings are consistent with a broad range of cognitive, functional and behavioural benefits with galantamine across the spectrum of AD and AD with CVD.