Showing papers in "Dementia and Geriatric Cognitive Disorders in 1999"

The effects of donepezil in Alzheimer's disease - results from a multinational trial.

Abstract: Donepezil has been shown to be well tolerated and to improve cognition and global function in patients with mild to moderately severe Alzheimer's disease (AD). The current trial was undertaken to investigate further the efficacy and safety of donepezil, in a multinational setting, in patients with mild to moderately severe AD. This 30-week, placebo-controlled, parallel-group study consisted of a 24-week, double-blind treatment phase followed by a 6-week, single-blind, placebo washout. Eight hundred and eighteen patients with mild to moderately severe AD were randomly allocated to treatment with single, daily doses of 5 or 10 mg donepezil, or placebo. The two primary efficacy measures were: a cognitive performance test, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and a global evaluation, the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus). Secondary outcome measures included the Sum of the Boxes of the Clinical Dementia Rating Scale (CDR-SB), a modified Interview for Deterioration in Daily living activities in Dementia (IDDD) and a patient rated quality of life assessment. Statistically significant improvements in cognitive and global function were observed, as evaluated by ADAS-cog and CIBIC plus, respectively, in both the 5 and 10 mg/day donepezil groups, compared with placebo. Treatment-associated changes were also observed in functional skills, as shown by improved scores on the CDR-SB and the complex-tasks component of the IDDD. A dose-response effect was evident, with the 10 mg/day donepezil group demonstrating greater benefits in all outcome measures than the 5 mg/day group. Donepezil was well tolerated by this patient population and did not produce any clinically significant laboratory test abnormalities. The results of this study confirm that donepezil is effective and well tolerated in treating the symptoms of mild to moderately severe AD.

Predisposing and precipitating factors for delirium in hospitalized older patients.

Abstract: Delirium is a common and serious problem for older hospitalized patients. This investigation proposes a multifactorial model of delirium etiology, involving a complex interrelationship of predisposing (vulnerability) factors and precipitating factors (acute insults). An overview of risk factors for delirium identified in 14 studies published since 1980 is provided. Although these studies identify key risk factors for delirium, they do not allow the examination of the interrelationship of predisposing and precipitating factors. Thus, we present two prospective cohort studies by our group which empirically examine: (1) predisposing (vulnerability) factors, (2) precipitating factors, and (3) the interrelationship of predisposing and precipitating factors. Understanding these risk factors is the key to developing appropriate preventive strategies and to target intermediate and high risk patients for intervention efforts.

Identification of Cognitive Impairment in the Elderly: Homocysteine Is an Early Marker

Abstract: In 336 consecutive patients attending a university-affiliated memory unit, clinical and psychological findings, neuroimaging and laboratory tests were analyzed. The patients were diagnosed with early Alzheimer's disease 3%, senile dementia (SDAT) 16%, vascular dementia (VAD) 20%, other dementias 9%, minor cognitive impairment (dysmentia) 32% and subjective symptoms only 21%. Increases in vascular risk factors, serum homocysteine, ApoE4 load and neuroimaging pathology were found in dementia but also in dysmentia and in patients with subjective symptoms only. The homocysteine levels correlated inversely with cognitive performance. The increases in serum homocysteine, which were pathological in VAD, Dysmentia and SDAT, may be indicative of a disturbed cerebral one-carbon metabolism and signal-accelerated development of cognitive disease.

Behavioral syndromes in Alzheimer's disease: description and correlates.

Abstract: Introduction: Behavioral disturbances in patients with Alzheimer’s disease (AD) are ill-defined conditions. We hypothesize that the many behavioral disturbances hitherto described and studied might be grouped into few syndromes with separate determinants and correlates. Patients and Methods: 162 consecutive patients with probable AD admitted to a dementia unit were assessed by the UCLA Neuropsychiatric Inventory (NPI). Results: Factor analysis was carried out on NPI subscales, leading to three syndromes: ‘mood’, ‘psychotic’ and ‘frontal’. Patients with the ‘psychotic’ syndrome were older, had older age at dementia onset, had poorer cognition, were more often males, and had faster rate of dementia progression. Patients with the ‘frontal’ syndrome had higher education, longer disease duration, and slower rate of progression. Discussion: Some combinations of behavioral disturbances occur more frequently together and might represent separate behavioral syndromes. Different clinical correlates of the syndromes suggest separate etiologies.

Update on the Neuropathogenesis of Delirium

Abstract: Delirium has been considered a syndrome of generalized dysfunction of higher cortical functions due to its breadth of symptoms and associated diffuse slowing on electroencephalogram. Advances in neuropsychiatry have revealed differences between brain regions, including the hemispheres, which may underlie the constellation of symptoms among different psychiatric disorders. For example, different neural pathways are involved in major depression and obsessive-compulsive disorder, including lateralization to one or the other hemisphere. In this article the author proposes that delirium, too, involves particular neural pathways and that lateralization to the right may be relevant. Structural and functional neuroimaging reports and recent neuropsychological studies support this lateralization. Prefrontal cortices, anterior and right thalamus, and right basilar mesial temporoparietal cortex may play a significant role in subserving delirium symptoms and may be the 'final common pathway' for delirium from a variety of etiologies. The final common pathway may be responsible for certain 'core symptoms' (disorientation, cognitive deficits, sleep-wake cycle disturbance, disorganized thinking, and language abnormalities), while other symptoms (delusions, hallucinations, illusions, and affective lability) may occur depending on the etiology causing delirium. An imbalance in the cholinergic and dopaminergic neurotransmitter systems is most commonly implicated in causing delirium, and could both account for delirium symptoms and be consistent with the neuroanatomical pathways being implicated.

Neuroimaging Findings in Twins Discordant for Alzheimer’s Disease

Abstract: Data from computed tomography (CT) scans of 12 twin pairs in which one partner had Azheimer’s disease (AD) and the other partner is cognitively intact were analyzed to study structural brain features

Acetylcholine and Delirium

Abstract: The neurotransmitter acetylcholine has been implicated in animal and human studies of delirium. This chapter will briefly review the clinical studies focussing on measurement of serum levels of anticholinergic activity in delirious states. Three approaches have been taken. First, to identify medications currently prescribed that have subtle anticholinergic effects. The current 'list' includes 48 commonly prescribed medications. Second, to associate serum anticholinergic activity with delirium in various clinical states including postcardiotomy delirium, postelectroconvulsive delirium, delirious elderly medical inpatients, and nursing home patients. Third, to intervene in patients with elevated anticholinergic activity by reducing known anticholinergics and correlating this reduction with clinical measures of cognition and delirium. Our most recent data investigates the impact of anticholinergics on demented patients. Rates of delirium were significantly higher in patients receiving larger numbers of anticholinergics.

Epidemiology of delirium

Abstract: Delirium is one of the most frequent symptoms of disease in the elderly. A large variation of incidence and prevalence data is reported probably due to different patient populations and inconsistent diagnostic criteria. In medical and surgical elderly inpatients recent studies report a prevalence rate of approximately 15% and in postoperative patients the incidence and prevalence rates vary greatly, 7-52%, depending on patient population and clinical setting. In nursing homes the prevalence is even higher and delirium is often combined with dementia. Data supports the statement that delirium is most often found in hospitalized somatically ill elderly patients. As a consequence of the rising number of elderly in hospitals we have to expect an increase in the prevalence and incidence of delirium.

14-3-3 protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

Abstract: We explored simultaneously 14-3-3 protein, neuron-specific enolase (NSE), and one astroglial protein, S-100, recently proposed as Creutzfeld-Jakob disease (CJD) markers, in the cerebrospinal fluid (CS

Apolipoprotein E genetic variation and Alzheimer's disease. a meta-analysis.

Abstract: In order to quantify the effects of apolipoprotein (apo) E on early- and late-onset, sporadic and familial Alzheimer’s disease (AD) more precisely we performed a meta-analysis of 42 case-control serie

Clinical profile of delirium in patients treated for femoral neck fractures.

Abstract: The incidence of delirium, its predisposing factors, clinical profile, associated symptoms and consequences were investigated in 54 consecutive patients, 19 men and 35 women, mean age 77.1 years, a ...

Impairment of neocortical metabolism predicts progression in Alzheimer's disease

Abstract: Progression rates of Alzheimer’s disease (AD) vary considerably, and they are particularly difficult to predict in patients with mild cognitive impairment. We performed a prospective multicenter cohor

Neurochemical Features of Frontotemporal Dementia

Abstract: This study examines neurochemical measures of cholinergic, serotonergic and glutamatergic innervation in frontal temporal and parietal cerebral cortex from 16 subjects with frontotemporal dementia (FT

The Clinical Picture of Frontotemporal Dementia: Diagnosis and Follow-Up

Abstract: Frontotemporal dementia (FTD) was diagnosed in 74 outpatients with a standardized assessment including neuropsychological tests, behavioural scale, structural and functional imaging. Clinical characteristics were consistent with the literature data. The cohort was followed for 2-6 years to determine the reliable variable for evaluating the progression of FTD. Every fourth patient died after a mean duration of 7 years. At first, FTD manifests itself in behavioural changes with relatively stable global cognition although language, verbal fluency and memory tests were reliable tools to follow the progression of the disease. Below 18 of Mini-Mental State Examination, mutism and apathy prevented from neuropsychological testing within the next 6 months. Behavioural disorders evolved with time but restlessness and hyperorality were long-lasting. Imaging showed the progression of a consistent pattern of anterior abnormalities with frequent leukoaraiosis.

Behavioral and psychological symptoms in Alzheimer's disease. Relation between apathy and regional cerebral perfusion.

Abstract: Fundamental and therapeutic research in Alzheimer's disease (AD) focused for a long time exclusively on cognitive aspects. However, AD also frequently involves complex disorders of affect and behavior, which are currently grouped under the heading 'behavioral and psychological signs and symptoms of dementia' (BPSSD). Several rating tools have been developed over the years on the basis of a variety of source data. Some are derived from psychiatric practise or have specifically been developed for dementia, such as the Neuropsychiatric Inventory (NPI). In this study we prospectively used the NPI to examine BPSSD. Sixty-three French patients (mean age 74.7 years, SD 7.9) with a Mini-Mental State Examination (MMSE) score higher than 10 were examined. BPPSD were detected by NPI in 95. 2% of the patients. Anxiety was the most common abnormality (65.1%), followed by apathy and dysphoria (58.7%). The highest frequency x severity NPI score was observed for apathy. In order to identify the relationship between regional cerebral perfusion and apathy, 20 of these AD patients underwent a technetium-99m-bicisate SPECT protocol within the same week as the NPI evaluation. The mean age of this population was 74.4 years (SD 5.3) and the mean MMSE score was 21 (SD 4.1). The apathy NPI score was correlated with right cingulate deficit whereas the highest correlation for the MMSE was with the left temporoparietal area. This stresses the interest to focus on SPECT imaging of AD patients not only in the posterior areas. CopyrightCopyright 1999S.KargerAG,Basel

Diffusion-weighted magnetic resonance imaging in Alzheimer's disease.

Abstract: Diffusion-weighted imaging (DWI) is a powerful new magnetic resonance imaging technique for evaluating tissue pathophysiology in vivo. We performed DWI in three orthogonal spatial directions in 10 pat

Oxidation of Cytosolic Proteins and Expression of Creatine Kinase BB in Frontal Lobe in Different Neurodegenerative Disorders

Abstract: The presence of the biomarkers of oxidative damage, protein carbonyl formation and the inactivation of oxidatively sensitive brain creatine kinase (CK BB, cytosolic isoform), were studied in frontal lobe autopsy specimens obtained from patients with different age-related neurodegenerative diseases: Alzheimer's disease (AD), Pick's disease (PkD), diffuse Lewy body disease (DLBD), Parkinson's disease (PD), and age-matched control subjects. The CK activity was significantly reduced in the frontal lobe of AD, PkD and DLBD subjects, and CK BB-specific mRNA was significantly reduced in AD and DLBD. Protein carbonyl content was significantly increased in AD, PkD and DLBD. The results of this study confirm that the presence of biomarkers of oxidative damage is related to the presence of histopathological markers of neurodegeneration. Our data suggest that oxidative damage contributes to the development of the symptoms of frontal dysfunction in AD, PkD and DLBD. The development of frontal dysfunction in idiopathic PD might be secondary to oxidative damage and neuronal loss primarily located in the nigrostriatal system. The results of CK BB expression analysis demonstrate that the loss of the isoenzyme in different neurodegenerative diseases is likely the consequence of its posttranslational modification, possibly oxidative damage. Changes in CK BB expression may be an early indicator of oxidative stress in neurons.

The prevalence, assessment and associations of falls in dementia with Lewy bodies and Alzheimer's disease.

Abstract: Falls were assessed for 3 months using a daily fall diary in 65 (30 dementia with Lewy bodies, DLB; 35 Alzheimer's disease, AD) dementia patients from a case register, diagnosed using operationalised clinical criteria, with established accuracy against post-mortem. Multiple falls (>5) occurred in 37% of DLB patients and 6% of those with AD, often resulting in injury. None of the standard risk assessment tools identified fallers, but they did identify multiple fallers. More detailed evaluation methods examining gait patterns, sway and neurovascular instability were not helpful. Multiple falls were associated with DLB, parkinsonism, previous falls, greater impairment of activities of daily living and older age. Falls are particularly common in DLB sufferers and may aid diagnosis. Treatment studies evaluating fall reduction strategies are a priority.

Clinical subtypes of delirium in the elderly.

Abstract: Psychomotor disturbance is common in delirium, with some patients being restless and hyperactive and others lethargic and hypoalert. Although patients with hyperactive delirium may be recognised more readily, hypoactive and mixed forms of delirium are more common on general hospital wards. Recent evidence suggests that hyperactive delirium has a better prognosis than other subtypes. It remains uncertain whether this reflects fundamental differences in the pathophysiology of different subtypes.

Key methodological features of randomized controlled trials of Alzheimer's disease therapy. Minimal clinically important difference, sample size and trial duration.

Abstract: Background: The results of clinical trials are routinely presented in terms of statistical significance, which may or may not indicate clinical significance. Analysis of the minimal clinically important difference (MCID) of cognitive scales has received little attention to date. Objectives: By reviewing the key methodological features (sample size, duration, statistical and clinical significance) of clinical trials examining the efficacy of tacrine in the treatment of Alzheimer’s disease (AD), we assessed their ability to detect clinically important changes in cognition. Design: The value for the MCID of the Mini-Mental State Examination (MMSE) was determined by surveying specialists in neurology and geriatric medicine. This value was then used to interpret the clinical significance of the results of published randomized controlled trials (RCTs) assessing the efficacy of tacrine in the treatment of AD and to retrospectively determine their optimal sample size and trial duration. Results: The mean survey MCID for the MMSE was 3.72 (95% confidence interval 3.50–3.95) points. Only 2 of 12 tacrine RCTs using the MMSE found a statistically significant difference in MMSE scores for patients taking tacrine compared with those taking placebo. These improvements were not clinically significant when compared with the survey MMSE MCID. For parallel trials of tacrine in AD, the smallest sample size and minimum trial duration required to demonstrate a clinically significant difference were calculated to be 53 subjects and 1 year, respectively. Five of the 7 parallel trials met the required sample size; however, none of them met the criteria for trial duration. Conclusions: When using the MMSE as an outcome measure, no tacrine trial reported results that were clinically significant as perceived by clinicians working with dementia patients. Application of a range of plausible MCIDs to the parallel design RCTs also demonstrated that 2 of 7 of these trials did not have sufficient sample size, and none had sufficient duration of treatment to reliably detect clinically meaningful changes in cognition. Future clinical trials in this area will need to incorporate the evolving knowledge of MCIDs in order to increase their chance of detecting clinically relevant results.

Decreased plasma insulin-like growth factor-I level in familial Alzheimer's disease patients carrying the Swedish APP 670/671 mutation.

Abstract: The plasma insulin-like growth factor I (IGF-I) level was determined in family members carrying the Swedish amyloid precursor protein (APP) 670/671 mutation with or without Alzheimer's disease (AD) and in age-matched controls from the same family. Plasma growth hormone (GH) and prolactin (PRL) levels were also determined. Measurement of the plasma IGF-I level by radioimmunoassay revealed a significant reduction only in the family members with AD compared to age-matched controls. However, there was no significant difference in the levels of GH and PRL between the mutation carriers with or without AD and their respective age-matched controls. These findings indicate that the mechanism(s) regulating GH and PRL were preserved and those regulating IGF-I levels might be affected in AD patients with the Swedish APP 670/671 mutation. CopyrightCopyright 1999S.KargerAG, Basel

Lymphomatosis cerebri presenting as a rapidly progressive dementia: clinical, neuroimaging and pathologic findings.

Abstract: Primary central nervous system lymphoma (PCNSL) usually presents with clinical and neuroimaging findings consistent with single or multiple intracranial mass lesions. On cranial magnetic resonance ima

The Progression of Alzheimer’s Disease from Limbic Regions to the Neocortex: Clinical, Radiological and Pathological Relationships

Abstract: Alzheimer’s disease (AD) is characterised by the gradual accumulation of neurofibrillary pathology in selected regions of the brain. Earlier studies indicate that the accumulation of neurofibrillary tangles is associated both with decline in patient’s cognitive performance as well as with medial temporal lobe atrophy on CT scans. There are also indications that progression through the pathological stages of AD is associated with decline in cognitive functions. The results of this study indicate that progression of disease, especially beyond the boundaries of the limbic regions, is associated with marked decline in the cognitive performance of patients suffering from AD. However the clinical manifestations of early pathological stages are not so well defined. We also found that the atrophy of the medial temporal lobe on CT scans is related to the progression of pathology. Atrophy is most apparent when the disease reaches its isocortical stages and is not marked in the limbic stages of the disease. The additive effect of pathologies co-existing with AD is apparent in reduced cognitive scores, while the atrophy of limbic structures, as measured on CT scans, seems to be mainly attributable to AD-related pathology.

Living alone with dementia.

Abstract: This report describes a population of individuals with dementia living alone in the community. Data were collected as part of the Canadian Study of Health and Aging (CSHA). We found that one third of

Clinical and pathological overlap between frontotemporal dementia, primary progressive aphasia and corticobasal degeneration: the Pick complex.

Abstract: A substantive overlap between the clinical syndromes of frontal lobe dementia (FLD), frontotemporal dementia (FTD), or primary progressive aphasia (PPA), and corticobasal degeneration syndrome (CBDS)

Neurons and their dendrites in frontotemporal dementia.

Abstract: Regional and areal patterns of cell vulnerability (manifested as cell death and neuron loss) and cell sensitivity (as revealed by the presence of intracytoplasmic inclusions) are described in patients with frontotemporal dementia (FTD) and FTD+ motor neuron disease (MND). This is followed by studies geared to learning about possible mechanisms involved in selective neuron loss and studies focused on recognizing the identity of vulnerable populations of local-circuit neurons and the impact of FTD on individual cells as well as on postsynaptic and presynaptic terminals in the frontal cortex. Neuron loss is not associated with increased vulnerability to nuclear DNA fragmentation, and nor is it accompanied by modifications in the expression of the proteins Bcl-2 and Bax, and transcription factors c-Fos and c-Jun, thus suggesting that these proteins are probably not involved in cell death in these disorders. In the frontal and temporal cortices, glutamatergic pyramidal cells and calbindin-D28k-immunoreactive GABAergic local-circuit neurons are lost in the upper cortical layers. Parvalbumin-immunoreactive cells are preserved. In addition, reduction of putative postsynaptic sites (as inferred from the decreased numbers of dendritic branches in both pyramidal and nonpyramidal neurons, and of dendritic spines in pyramidal cells) in remaining neurons of the upper layers, as well as reduction of presynaptic terminals (as suggested by the decreased expression of synaptic vesicle-associated proteins, synaptophysin, synaptotagmin, rab 3a and synapsin 1, and presynaptic plasma membrane proteins SNAP-25 and syntaxin 1) in the upper layers of the frontal cortex, but not of the posterior parietal cortex, demonstrate the combined devastating effects of FTD on cortico-cortical connections.

Do Delirium and Alzheimer’s Dementia Share Specific Pathogenetic Mechanisms?

Abstract: Dementia is the most common risk factor for delirium in the elderly. Here we will review the evidence that proposed pathogenetic mechanisms for delirium (such as reduced cerebral metabolism, imbalance of the noradrenergic/cholinergic neurotransmission, inflammation, disturbances in neuronal systems which regulate stress and the sleep/wake cycle) are also a part of the pathophysiology of Alzheimer's disease. In particular, the role of inflammatory mechanisms in both disorders will be discussed.

The role of the polymorphic genes apolipoprotein E and methylene- tetrahydrofolate reductase in the development of dementia of the Alzheimer type.

Abstract: The gene for apolipoprotein E (APOE) is polymorphic, and its variant APOE4 is a major risk factor for the development of Alzheimer-type dementia (AD). Another risk factor for AD appears to be negative cobalamin balance, which is very common in elderly people. Cobalamin and folate are interdependent and essential components of the one-carbon metabolism. Another important component is methylenetetrahydrofolate reductase (MTHFR), the gene for which is also polymorphic. Thermolabile MTHFR (tMTHFR), a gene variant that reduces the activity of its enzyme, is common in the general population. In the present study, 75% of 140 AD patients had at least one APOE4 allele. The numbers of APOE4 and tMTHFR alleles correlated significantly with the serum folate levels, however, in opposite directions. The significance of this was augmented by an inverse correlation between APOE4 and tMTHFR. Thus, not only MTHFR but also APOE appears to be related to the one-carbon metabolism, suggesting that APOE4 and insufficient one-carbon metabolism may be synergistic risk factors for AD.

Simple standardised neuropsychological assessments aid in the differential diagnosis of dementia with Lewy bodies from Alzheimer's disease and vascular dementia.

Abstract: Consecutive patients from a dementia case register received a standardised evaluation which incorporated a neuropsychological assessment with the Cambridge Assessment for disorders in the elderly (CAMCOG). Operationalised clinical diagnoses were made (consensus criteria for dementia with Lewy bodies, DLB; NINCDS- ADRDA for Alzheimer’s disease, AD, NINCDS AIRENS for vascular dementia, VaD). Two-hundred and twenty-eight patients were studied (DLB 54, AD102, VaD 72). DLB patients had significantly better performance on recent memory than AD patients, but more impaired visuospatial praxis. DLB patients also had significantly better recent memory than those with VaD. Optimal cut-off points for the recent memory:praxis ratio achieved good discrimination between DLB and both other dementias.

Early-onset and late-onset depression are independent of the genetic polymorphism of apolipoprotein E.

Abstract: The recently shown association between apolipoprotein E (APOE) genotype and depressive illness has been challenged by subsequent studies. However, controversial results may derive from the different diagnostic criteria used for depression and from the small numbers of depressed patients included in the studies. We examined the association between depression and the genetic polymorphism of APOE in a large sample of depressed patients, Alzheimer's disease (AD) patients, and healthy controls following clear definitions for late-life depression. The cumulative incidence of depression depending on the age at onset of the first episode was examined by survival analysis. Our data do not disconfirm the hypothesis of depression sharing some common pathophysiologic features with AD, however, it seems very unlikely that the APOE genotype will elucidate the assumed common mechanisms.