Neuroleptic sensitivity in patients with senile dementia of Lewy body type.

OBJECTIVE--To determine the outcome of administration of neuroleptics to patients with senile dementia of Lewy body type confirmed at necropsy. DESIGN--Retrospective analysis of clinical notes blind to neuropathological diagnosis. SETTING--Specialist psychogeriatric assessment units referring cases for necropsy to a teaching hospital neuropathology service. PATIENTS--41 elderly patients with diagnosis of either Alzheimer type dementia (n = 21) or Lewy body type dementia (n = 20) confirmed at necropsy. MAIN OUTCOME MEASURES--Clinical state including extrapyramidal features before and after neuroleptic treatment and survival analysis of patients showing severe neuroleptic sensitivity compared with the remainder in the group. RESULTS--16 (80%) patients with Lewy body type dementia received neuroleptics, 13 (81%) of whom reacted adversely; in seven (54%) the reactions were severe. Survival analysis showed an increased mortality in the year after presentation to psychiatric services compared with patients with mild or no neuroleptic sensitivity (hazard ratio 2.70 (95% confidence interval 2.50-8.99); (chi 2 = 2.68, p = 0.05). By contrast, only one (7%) of 14 patients with Alzheimer type dementia given neuroleptics showed severe neuroleptic sensitivity. CONCLUSIONS--Severe, and often fatal, neuroleptic sensitivity may occur in elderly patients with confusion, dementia, or behavioural disturbance. Its occurrence may indicate senile dementia of Lewy body type and this feature has been included in clinical diagnostic criteria for this type of dementia.     

The Science of Vascular Contributions to Cognitive Impairment and Dementia (VCID): A Framework for Advancing Research Priorities in the Cerebrovascular Biology of Cognitive Decline

The World Health Organization reports that 47.5 million people are affected by dementia worldwide. With aging populations and 7.7 million new cases each year, the burden of illness due to dementia approaches crisis proportions. Despite significant advances in our understanding of the biology of Alzheimer’s disease (AD), the leading dementia diagnosis, the actual causes of dementia in affected individuals are unknown except for rare fully penetrant genetic forms. Evidence from epidemiology and pathology studies indicates that damage to the vascular system is associated with an increased risk of many types of dementia. Both Alzheimer’s pathology and cerebrovascular disease increase with age. How AD affects small blood vessel function and how vascular dysfunction contributes to the molecular pathology of Alzheimer’s are areas of intense research. The science of vascular contributions to cognitive impairment and dementia (VCID) integrates diverse aspects of biology and incorporates the roles of multiple cell types that support the function of neural tissue. Because of the proven ability to prevent and treat cardiovascular disease and hypertension with population benefits for heart and stroke outcomes, it is proposed that understanding and targeting the biological mechanisms of VCID can have a similarly positive impact on public health.     

Is 'attention' important for the results of dementia screening? Relation among Digit Span Test, CST amd ADS in elderly patients

This study focused on the relationship between attention and dementia screening test performance, using the adapted Wechsler's Digit Span test for elderly patients, the Cognitive Screening Test (CST) and the Amsterdam Dementia Screening Test (ADS6). Participants were dementia patients and psychiatric patients (n = 147). In both groups no floor-effect was found on the Digit Span test. Principal components analysis showed that CST and ADS6-scores had relatively high loadings on one factor, in contrast to digit span scores that loaded on a second factor. On average, psychiatric patients did hardly worse than normal controls. Attention deficits were more apparent in dementia patients. Considering a maximum of r = .41, these more or less subtle deficits were only moderately related to dementia screening test performance. It is concluded that the adapted Digit Span test is suitable for measuring attention deficits in elderly patients. However, Digit Span predicts performance on dementia screening test only to a modest degree.     

The evolution of Kraepelin's nosological principles

Emil Kraepelin developed a new psychiatric nosology in the eight editions of his textbook. Previous papers have explored his construction of particular diagnoses, including dementia praecox and manic‐depressive insanity. Here we are providing a close reading of his introductory textbook chapter, that presents his general principles of nosology. We identify three phases: 1) editions 1‐4, in which he describes nosological principles in search of data; 2) editions 5‐7, in which he declares the mature version of his nosological principles and develops new disease categories; 3) edition 8, in which he qualifies his nosological claims and allows for greater differentiation of psychiatric disorders. We propose that Kraepelin's nosology is grounded in three principles. First, psychiatry, like other sciences, deals with natural phenomena. Second, mental states cannot be reduced to neural states, but science will progress and will, ultimately, reveal how nature creates abnormal mental states and behavior. Third, there is a hierarchy of validators of psychiatric diagnoses, with the careful study of clinical features (signs, symptoms and course) being more important than neuropathologic and etiological studies. These three principles emerged over the course of the eight editions of Kraepelin's textbook and were informed by his own research and by available scientific methods. His scientific views are still relevant today: they have generated and, at the same time, constrained our current psychiatric nosology.     

Increased activity of brain and platelet monoamine oxidase in dementia of Alzheimer type

Two groups of patients with dementia of Alzheimer type were studied with respect to monoamine oxidase (MAO) activity. In one group of 11 patients MAO activity was determined in platelets and in the other group of 14 patients in the brain (hypothalamus, caudate nucleus, hippocampus and cortex gyrus cinguli) post mortem. The results were compared to controls matched for age and sex. Platelet MAO activity was significantly higher in patients with dementia of Alzheimer type compared to controls. Brain MAO-B activity but not MAO-A activity was significantly higher in the dementia group in hyppocampus and cortex gyrus cinguli. In the controls there were positive correlations for MAO-B activity with age in the four brain regions, but these correlations were absent in the dementia group. This could be explained by differences in age of onset of dementia and that the disease process does not develop homogeneously in different brains.     

Ca2+ dysfunction in neurodegenerative disorders: Alzheimer's disease

More than one century ago "a peculiar disorder of the cerebral cortex" was noticed in a middle-aged patient who had been affected by dementia in the last years of his life. The postmortem hallmarks of his brain were protein plaques, neurofibrillary tangles, and atherosclerotic changes: the neuropathologist who found these alterations and gave his name to the disease that underlied them was Alois Alzheimer (Alzheimer et al., Clin Anat 1995;8:429-431). Following its discovery, the disease has been studied with a vigor that went parallel to the increase of its social importance. The amount of information amassed in the literature is impressive, but knowledge on the mechanism underlying its onset and its progression is still very limited. Numerous hypotheses on the molecular pathogenesis of the Alzheimer's disease (AD) have been proposed and two have gradually gained wide consensus: (i) the amyloid cascade hypothesis, first proposed on the basis of the toxicity evoked by the deposition of amyloid β (Aβ) aggregates; (ii) the Ca(2+) hypothesis, which focuses on the correlation between the dysfunction of Ca(2+) homeostasis and the neurodegeneration process. This succinct review will discuss the essential aspects of the role of Ca(2+) homeostasis dysregulation in the onset and development of AD.     

La « maladie d’Alzheimer » commune : un syndrome hétérogène avant tout vasculaire ?

Clinical diagnostic of “Alzheimer’s disease” is currently based on neuropsychological tests. This most common form of dementia is a syndrome rather than a disease. Magnetic resonance imaging has permitted to characterize the structural and functional brain changes accompanying progression to clinical “Alzheimer’s disease”. It provides evidence of distinct subgroups of patients and enhances the role of cerebrovascular dysfunction in the “Alzheimer’s syndrome”.     

Proteins and mutations: a new vision (molecular) of neurodegenerative diseases

Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.     

A Modified Hortega-Globus Stain is Superior to Bielschowsky and Bodian Stains for Demonstrating Neuritic Plaques

The quantitative assessment of the age-dependent number of neuritic plaques is essential for the diagnosis of Alzheimer type dementia. This study reports the superiority of a modified Hortega-Globus stain compared to Bielschowsky and Bodian stains applied to samples obtained from ten brains of patients with a clinical history of progressive dementia. In two of ten cases only the modified Hortega-Globus stain allowed confirmation of the diagnosis of senile dementia of the Alzheimer type (SDAT). The counts of neuritic plaques in sections stained by other methods were not sufficient to establish the histological diagnosis of SDAT. These results indicate that the choice of the most sensitive staining method is critical for the correct histopathologic diagnosis of the Alzheimer type dementia.     

Essential fatty acids and their role in the treatment of impulsivity disorders

Essential fatty acids (EFAs) have been shown to benefit patients with depression, schizophrenia and dementia. More recently, their role in disorders characterised by impulsivity has attracted some attention. The psychiatric conditions of attention-deficit hyperactivity disorder and borderline personality disorder as well as the phenomena of deliberate self-harm and violence have been ameliorated by the supplementation of EFAs in a number of recent clinical trials. This paper summarises the burgeoning clinical and basic research indicating the existence of significant deficits of EFAs in impulsivity disorders and the supplementation studies of EFAs in these diverse conditions, all of which remain a major therapeutic challenge.     

Sporadic Alzheimer’s Disease Begins as Episodes of Brain Ischemia and Ischemically Dysregulated Alzheimer’s Disease Genes

The study of sporadic Alzheimer’s disease etiology, now more than ever, needs an infusion of new concepts. Despite ongoing interest in Alzheimer’s disease, the basis of this entity is not yet clear. At present, the best-established and accepted “culprit” in Alzheimer’s disease pathology by most scientists is the amyloid, as the main molecular factor responsible for neurodegeneration in this disease. Abnormal upregulation of amyloid production or a disturbed clearance mechanism may lead to pathological accumulation of amyloid in brain according to the “amyloid hypothesis.” We will critically review these observations and highlight inconsistencies between the predictions of the “amyloid hypothesis” and the published data. There is still controversy over the role of amyloid in the pathological process. A question arises whether amyloid is responsible for the neurodegeneration or if it accumulates because of the neurodegeneration. Recent evidence suggests that the pathophysiology and neuropathology of Alzheimer’s disease comprises more than amyloid accumulation, tau protein pathology and finally brain atrophy with dementia. Nowadays, a handful of researchers share a newly emerged view that the ischemic episodes of brain best describe the pathogenic cascade, which eventually leads to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible dementia of Alzheimer type. The most persuasive evidences come from investigations of ischemically damaged brains of patients and from experimental ischemic brain studies that mimic Alzheimer-type dementia. This review attempts to depict what we know and do not know about the triggering factor of the Alzheimer’s disease, focusing on the possibility that the initial pathological trigger involves ischemic episodes and ischemia-induced gene dysregulation. The resulting brain ischemia dysregulates additionally expression of amyloid precursor protein and amyloid-processing enzyme genes that, in addition, ultimately compromise brain functions, leading over time to the complex alterations that characterize advanced sporadic Alzheimer’s disease. The identification of the genes involved in Alzheimer’s disease induced by ischemia will enable to further define the events leading to sporadic Alzheimer’s disease-related abnormalities. Additionally, knowledge gained from the above investigations should facilitate the elaboration of the effective treatment and/or prevention of Alzheimer’s disease.     

Validering van de Seven Minute Screen voor gebruik in de geheugenpolikliniek

Cognitive tests play a crucial part in the assessment of dementia. In 1998 the Seven Minute Screen was developed by Solomon and colleagues. The test was originally designed to distinguish between Alzheimer’s disease (AD) and normal ageing, and research showed that the instrument is highly sensitive to AD. Subsequent research also proved the diagnostic accuracy of the Seven Minute Screen in the detection of other common types of dementia, such as vascular dementia, frontotemporal dementia and dementia with Lewy bodies. This article reports new research on the predictive validity of the Seven Minute Screen using 289 cognitively intact subjects, 175 patients with MCI and 563 patients with dementia in the setting of a memory clinic. In addition, a comparison is made with the Mini Mental State Examination (MMSE). The study demonstrates that the Seven Minute Screen is a valuable screening instrument for all common types of dementia, and it has added value to the MMSE. The sensitivity for dementia is 96?% and the specificity 93?%, in comparison to 69 and 98?% for the MMSE (<?24). The sensitivity for the various types of dementia is consistently high, ranging from 92?% for a subcortical dementia to 97?% for AD. The Seven Minute Screen requires little training, and combines a short administration time with a high diagnostic accuracy. This makes the Seven Minute Screen useful for application in memory clinics.     

Animal Models of Vascular Cognitive Impairment and Dementia (VCID)

Vascular cognitive impairment and dementia (VCID) is the most common etiology of dementia in the elderly. Both, vascular and Alzheimer’s disease, pathologies work synergistically to create neurodegeneration and cognitive impairments. The main causes of VCID include hemorrhage/microbleed (i.e., hyperhomocysteinemia), cerebral small vessel disease, multi-infarct dementia, severe hypoperfusion (i.e., bilateral common carotid artery stenosis), strategic infarct, angiopathy (i.e., cerebral angiopathy), and hereditary vasculopathy (i.e., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). In this review, we will discuss the experimental animal models that have been developed to study these pathologies. We will discuss the limitations and strengths of these models and the important research findings that have advanced the field through the use of the models.     

老年痴呆与血浆同型半胱氨酸水平关系的临床研究

目的:探讨血浆同型半胱氨酸(homocysteine,Hcy)水平与老年痴呆的相关性。方法:应用全自动生化分析仪以循环酶法检测90例老年痴呆患者的血浆Hcy浓度,并与30例非痴呆患者作为同龄对照组血浆Hcy浓度进行比较;根据Hachinski缺血指数量表评分将老年痴呆分为阿尔茨海默病(Alzheimer’s disease,AD),混合性痴呆(mixed dementia,MD),血管性痴呆(vascular dementia,VD);根据简易精神状态检查量表(Mini-Mental State Examination,MMSE)评分划分痴呆患者严重程度,分为轻度、中度、重度。结果:AD、MD、VD组血浆Hcy水平均显著高于对照组(P<0.01);不同程度痴呆患者血浆Hcy水平有显著性差异(P<0.05),血浆Hcy浓度越高,认知功能损害的程度越重。结论:高Hcy血症可能是老年期痴呆发病的一个重要危险因素,且认知功能减退的程度与血浆同型半胱氨酸浓度呈正相关。     

Is Alzheimer's senile dementia associated with the phenomena of reactive synaptogenesis in the hippocampus?

The densities of specific binding sites for glutamate or its analogue kainate were determined in the hippocampi of patients having suffered of senile dementia of the Alzheimer type (SDAT) and compared to age matched controls. The densities of sites were reduced in SDAT cases. These results indicate a lack of hippocampal plasticity in senile dementia of Alzheimer type.     

Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type.

Several histopathological studies suggest that amyloidogenesis in dementia of the Alzheimer type is accompanied by activated glia and glia-derived cytokines, leading to chronic, self-propagating, cytokine-mediated molecular and cellular reactions. As studies regarding inflammatory changes in cerebrospinal fluid of patients with dementia of the Alzheimer type has been inconclusive, we set up a prospective study to assess cerebrospinal fluid levels of interleukin-1beta, interleukin-6, interleukin-10, interleukin-12, soluble interleukin-2 receptor, interferon-gamma, tumor necrosis factor-alpha and neopterin in 20 patients with dementia of the Alzheimer type and 20 age- and sex-matched controls. Comparing both groups, no significant differences in concentrations and specific activities could be revealed. An additional 22 patients were included to enlarge the study population. No statistically significant differences were shown comparing patients (n=42) with the control group (n=20). We conclude that the immune-mediated inflammatory changes found in histopathological studies are not reflected in cerebrospinal fluid of patients with dementia of the Alzheimer type. Probably, cytokine production appears very localized in the central nervous system, not allowing representative detection in cerebrospinal fluid. Further studies assessing cytokine levels in various regions of central nervous system of patients with dementia of the Alzheimer type will be of interest to confirm this hypothesis.     

阿尔茨海默病与雌激素和褪黑素的相关性研究进展

阿尔茨海默病（AD）是引起痴呆的第一病因,其发病机制尚不十分明确。目前尚无特效的药物可逆转脑功能缺损或阻止病情进展,临床上用胆碱乙酰转移酶抑制剂、抗精神症状药物、维生素E等均只能轻微改善症状。雌激素和褪黑素在基础和临床研究中都显示对AD有治疗作用,且二者的疗效与AD的病程有明显相关性。     

Vitamin B12 in neurology and ageing; Clinical and genetic aspects

The classic neurological and psychiatric features associated with vitamin B₁₂ deficiency have been well described and are the subject of many excellent review articles. The advent of sensitive diagnostic tests, including homocysteine and methylmalonic acid assays, has revealed a surprisingly high prevalence of a more subtle ‘subclinical’ form of B₁₂ deficiency, particularly within the elderly. This is often associated with cognitive impairment and dementia, including Alzheimer's disease. Metabolic evidence of B₁₂ deficiency is also reported in association with other neurodegenerative disorders including vascular dementia, Parkinson's disease and multiple sclerosis. These conditions are all associated with chronic neuro-inflammation and oxidative stress. It is possible that these clinical associations reflect compromised vitamin B₁₂ metabolism due to such stress. Physicians are also increasingly aware of considerable inter-individual variation in the clinical response to B₁₂ replacement therapy. Further research is needed to determine to what extent this is attributable to genetic determinants of vitamin B₁₂ absorption, distribution and cellular uptake.     

Familial idiopathic basal ganglia calcification (Fahr's disease) without neurological, cognitive and psychiatric symptoms is not linked to the IBGC1 locus on chromosome 14q

Idiopathic basal ganglia calcification (IBGC) is characterised by radiological, neurological, cognitive and psychiatric abnormalities. The associations between these abnormal phenotypes and abnormal genes remain unclear despite the recent mapping to chromosome 14q of a susceptibility locus for IBGC ( IBGC1). We identified two siblings, from a large multigenerational pedigree, who had both been diagnosed with radiological IBGC, dementia, bipolar affective disorder and Parkinsonism. We assessed (1) other family members to determine whether these four phenotypes were co-segregating as symptoms of IBGC, and (2) possible IBGC linkage to the IBGC1 locus on chromosome 14q or to any known or potential dementia genes. Nine second-generation and 21 third-generation members received radiological, neurological, neuropsychological and psychiatric assessments. We genotyped all family members for microsatellite markers at the IBGC1 locus and polymorphisms of the ApoE, VLDL, alpha1-ACT, BChE-K, APP, PS1, PS2 and tau genes and tested these for linkage to IBGC, dementia and bipolar disorder. Of the ten family members with radiological intracranial calcification, all except the two index cases were normal. There was no significant association between IBGC status and severe cognitive impairment or dementia ( P=0.335) or bipolar affective disorder or Parkinsonism ( P=1.0). Linkage to the IBGC1 locus was excluded. Of the eight dementia gene markers tested, the only positive LOD score was for the ApoE epsilon4 polymorphism and dementia/severe cognitive impairment. We have identified a form of IBGC in which calcification is inherited independently of neurological, cognitive and psychiatric symptoms. This may represent a second locus for this disorder.     

Cerebrovascular Effects of Amyloid-ß Peptides: Mechanisms and Implications for Alzheimer's Dementia

1. The amyloid ß-peptide (Aß) is involved in the mechanisms of Alzheimer dementia. This paper reviews experimental evidence indicating that Aß exerts profound effects on the regulation of the cerebral circulation.2. Thus, Aß compromises the ability of cerebral endothelial cells to produce vascular relaxing factors, impairs the ability of cerebral blood vessels to maintain adequate flow during hypotension, and attenuates the increases in CBF evoked by enhanced brain activity.3. Studies in transgenic mice overexpressing the amyloid precursor protein suggest that these cerebrovascular alterations disrupt the delicate balance between the brain's energy requirements and cerebral blood supply, rendering the brain more vulnerable to ischemic injury.4. The findings support the recently emerged notion that vascular factors play a pathogenic role in the early stages of Alzheimer dementia.