Form Of Alzheimer Research Articles

Identification of Novel NPRAP/δ-Catenin-Interacting Proteins and the Direct Association of NPRAP with Dynamin 2

Neural plakophilin-related armadillo protein (NPRAP or δ-catenin) is a neuronal-specific protein that is best known for its interaction with presenilin 1 (PS1). Interestingly, the hemizygous loss of NPRAP is associated with severe mental retardation in cri du chat syndrome (CDCS), and mutations in PS1 cause an aggressive, early-onset form of Alzheimer's disease. Until recently, studies on the function of NPRAP have focused on its ability to modulate dendritic protrusion elaboration through its binding to cell adhesion and scaffolding molecules. However, mounting evidence indicates that NPRAP participates in intracellular signaling and exists in the nucleus, where it modulates gene expression. This apparent bifunctional nature suggests an elaborate neuronal role, but how NPRAP came to participate in such distinct subcellular events remains a mystery. To gain insight into this pathway, we immunoprecipitated NPRAP from human SH SY5Y cells and identified several novel interacting proteins by mass spectrometry. These included neurofilament alpha-internexin, interferon regulatory protein 2 binding factors, and dynamins 1 and 2. We further validated dynamin 2/NPRAP colocalization and direct interaction in vivo, confirming their bona fide partnership. Interestingly, dynamin 2 has established roles in endocytosis and actin assembly, and both of these processes have the potential to interface with the cell adhesion and intracellular signaling processes that involve NPRAP. Our data provide new avenues for approaching NPRAP biology and suggest a broader role for this protein than previously thought.

Diagnosing Clapham Junction syndrome

People who have dementia in this country are not heard. I’m fortunate; I can be heard. Regrettably, it’s amazing how people listen if you stand up in public and give away $1million for research into the disease, as I have done. Why did I do it? I regarded finding I had a form of Alzheimer’s as an insult and decided to do my best to marshal any kind of forces I could against this wretched disease. I have posterior cortical atrophy or PCA. They say, rather ingenuously, that if you have Alzheimer’s it’s the best form of Alzheimer’s to have. This is a moot point, but what it does do, while gradually robbing you of memory, visual acuity and other things you didn’t know you had until you miss them, is leave you more or less as fluent and coherent as you always have been. I spoke to a fellow sufferer recently (or as I prefer to say, ‘‘a person who is thoroughly annoyed with the fact they have dementia’’) who talked in the tones of a university lecturer and in every respect was quite capable of taking part in an animated conversation. Nevertheless, he could not see the teacup in front of him. His eyes knew that the cup was there; his brain was not passing along the information. This disease slips you away a little bit at a time and lets you watch it happen. When I look back now, I suspect there may be some truth in the speculation that dementia (of which Alzheimer’s is the most common form) may be present in the body for quite some time before it can be diagnosed. For me, things came to a head in the late summer of 2007. My typing had been getting progressively worse and my spelling had become erratic. I grew to recognize what I came to call Clapham Junction days when the demands of the office grew too much to deal with. I was initially diagnosed not with Alzheimer’s but with an ischemic change, a simple loss of brain cells due to normal ageing. That satisfied me until the next Clapham Junction day. I went back to my GP and said I knew there was something more going on. Fortunately, she knew well enough not to bother with the frankly pathetic MMSE test (the 30-point questionnaire used to determine brain function) and sent me to Addenbrooke’s Hospital in Cambridge, where, after examination of my MRI scan and an afternoon of complex tests, I was diagnosed with PCA, an uncommon variant of dementia, which had escaped the eagle eye of the original diagnostician. When in Paradise Lost Milton’s Satan stood in the pit of hell and raged at heaven, he was merely a trifle miffed compared to how I felt that day. I felt totally alone, with the world receding from me in every direction and you could have used my anger to weld steel. Only my family and the fact I had fans in the medical profession, who gave me useful advice, got me through that moment. I feel very sorry for, and angry on behalf of, the people who don’t have the easy ride I had.

Cognitive rehabilitation in posterior cortical atrophy

Posterior cortical atrophy (PCA) is a rare early-onset dementing syndrome presenting with visuo-perceptual deficits. Clinicopathologically, it is most commonly considered a form of Alzheimer's disease. We present the case of a 64-year-old male patient with posterior cortical atrophy who took part in a cognitive rehabilitation programme that included psychoeducation, compensatory strategies, and cognitive exercises. After the cognitive rehabilitation programme, subtle differences were found in visuoperceptual tasks and in the patient's subjective perception of difficulties. Cognitive rehabilitation may temporarily improve functioning in patients with posterior cortical atrophy.

Association study between P53 and P73 gene polymorphisms and the sporadic late-onset form of Alzheimer’s disease

An important pathological aspect of Alzheimer's disease (AD) is the apoptosis of neuronal and glial cells. Two members of the same protein family that regulates many genes involved in apoptosis are P53 and the heterologue P73. One single nucleotide polymorphism (SNP) in the gene encoding P53 (Arg72Pro, RS1042522), one dinucleotide polymorphism (G4C14-to-A4T14, RS 2273953, RS1801173) in the gene encoding P73, and two further SNPs in the same gene (-386 G/A, RS3765728; exon 5 T/C, RS1801174) were studied to determine whether DNA variations could influence the occurrence of the disease in a sample of Italian subjects with the sporadic late-onset form of AD. We observed that carrying the Pro/Pro genotype of P53 Arg72Pro was a risk factor with respect to the Pro/Arg + Arg/Arg genotypes [Odds Ratio (OR) = 2.02; 95% Confidence Interval (CI) 1.02-4.00; p = 0.047]. Furthermore, carrying the G/G genotype of the P73 -386 G/A was a risk factor with respect to the G/A + A/A genotypes (OR = 4.27; 95% CI 1.00-18.65; p = 0.047). A significant result was also obtained for P73 G4C14-to-A4T14. Among the patients, the homozygotes for the AT allele of this SNP had developed AD symptoms 5 years earlier than other genotypes (ANOVA p = 0.017). Though the results of particular polymorphisms analyses were not highly significant after correction for multiple comparisons, present data suggest that variation at the two genes may have a role in AD occurrence.

Attitudes and Knowledge About Genetic Testing Before and After Finding the Disease-Causing Mutation Among Individuals at High Risk for Familial, Early-Onset Alzheimer's Disease

This study was designed to investigate the influence of finding a disease-causing mutation for an early-onset form of Alzheimer's disease, with the intention of taking a presymptomatic genetic test. First-degree relatives of patients with Alzheimer's disease from a large Cuban family with a newly described mutation in presenilin 1 gene were interviewed before and after molecular studies. Significant differences were observed regarding the knowledge of the disease (p=0.0004), interest in presymptomatic testing (p=0.000), and possible reproductive behavior (p=0.0087) in the same individuals in two different periods, 1997 and 2007. Our results show that there is a marked difference in the attitudes concerning genetic testing when individuals gain more knowledge about the disease and when there is more certainty about the test.

Cognitive decline from estimated premorbid status predicts neurodegeneration in Alzheimer's disease.

This study investigated the relationship between premorbid and current cognitive function with respect to the clinical features of patients with various types of neurodegeneration in the form of Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive impairment (SCI), as compared with a healthy control group (C). Clinical features (MMSE, cognitive and depressive symptoms), genetics (apolipoprotein E; APOE) and measures of neurodegeneration (Abeta(42), t-tau, and p-tau) were examined, as well as present cognitive function. Various methods of assessing premorbid cognitive function were compared, including a Swedish NART-analogous test (Irregularly Spelled Words; ISW), a Swedish lexical decision test (SLDT), a Hold test (Information in WAIS-R), Best current performance test, and combined demographic characteristics. Results showed that cognitive decline (premorbid minus current cognitive function) based on SLDT and ISW was a significant predictor for MMSE and Abeta(42), whereas corresponding associations for present cognitive function and decline measures based on other methods were less powerful. Results also showed that specific verbal abilities (e.g., SLDT and ISW) were insensitive to AD and that these abilities indicated premorbid cognitive function in retrospect. In conclusion, cognitive decline from premorbid status reflects the disease processes.

Interview

Alison M Goate is the Samuel & Mae S Ludwig Professor of Genetics in Psychiatry, Professor of Genetics and Professor of Neurology at Washington University School of Medicine in St Louis (MO, USA). Dr Goate studied for her undergraduate degree in biochemistry at the University of Bristol (UK) and received her graduate training at Oxford University (UK). She performed postdoctoral studies with Professor Theodore Puck, Professor Louis Lim and Dr John Hardy before receiving a Royal Society University Research Fellowship to support her independent research program at St Mary's Hospital Medical School in London. In 1991, Dr Goate and colleagues reported the first mutation linked to an inherited form of Alzheimer's disease, in the amyloid precursor protein (APP) gene on chromosome 21. The mutation was found to be linked to inherited cases of early-onset Alzheimer's disease. In 1992, Dr Goate moved to Washington University as an Associate Professor in Genetics and Psychiatry. Dr Goate and colleagues have since identified mutations in four other genes, including two that cause Alzheimer's disease and two that cause the related dementia frontotemporal dementia. In addition to her work on dementia, Dr Goate's laboratory also studies the genetics of alcohol and nicotine dependence. Dr Goate has received numerous awards including the Potamkin Award from the American Academy of Neurology, the Zenith Award from the Alzheimer's Association, the Senior Investigator Award from the Metropolitan Life Foundation, the St Louis Academy of Science Innovation Award and the Carl and Gerty Cori Faculty Achievement Award at Washington University. Dr Goate has been a member of many scientific Review Boards and currently serves on the Editorial Boards of several journals.

Pratchett brings cash and publicity to alzheimer’s disease

BRITISH RESEARCH into Alzheimer's disease has been boosted financially and publicly by the best-selling British fantasy author, Terry Pratchett. The writer has donated $1 million (£500,000) to medical research into the disease after announcing in December that he was suffering from a rare and early onset form of Alzheimer's.

Unique Problems of Dementia in the Younger Patient

While dementia is often thought of as a problem unique to the elderly patient, nearly one in ten patients with dementia is younger than 65. The etiologies of dementia in this population are varied, including a genetically inherited form of Alzheimer's disease, as well as dementia related to other problems such as Parkinson's disease, Down syndrome, and cerebrovascular disease. Health care practitioners may have difficulty diagnosing early onset dementia because the diagnostic tools and the disease manifestation differ from those of the elderly patient. In addition, treatment of early-onset dementia can also pose unique challenges related to the speed of progression of the disease, depression, and behavioral disturbances, which often plague younger patients with dementia.

Expression of mitochondrial genes and transcription estimation in different brain areas in Alzheimer's disease patients

Accumulation of mitochondrial defects is hypothesised to play a role in the complex pathophysiology of the sporadic form of Alzheimer's disease (SAD). Changes in expression of mtDNA encoded genes have been reported in SAD. However no conclusive results were obtained by using different methodologies and analysing distinct transcripts in a variety of brain areas. Here, we measured the expression of five mitochondrial-encoded genes in three brain areas and in lymphocytes from patients and controls by performing reverse transcription followed by quantitative real-time PCR. The analysis of gene expression was also performed by carrying out classic dot-blot experiments to evaluate the two techniques. SAD and control samples showed similar gene expression levels. Estimation of the transcription rate was also measured. No differences were observed when comparing patients and controls. Selective differences in transcription rates were observed only when samples were pooled by tissue, lymphocytes being the tissue with the highest rates.

Progress toward identification of protease activity involved in proteolysis of apolipoprotein e in human brain.

Apolipoprotein E (apoE) genotype is the single most important genetic risk factor for the most common (sporadic) form of Alzheimer's disease (AD). Increasing evidence supports the hypothesis that the presence of the E4 isoform of this cholesterol-binding protein contributes directly to disease risk, age of onset, and severity of the neuropathology. For example, studies in transgenic mice demonstrate that apoE is necessary for the formation of plaques with neuritic pathology. The precise mechanism by which apoE contributes to the disease remains unknown. However, several lines of investigation from a number of laboratories now point to a role for proteolytic fragments of apoE in the formation of both plaques and tangles, the two pathological hallmarks of the disease. In particular, the C-terminal portion of apoE has been implicated in binding to amyloid and is localized to plaques. The N-terminal domain, on the other hand, is neurotoxic in culture and has been localized to, and implicated in the formation of, neurofibrillary tangles. These results suggest that inhibition of apoE proteolysis is a potential therapeutic strategy for AD. Using human brain homogenates, we have determined that proteolysis of apoE is greatest at acidic pH and can be inhibited by compounds targeting aspartic proteases. The feasibility of screening candidate inhibitors is supported by both ELISA and immunoblotting methods. Future studies will use a combination of in vitro and in vivo assays to test the efficacy of the most effective compounds for their ability to inhibit apoE proteolysis in human brain and apoE transgenic mouse brain tissue.

Apolipoprotein E is a prime suspect, not just an accomplice, in Alzheimer's disease.

There is now a large body of evidence suggesting that apolipoprotein E (apoE) genotype is the single most important genetic risk factor for the most common (sporadic) form of Alzheimer's disease. Yet in proportion to the total number of investigations in this field, relatively few groups are studying the contribution of this cholesterol-binding protein to disease risk and severity. Of those that are, a major focus is on the impact of apoE on amyloid-related mechanisms of disease. I argue here that apoE should be considered a major culprit in its own right, not simply in a supporting role. The argument is based on several lines of evidence, including the fact that apoE is associated with both plaques and tangles, the overwhelming evidence for genetic risk of the disease attributed to apoE, increasing evidence that apoE might also modify risk of other nonamyloidogenic neurological diseases, neurotoxicity attributed to apoE and/or proteolytic fragments of apoE, negative consequences of transgenic expression of apoE4 in mice, and genetic evidence for polymorphisms that increase both apoE expression and disease risk, regardless of isoform.

Posterior Cortical Atrophy: Clinical Characteristics and Differences Compared to Alzheimer’s Disease

Background: Predominant and progressive complex visual disorders are often due to posterior cortical atrophy (PCA), a rare early-onset dementing syndrome presenting with visual complaints. In clinicopathological studies, PCA is most commonly considered a form of Alzheimer’s disease (AD); no prior study has evaluated clinical differences between PCA and AD. Methods: This study identified 15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypoperfusion on SPECT. These patients were retrospectively compared on clinical variables with 30 patients with clinically probable AD matched for gender, age and duration of illness. Results: The PCA patients presented with alexia, elements of Balint’s syndrome, apperceptive visual agnosia, dressing apraxia and environmental disorientation along with elements of Gerstmann’s syndrome. Compared to the AD patients, the 15 PCA patients (mean age of onset 58 years, range 51–64) had significantly better verbal fluency, less memory difficulty, more depression and greater insight into their illness but similar familial and apolipoprotein E risk factors. In the PCA patients, MRI often showed occipitoparietal atrophy without detectable mesiotemporal atrophy. Conclusions: PCA is a distinct clinical syndrome and not just AD with prominent visual deficits. Compared to AD controls, PCA patients have better language and memory but more insight and depression and more posterior atrophy on MRI. These results indicate clinical criteria for the diagnosis of PCA and recommend specific interventions such as visual aids and antidepressant medications. Similar risk factors and course suggest that PCA is most commonly an early-onset posteriorly shifted AD variant.

High resolution free form deformation analysis of atrophy from longitudinal mri studies of mild cognitive impairment

A fraction of elderly subjects are found to have some form of mild cognitive impairments, especially memory deficits, on neuropsychological testing. These patients are beleived to be at a higher risk to develop the clinical criteria of Alzheimer’s dementia, than non-impaired elderly. It is thought that many subjects with mild cognitive impairment have an early form of Alzheimer’s disease. To test for associated structural changes in the brain, a group of six subjects, who were diagnosed with mild cognititive impairment according to Mayo Clinic criteria, were imaged using sequential anatomical MRI acquisitions[ 11. Two images were acquired on each subject, between 1 and 5 years apart, using a high-resolution 3D MPRAGE acquisition(lxlxl.5mm) on a 1.5T Seimens system. A group of 14 age matched control subjects were scanned over similar time periods to form an age-atrophy reference. An additional age matched normal was used as a reference MRI anatomy for the analysis. A high-resolution free form registration algorithm was used[2] to estimate a fine Cubic B-Spline deformation mapping each subject’s first time point scan into the coordinates of the reference MRI. An hierarchical multi-grid deformation refinement scheme was used, with the finest deformation lattice spacing set to 2.4mm. A single level (2.4mm spacing) version of this registration procedure was then used to estimate the deformation between each subjects two longitudinal acquisitions. The point wise volume change was estimated analytically at each voxel location from the B-Spline model of the deformation, to Figure 1: Average Normal MRI with overlay of iso create an atrophy map in the coordinate system of the first time point Z-score contour (Z= 1.6) showing the common regions scan of each subject Using the transformation to the reference atlas, of loss in the MCI group with respect to the normal each atrophy map was then transformed to the common reference group. anatomy coordinates. Two statistical maps were then created, one for the normal control group and one for the M.C.I. group. These consisted of the mean and standard deviation of the normalised annual point wise volume change at each voxel. The voxels with significantly different atrophy rates were then evaluated based on the Z-Score of the statistics at each voxel in the two groups. Significant decreases in tissue volume from normal to MCI group are illustrated in figure 1, showing the average normal MRI, with a Z-Score contour(Z= 1.6) of the volume changes overlayed. Decreases were observed in white matter around the ventricles and in gray matter at the head of the hippocampus, a region which is known to be particularly vulnerablke to Alzeimer’s disease. In addition, smaller regions of loss were observed in the gray matter of the cortex. Overall, the results demonstrate that mild cognitive impairment is associated with increased rates of brain atrophy in regions that are known to be involved in Alzheimer’s disease. Additional studies are necessary to determine the diagnostic value of these atrophy measurements for the early diagnosis of Alzheimer’s disease.

Impact of the genome project on the identification of disease genes

Cognitive defects and neurological diseases represent a major issue for human health, especially in aging populations. An estimated 15% of people >65 years are affected by mild-to-severe conditions of genetic origin affecting the central nervous system. Etiological factors of common neurological and psychiatric disorders remain elusive, apart from a few genes associated with rare disorders, such as one form of Alzheimer's disease(APP),a form of amyotrophic lateral sclerosis (SOD1), expanded polyglutamine track in Huntington's disease, and several types of ataxia or ion channel-associated conditions. With the human DNA sequence unveiled as a huge book of 3 gigabases,1,2how can we exploit the genome readout to identify disease-associated alleles and what is the projected impact for clinical genetics? The “book of life” is complete to >90% of euchromatic gene-rich regions, opening unprecedented possibilities for the characterization of all genes. The emerging human catalogue is thought to contain about 30 000 genes. Until now, factors underlying inherited conditions were mostly identified by positional cloning without prior knowledge of their biochemical function, and the catalogue unlocks the door to fast in silico searching(Figure 1, Parti I). Figure 1. The human genome catalogue unlocks the door to fast in silico searching and the design of novel high-throughput genotyping strategie. Complex molecular processes govern organogenesis and fitness builds upon the correct orchestration of gene actions throughout life. Most clinical phenotypes result from alterations of genetic instructions perturbing this tightly regulated system, while being strongly influenced by individual genetic makeup. The profound transition seen with the sequence information is the ability to foster novel concepts in our way of addressing biology as a global entity. Comprehensive studies of genome landscape and common polymorphisms will help identify causal and susceptibility factors at a much greater pace(Figure 1, Parts II and III). Although 60% of human genes have no characterized function yet, the sequence provides a body of information for the design of global strategies in functional genomics, for instance, using molecular evolution to underpin function by inference. Comparative genomics is one of the most powerful approaches to deciphering the molecular basis of disease pathogenesis(Figure 2). Figure 2. Genome sequences boost the power of model organisms and comparative genomics for identifying disease genes and understanding their function. Another essential approach to extracting biological meaning from the genetic message is illustrated by global transcriptome analysis(Figure 3).Grasping how global gene expression is processed into phenotype will be essential to any progress in molecular medicine. Hunting for disease-associated alleles by surveying dynamic biological systems at all relevant developmental stages and in all relevant tissues brings novel perspectives that will allow the correlation of molecular phenotype with clinical phenotype. Figure 3. Global analysis of the transcriptome by complex hybridization on assays: identifying and spotting all of the ≈ 16 000 to 20 000 genes that could be expressed in the human brain.

N-Acetyl-L-Cystein downregulates beta-amyloid precursor protein gene transcription in human neuroblastoma cells.

The causes for the sporadic form of Alzheimer's disease (AD) are still poorly understood, except from the fact that age is an important risk factor. The main component of the characteristic amyloid plaques in brains of AD patients are Abeta peptides, derivatives of the amyloid precursor protein APP. Oxidative stress may contribute to the aetiology of AD by dysregulation of APP metabolism. Overexpression of the APP gene could result in an increased secretion of neurotoxic Abeta peptides, while preventing the overexpression might be protective. We here report that the antioxidant N-Acetyl-L-Cystein (NAC) downregulates APP gene transcription in human neuroblastoma cells. The effect is reversible when cells are returned to NAC free medium. These results open up new possibilities for the development of therapeutic agents that intervene at the transcriptional level.

Apolipoprotein E gene promoter polymorphisms in Alzheimer's disease.

Alzheimer's disease, the most frequent form of senile dementia, presents in the vast majority of cases as a multifactorial trait, where a series of genetic and environmental risk factors converge. The increasing body of data, both epidemiological and functional, is strengthening the evidence that apolipoprotein E (APOE, gene; apoE, protein) is a true susceptibility factor for the onset of the common form of Alzheimer's disease. The E4 isoform of apoE remains to date as the main genetic risk factor for the disease, although the mechanisms responsible for this association are not well understood. It is also clear that apoE4 is not necessary or sufficient to cause the disease, indicating that other risk and protecting factors exist. ApoE is upregulated in response to nervous system injury, suggesting that it could have a neuroprotective role; on the other hand, there is evidence indicating that apoE is neurotoxic when present at high levels. Thus, apoE levels seem to be relevant for the functionality of the protein. The APOE proximal promoter hosts numerous regulatory elements, raising the possibility that polymorphisms in this region could produce variation in apoE levels by altering APOE transcriptional activity, which could finally result in AD susceptibility. We will review here the current evidence on the relationship between APOE proximal promoter polymorphisms, APOE gene transcriptional activity and apoE protein levels, and risk for AD.

Vascular disease risk factors and findings in patients with Alzheimer's disease

Vascular risk factors and data of different examinations relating to extracerebral vascular conditions were analysed in demented patients. Data of demented patients subsequently admitted to the Memory Clinic of the National Institute of Psychiatry and Neurology between March 1995 and February 1996 were registered in a specially designed data sheet. Three vascular examinations (ECG, Doppler examination of main extracerebral arteries on the neck, ophthalmoneurological examination) were carried out. The risk factors and vascular alterations were condensed in two factors. Neither the descriptive data nor the two factors showed statistically significant differences in the main groups (probable Alzheimer's disease--n=24, vascular dementia--n=23, mixed forms--n=15). Based on our results: vascular risk factors and pathological changes can occur in probable form of Alzheimer's disease; they can be present in early onset form as well; the most marked changes are in the vascular dementia group; relevant findings lack any correlation with each other in the point of severity of vascular changes. The extremely high cardio-cerebrovascular morbidity in Hungary seems to be reflected in the results. The role of vascular risk factors and (subclinical) pathological findings seem worth exploring further in Alzheimer's disease.

On Estimating Incidence Rates of Diseases with Delayed Onset Using Biased Samples

Abstract Consistent estimators are derived for the age-specific and lifetime incidence rates of late-onset diseases from censored, biased samples, using a discrete time model and a traditional assumption for size-biased sampling. The estimators are alternatives to the so-called index case estimators often used by epidemiologists under similar circumstances. The asymptotic normality of the proposed estimators is established and an adaptation of Greenwood's formula is given for estimating and comparing their asymptotic variances. We show that index case estimators can be inconsistent and find a necessary and sufficient condition for their consistency. The results are applicable in the study of familial aggregation of diseases that are not manifest at birth when the sample consists of families identified through a family member who has the disease of interest. A survey of families of nursing home patients with a narrowly defined form of Alzheimer's disease, undertaken to clarify its mode of inheritance is an...

Psychopathology and cognitive decline in dementia.

This study investigated the correlation between the degree and quality of cognitive impairment and the presence and degree of severity of psychopathology. Sixty-four demented outpatients were rated for cognition by the Mental Status Questionnaire and for psychopathology by the BEHAVE-AD Reisberg questionnaire. A statistical analysis of the correlations between the cognitive and psychopathological parameters was performed. The study indicated a high rate of psychopathology (as high as 83% of the patients). No significant correlation was found between the cognitive grading score and the presence of psychopathology, except in the space of declined spatial orientation and the occurrence of hallucinations. Psychopathology is a common phenomenon occurring in the course of dementia in the form of Alzheimer's disease or multi-infarct dementia. There is a certain increase in the degree of psychopathology that correlated with cognitive impairment. The high correlation between impaired spatial orientation and the presence of hallucinations seems to point to a common neuropathological substrate.