Do disorders of movement cause movement disorders and dementia?

Neurons require long-distance microtubule-based transport systems to ferry vital cellular cargoes and signals between cell bodies and axonal or dendritic terminals. Considerable progress has been made on developing a molecular understanding of these processes and how they are integrated into normal neuronal functions. Recent work also suggests that these transport systems may fail early in the pathogenesis of a number of neurodegenerative diseases.     

What can Drosophila tell us about serpins,thrombosis and dementia?

The validity of the fruit-fly as a model of human disease has been confirmed in a striking way by Green and colleagues.1 They show that the mutations causing a necrotic disease phenotype in Drosophila, precisely mirror those resulting in a group of well-studied but perplexing diseases in the human. These diseases, ranging from thrombosis to dementia, arise from mutations causing a conformational instability of serpin protease inhibitors. The findings provide clues as to the unusual severity and variable onset of such conformational diseases and demonstrate the potential of Drosophila as a model for their future study.     

Folic acid and polyunsaturated fatty acids improve cognitive function and prevent depression, dementia, and Alzheimer's disease--but how and why?

Low blood folate and raised homocysteine concentrations are associated with poor cognitive function. Folic acid supplementation improves cognitive function. Folic acid enhances the plasma concentrations of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). EPA, DHA, and arachidonic acid (AA) are of benefit in dementia and Alzheimer's disease by up-regulating gene expression concerned with neurogenesis, neurotransmission and connectivity, improving endothelial nitric oxide (eNO) generation, enhancing brain acetylcholine levels, and suppressing the production of pro-inflammatory cytokines. EPA, DHA, and AA also form precursors to anti-inflammatory compounds such as lipoxins, resolvins, and neuroprotectin D1 (NPD1) that protect neurons from the cytotoxic action of various noxious stimuli. Furthermore, various neurotrophins and statins enhance the formation of NPD1 and thus, protect neurons from oxidative stress and prevent neuronal apoptosis Folic acid improves eNO generation, enhances plasma levels of EPA/DHA and thus, could augment the formation of NPD1. These results suggest that a combination of EPA, DHA, AA and folic acid could be of significant benefit in dementia, depression, and Alzheimer's disease and improve cognitive function.     

Sorting out frontotemporal dementia?

Mutations within the granulin (GRN) gene that encodes progranulin (PGRN) cause the neurodegenerative disease frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U). The receptor for PGRN in the CNS has not been previously identified. In this issue of Neuron, Hu and colleagues identify Sortilin (SORT1) as a key neuronal receptor for PGRN that facilitates its endocytosis and regulates PGRN levels in?vitro and in?vivo.     

A role for NOX NADPH oxidases in Alzheimer's disease and other types of dementia?

Because of population ageing, dementias are likely to become a major scourge of the 21st century. Causes of dementia include Alzheimer's disease, cerebrovascular disease, and lesser known entities such as frontotemporal dementia or dementia with Lewy bodies. Neuroinflammation is likely to play an important role in the pathogenesis of dementia by the killing of neurons through inflammatory mechanisms. Such a role of neuroinflammation is well documented for Alzheimer's disease, and it is likely to play a role in other types of dementia as well. Reactive oxygen species (ROS) play a key role in inflammatory tissue destruction. The phagocyte NADPH oxidase NOX2 is the best studied ROS-generating system. In the central nervous system, it is expressed in microglia and--to a lesser extent--in neurons. Indeed, there is emerging experimental evidence for a role of NOX2 in Alzheimer's and cerebrovascular disease. Recently, six novel ROS-generating NADPH oxidases with homology to NOX2 have been discovered. Several of them are also expressed in the central nervous system. In this article, we hypothesize a role of NOX-type NADPH oxidases in inflammatory neuronal loss. We review presently available evidence and suggest that NOX-type NADPH oxidases may become promising pharmacological targets for the treatment and prevention of dementia.     

An immunohistochemical study on cerebral vascular and senile plaque amyloid in Alzheimer’s dementia

Senile cerebral amyloidosis has been investigated using immunoperoxidase and enzyme histochemical techniques in six unfixed brains. Our findings do not support the opinion that vascular and senile plaque amyloid are immunoglobulin-derived. In contrast with recent reports we did not detect prealbumin in senile plaques and congophilic angiopathy lesions. All senile plaques contain complement factors C1q, C3 and C4. The highest peroxidase activity was found in the amyloid nucleus but the corona also showed evident peroxidase activity.     

Mitochondrial DNA polymorphisms as risk factors for Parkinson’s disease and Parkinson’s disease dementia

The activity of complex I of the mitochondrial respiratory chain has been found to be decreased in patients with Parkinsons disease (PD), but no mutations have been identified in genes encoding complex I subunits. Recent studies have suggested that polymorphisms in mitochondrial DNA (mtDNA)-encoded complex I genes (MTND) modify susceptibility to PD. We hypothesize that the risk of PD is conveyed by the total number of nonsynonymous substitutions in the MTND genes in various mtDNA lineages rather than by single mutations. To test this possibility, we determined the number of nonsynonymous substitutions of the seven MTND genes from 183 Finns. The differences in the total number of nonsynonymous substitutions and the nonsynonymous to synonymous substitution rate ratio (K_a/K_s) of MTND genes between the European mtDNA haplogroup clusters (HV, JT, KU, IWX) were analysed by using a statistical approach. Patients with PD (n=238) underwent clinical examination together with mtDNA haplogroup analysis and the clinical features between patient groups defined by the number of nonsynonymous substitutions were compared. Our analysis revealed that the haplogroup clusters HV and KU had a lower average number of amino acid replacements and a lower K_a/K_s ratio in the MTND genes than clusters JT and IWX. Supercluster JTIWX with the highest number of amino acid replacements was more frequent among PD patients and even more frequent among patients with PD who developed dementia. Our results suggest that a relative excess of nonsynonymous mutations in MTND genes in supercluster JTWIX is associated with an increased risk of PD and the disease progression to dementia.     

Neurochemical dementia diagnostics in Alzheimer's disease: where are we now and where are we going?

Neurochemical dementia diagnostics (NDD) is a routine laboratory tool used in the diagnostic process for patients with neurodegenerative disorders, such as Alzheimer's disease. Currently, two groups of biomarkers analyzed in the cerebrospinal fluid are considered - namely amyloid-β peptides and Tau proteins - along with the hyperphosphorylated forms of the latter (pTau). Current directions in the development of NDD include the following: search for novel biomarkers with improved analytical or diagnostic performance; optimization of the analysis of the biomarkers already available (e.g., by improved quality control and interlaboratory comparison of results); applications of novel technologies enabling better management of patient samples; and search for biomarkers in the blood. This article presents the state-of-the-art in the field of cerebrospinal fluid-based NDD, and also summarizes some of the hypotheses of how the future development of NDD tools might look.     

Squid (Loligo pealei) giant fiber system: a model for studying neurodegeneration and dementia?

In many neurodegenerative disorders that lead to memory loss and dementia, the brain pathology responsible for neuronal loss is marked by accumulations of proteins in the form of extracellular plaques and intracellular filamentous tangles, containing hyperphosphorylated cytoskeletal proteins. These are assumed to arise as a consequence of deregulation of a normal pattern of topographic phosphorylation-that is, an abnormal shift of cytoskeletal protein phosphorylation from the normal axonal compartment to cell bodies. Although decades of studies have been directed to this problem, biochemical approaches in mammalian systems are limited: neurons are too small to permit separation of cell body and axon compartments. Since the pioneering studies of Hodgkin and Huxley on the giant fiber system of the squid, however, the stellate ganglion and its giant axons have been the focus of a large literature on the physiology and biochemistry of neuron function. This review concentrates on a host of studies in our laboratory and others on the factors regulating compartment-specific patterns of cytoskeletal protein phosphorylation (primarily neurofilaments) in an effort to establish a normal baseline of information for further studies on neurodegeneration. On the basis of these data, a model of topographic regulation is proposed that offers several possibilities for further studies on potential sites of deregulation that may lead to pathologies resembling those seen in mammalian and human brains showing neurodegeneration, dementia, and neuronal cell death.     

Population-based neuropathological studies of dementia: design, methods and areas of investigation – a systematic review

Background  

Prospective population-based neuropathological studies have a special place in dementia research which is under emphasised.     

BRICHOS domain associated with lung fibrosis, dementia and cancer--a chaperone that prevents amyloid fibril formation?

The BRICHOS domain was initially defined from sequence alignments of the Bri protein associated with familial dementia, chondromodulin associated with chondrosarcoma and surfactant protein C precursor (proSP-C) associated with respiratory distress syndrome and interstitial lung disease (ILD). Today BRICHOS has been found in 12 protein families. Mutations in the Bri2 and proSP-C genes result in familial dementia and ILD, respectively, and both these conditions are associated with amyloid formation. Amyloid is of great medical relevance as it is found in several major incurable diseases, like Alzheimer's and Parkinson's disease and diabetes mellitus. Work on recombinant BRICHOS domains and transfected cells indicate that BRICHOS is a chaperone domain that, during biosynthesis, binds to precursor protein regions with high β-sheet propensities, thereby preventing them from amyloid formation. Regions prone to form β-sheets are present in all BRICHOS-containing precursor proteins and are probably eventually released by proteolytic cleavage, generating different peptides with largely unknown bioactivities. Recombinant BRICHOS domains from Bri2 and proSP-C have been found to efficiently prevent SP-C, the amyloid β-peptide associated with Alzheimer's disease, and medin, found in aortic amyloid, from forming amyloid fibrils. The data collected so far on BRICHOS raise several interesting topics for further research: (a) amyloid formation is a potential threat for many more proteins than the ones recognized so far in amyloid diseases; (b) amyloid formation of widely different peptides involves intermediate(s) that are recognized by the BRICHOS domain, suggesting that they have distinct structural similarities; and (c) the BRICHOS domain might be harnessed in therapeutic strategies against amyloid diseases.     

Differential patterns of planning impairments in Parkinson's disease and sub-clinical signs of dementia? A latent-class model-based approach

Planning impairments mark a well-documented consequence of neurodegenerative diseases such as Parkinson's disease (PD). Recently, using the Tower of London task we demonstrated that, rather than being generally impaired, PD patients selectively fail when planning requires flexible in-breadth search strategies. For a better understanding of the interindividual patterns underlying specific planning impairments, here we performed an explorative re-analysis of the original data using a latent-class model-based approach. Data-driven classification according to subjects' performance was based on a multinomial processing tree (MPT) model accommodating the impact of increased breadth versus depth of looking ahead during planning. In order to assess interindividual variability in coping with these different task demands, an extension of MPT models was used in which sample-immanent heterogeneity is accounted for by identifying different latent classes of individuals. Two latent classes were identified that differed considerably in performance for problems placing high demands on the depth of anticipatory search processes. In addition, these impairments were independent of PD diagnosis. However, latent-class mediated search depth-related deficits in planning performance were associated with poorer outcomes in dementia screenings, albeit sub-clinical. PD patients exhibited additional deficits related to the breadth of searching ahead. Taken together, results revealed dissociable impairments in specific planning processes within a single task of visuospatial problem solving. Present analyses put forward the hypothesis that cognitive sequelae of PD and sub-clinical signs of dementia may be related to differential patterns of planning impairments.     

Apolipoprotein E ε4 genotype as a risk factor for cognitive decline and dementia: data from the Canadian Study of Health and Aging

Background

Apolipoprotein E (ApoE) ε4 genotype is a well-established risk factor for Alzheimer''s disease (AD). However, its effect on predicting conversion from normal to “cognitive impairment, no dementia” (CIND) and from CIND to AD is less clear.

Methods

We used a nested case–control design from the population-based Canadian Study of Health and Aging (CSHA) to examine the effect of ApoE ε4 genotype on the conversion of subjects from normal to CIND and from CIND to AD. We also contrasted these findings with incident cases of AD and vascular dementia (VaD) in the CSHA cohort.

Results

The ApoE ε4 genotype was a significant risk factor for conversion from CIND to AD and from normal to AD and VaD. However, it was not a significant risk factor for conversion from normal to CIND. This effect is robust to adjustment for age, sex and education level. There is significant interaction between the ApoE ε4 genotype and age for AD and for conversion from CIND to AD. No interaction between ApoE ε4 genotype, sex, age, ethnicity and education level was found in other subgroup analyses. The positive predictive value of ApoE ε4 for predicting CIND conversion to AD was 0.48, and the negative predictive value was 0.65.

Interpretation

Possession of an ApoE ε4 allele increases the risk of AD developing from CIND. It is also associated with a decrease in the age at onset of AD. Its predictive values do not support its utility as a diagnostic test for predicting progression from CIND to AD, but it may be useful in research studies to enrich study samples that have a higher rate of progression to AD.Dementia has a profound impact on patients, families, caregivers and society in general. Data from the Canadian Study of Health and Aging (CSHA) show that 252 600 people had dementia in Canada in 1991; probable Alzheimer''s disease (AD) was diagnosed in 64% of those people.¹ It was also estimated that the net annual cost to society of care for dementia in Canada in 1991 was over $3.9 billion.² The prevalence of AD rises exponentially, doubling approximately every 5 years between the ages of 65 and 85. In recent years, rapid progress in molecular genetics has fostered the discovery of at least 4 genes associated with AD: the amyloid precursor protein (APP), the presenilin-1 gene (PS-1), the presenilin-2 gene (PS-2) and the apolipoprotein E gene (ApoE).^3,4,5Mutations in APP, PS-1 and PS-2 account for virtually all autosomal dominant inherited early-onset forms of AD. However, this form of AD represents less than 10% of all AD cases. By contrast, ApoE ε4 polymorphism does not cause AD, but it operates as a susceptibility gene or genetic risk factor. The gene exists in 3 different allele polymorphisms — ε2, ε3 and ε4 — in the general population. From previous epidemiological studies, it is estimated that people who carry 1 ε4 allele are 3 times more likely to have AD than those who do not carry any ε4 allele, and those who carry 2 ε4 alleles are 9 times more likely to develop AD than those who do not.^6,7 In addition, the ε4 allele appears to exert maximal effect in patients in whom AD is diagnosed between the ages of 55 and 75.^8,9 The ApoE ε4 allele also has been implicated as a risk factor for vascular dementia (VaD), but the findings have been inconsistent, with some studies showing positive association^{10,11,12,13,14} and others not.^{15,16,17,18,19} Recently, it has been recognized that patients who have “cognitive impairment but no dementia” (CIND) are an important group at risk for dementia. Few studies have examined ApoE ε4 as a predictor for progression from normal to CIND and from CIND to dementia.^17,19,20 To further define the relation between ApoE ε4 polymorphism and the risk of dementia in the Canadian population, we examined ApoE ε4 genotype as a predictor for conversion from normal to CIND and from CIND to AD or VaD using data obtained from the CSHA cohort. We also investigated the role of ApoE ε4 genotype as a risk factor for incident cases of AD and VaD, while controlling for the effects of age, sex and level of education.     

Do general practitioners miss dementia in elderly patients?

General practitioners and community nurses were asked to rate the likelihood of dementia for each of their elderly patients. Cases of dementia were identified by research psychiatrists using the Cambridge mental disorders of the elderly examination (CAMDEX), a new structured diagnostic interview. General practitioners correctly identified dementia as at least a possibility in 121 of the 208 cases found. Nevertheless, they mistakenly rated as demented several patients suffering from functional psychiatric disorders, in particular depression. Community nurses correctly identified dementia as at least a possibility in 64 of the 74 demented patients known to them, but they incorrectly suspected dementia in a greater proportion of instances. Both general practitioners and families appeared to have low expectations of what general practice has to offer demented elderly people. General practitioners should take the initiative in diagnosing dementia in very elderly patients who show signs of the condition. In some cases it may be secondary to treatable disorders, and in others all that may be required are understanding, support, and advice to families.     

Diagnosing dementia: do we get it right?

To find out whether the diagnosis of dementia agreed with findings at necropsy a detailed assessment of 27 elderly patients (mean age 82 (range 70-94] presenting with dementia was conducted at a combined department of geriatric medicine and psychiatry for the elderly. On the basis of the results the cause of the dementia was diagnosed clinically. Neuropathological examinations were performed after death. The clinical diagnosis made during life was not supported by the findings at necropsy in 11 cases. Alzheimer''s disease was overdiagnosed in life (13 cases, of which only six were confirmed at necropsy). Although the clinical investigation was limited by availability of resources, neither cranial computed tomography nor the Hachinski score helped to distinguish between multi-infarct dementia and Alzheimer''s disease in this age group. This study confirms the value of neuropathological studies in the precise diagnosis of dementia.     

Mild cognitive impairment: a prodromal phase of dementia?

Cognitive decline without dementia is common among older persons. A variety of clinical concepts have been introduced in the past 30 years, in order to describe these cognitive deficits arising in older persons. The most frequently used concept is Mild Cognitive Impairment (MCI). MCI is generally seen as a prodromal phase of Alzheimer disease (AD). Several concepts are described, with the neuropsychiatric features and predictors of conversion to dementia c.q. AD. Finally, consequences of preclinically diagnoses for health care are clarified.     

Is amyotrophic lateral sclerosis/frontotemporal dementia an autophagy disease?

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that share genetic risk factors and pathological hallmarks. Intriguingly, these shared factors result in a high rate of comorbidity of these diseases in patients. Intracellular protein aggregates are a common pathological hallmark of both diseases. Emerging evidence suggests that impaired RNA processing and disrupted protein homeostasis are two major pathogenic pathways for these diseases. Indeed, recent evidence from genetic and cellular studies of the etiology and pathogenesis of ALS-FTD has suggested that defects in autophagy may underlie various aspects of these diseases. In this review, we discuss the link between genetic mutations, autophagy dysfunction, and the pathogenesis of ALS-FTD. Although dysfunction in a variety of cellular pathways can lead to these diseases, we provide evidence that ALS-FTD is, in many cases, an autophagy disease.