Frontotemporal dementia to Alzheimer's disease

Behavioral manifestations may dominate the clinical picture of the frontal variant of frontotemporal dementia (fv-FTD) for a long time before the appearance of true cognitive deficits. On the other hand, a deficit in the episodic memory domain represents the main manifestation of Alzheimer's disease (AD). Many behavioral disorders have been described in the clinical course of both FTD and AD; however, apathy and personality changes characterize frontal dementias, while depression dominates in AD, at least in the earlier stages. Depending on the distribution of neural damage, different patterns of noncognitive manifestations may be expected in different subtypes of FTD. Recent research on the social cognition deficit in FTD has offered new insights into the relationship between cognition and behavior, suggesting that some aspects of the behavioral changes in dementia may be generated by impairment in this domain.     

Cost of Alzheimer's disease

The progressive deterioration associated with Alzheimer's disease (AD) results in high economic cost to the patients, caregivers, and the society as a whole. Cost-of-AD studies conducted over the last decade have produced discrepant results, mainly as a consequence of the different methodologies employed. The present review is an attempt to present the methodology of the cost studies in AD and provide the reader with the tools necessary for a critical assessment of the results.     

Treatment of cognitive impairment in Alzheimer's disease

In Alzheimer's disease, cognition now responds to several drugs. Anticholinesterases target the acetylcholine deficit. In mild-to-moderate Alzheimer's disease, they all provide significant benefit versus placebo on the Alzheimer's Disease Assessment ScheduleCognitive Section (ADAS-Cog), Side effects, in 5% to 15% of cases, include nausea, vomiting, diarrhea, anorexia, and dizziness. Tacrine, the leading anticholinesterase, caused frequent hepatic enzyme elevation and was withdrawn; once-daily donepezil spares the liver and improves global measures of change in severe dementia; rivasiigmine is indicated in comorbid vascular disease; while galaniamine modulates the cerebral nicotinic acetylcholine receptors that potentiate the response to acetylcholine. Alternative agents include the N-methyl-D-aspartate (NMDA) receptor antagonist, memaniine, licensed in Europe for moderately severe to severe Alzheimer's disease; it acts on a different neurotransmitter system present in 70% of neurons, protecting against pathologic glutamergic activation while preserving or even restoring physiologic glutamergic activation. The clinician's armamentarium in AD has never been greater.     

Pharmacological models in Alzheimer's disease research

Wider use of pharmacological models would facilitate the development of new drugs for Alzheimer's disease (AD), The two main models currently used are based on the cholinergic and glutamatergic hypotheses of AD, Although they lead to some of the attention and memory impairment observed in AD, they do not fully reproduce the AD pattern. The few studies that used a combination modeling approach, ie, the simultaneous administration of several drugs with the aim of impairing several neurotransmitters or different aspects of a single system, have reported no or marginal cumulative effect. On the basis of current understanding of glutamate and acetylcholine involvement in AD pathophysiology, we suggest that models using selective muscarinic-1 (M(1)) receptor blockers would better mimic the status of the cholinergic system in AD, This kind of model might be suitable for the assessment of drugs that do not act directly on the cholinergic system.     

Biological markers for early detection and pharmacological treatment of Alzheimer's disease

The introduction of biological markers in the clinical management of Alzheimer''s disease (AD) will not only improve diagnosis relating to early detection of neuropathology with underlying molecular mechanisms, but also provides tools for the assessment of objective treatment benefits. In this review, we identify a number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy of AD, and hold promise as meaningful biomarkers in the early diagnostic process, as well as for the tracking of disease-modifying pharmacological effects. These neurobiological measures appear to relate closely to pathophysiological, neuropathological, and clinical data, such as hyperphosphorylation of tau, abeta metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, and functional and cognitive decline, as well as risk of future decline. As a perspective, the important role of biomarkers in the development of innovative drug treatments for AD and the related regulatory process is discussed.     

Inflammation and the pathophysiology of Alzheimer's disease

There is increasing evidence that a chronic inflammatory response in the brain in Alzheimer's disease (AD) ultimately leads to neuronal injury and cognitive decline. Microglia, the primary immune effector cells of the brain, are thought to be key to this process. This paper discusses the evidence for inflammation in AD, and describes the mechanism whereby microglia generate neurotoxic cytokines, reactive oxygen species, and nitric oxide. Evidence that the cytokine macrophage colony-stimulating factor (M-CSF) is an important cofactor in microglial activation in AD is presented. Ongoing work using organotypic hippocampal expiant cultures to model the inflammatory process in the AD brain is also discussed. Potential avenues for therapeutic intervention are outlined.     

Sensitivity and specificity of neuroimaging for the diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is one of the most devastating and cosily disorders affecting the aging population. Structural imaging (computed tomography [CT] and magnetic resonance imaging [MRI]) and functional imaging (single photon emission computed tomography [SPECT] and positron emission tomography [PET]) have been evaluated for their roles in the imaqinq diagnosis of AD. We have reviewed the recent literature to determine the capabilities of these neuroimaging techniques in comparison to current standards of clinical diagnosis. Our results indicate that there is wide variability in the accuracy of clinical assessments, in contrast to a more limited ranqe of variability of the accuracy of neuroimaqinq measurements. These results suggest that neuroimaging may serve an adjunctive role in raising this lower bound of diagnostic accuracy. Furthermore, we suggest that neuroimaging should be considered: (I) when clinical expertise is insufficient; (il) as a complement to specific likelihood ratios; and (iii) in specific types of patients, for whom clinical evaluation is inappropriate or inadequate.     

Genetic studies in Alzheimer's disease

Alzheimer's disease (AD), the most common cause of dementia in aged populations, is believed to be caused by both environmental factors and genetic variations. Extensive linkage and association studies have established that a broad range of loci are associated with AD, including both causative and susceptibility (risk factor) genes. So far, at least three genes, APP, PS1, and PS2, have been identified as causative genes. Mutations in these genes have been found to cause mainly early-onset AD. On the other hand, APOE has been identified to be the most common high genetic risk factor for late-onset AD. Polymorphisms in the coding region, intron, and promoter region of certain genes constitute another kind of genetic variation associated with AD. A number of other genes or loci have been reported to have linkage with AD, but many show only a weak linkage or the results are not well reproduced. Currently, the measurable genetic associations account for about 50% of the population risk for AD. It is believed that more new loci will be found to associate with AD, either as causative genes or genetic risk factors, and that eventually the understanding of genetic factors in the pathogenesis of AD will be important for our efforts to cure this illness.     

Imaging in Alzheimer's disease

Neuroimaging in the early differential diagnosis of dementia has gained considerable interest over the last decade. From being used for exclusive purposes only, neuroimaging is now in the forefront of aiding in the diagnosis of Alzheimer''s disease (AD), frontotemporal dementia, vascular dementia, and and dementia with Lewy bodies (DLB). With the exception of dopamine transporter single photon-emission computed tomography imaging in DLB, imaging has not yet been incorporated into the diagnostic criteria for the various dementia syndromes, but that will soon change. The recently formulated research criteria for early AD recently formulated by Dubois et al explicitly mention magnetic resonance imaging and positron emission tomography for AD, and are an example of a new diagnostic process developing. In this review, the various imaging techniques will be highlighted, with an emphasis on their ability to diagnose Alzheimer''s disease and separate it from other entities.     

Alzheimer's disease

Alzheimer's disease is one of the most devastating brain disorders of elderly humans. It is an undertreated and under-recognized disease that is becoming a major public health problem. The last decade has witnessed a steadily increasing effort directed at discovering the etiology of the disease and developing pharmacological treatment. Recent developments include improved clinical diagnostic guidelines and improved treatment of both cognitive disturbance and behavioral problems. Symptomatic treatment mainly focusing on cholinergic therapy has been clinically evaluated by randomized, double-blind, placebo-controlled, parallel-group studies measuring performance-based tests of cognitive function, activities of daily living, and behavior. Cholinesterase inhibitors, including donepezil, tacrine, rivastigmine, and galantamine are the recommended treatment of cognitive disturbance in patients with Alzheimer's disease. The role of estrogen replacement, anti-inflammatory agents, and antioxidants is controversial and needs further study. Antidepressants, antipsychotics, mood stabilizers, anxiolytics, and hypnotics are used for the treatment of behavioral disturbance. Future directions in the research and treatment of patients with Alzheimer's disease include: applying functional brain imaging techniques in early diagnosis and evaluation of treatment efficacy; development of new classes of medications working on different neurotransmitter systems (cholinergic, glutamatergic, etc), both for the treatment of the cognitive deficit and the treatment of the behavioral disturbances; and developing preventive methods (amyloid p-peptide immunizations and inhibitors of β-secretase and γ-secretase).     

The discovery of Alzheimer's disease

On Novembers, 1306, a clinical psychiatrist and neuroanatomist, Alois Alzheimer, reported "A peculiar severe disease process of the cerebral cortex" to the 37th Meeting of South-West German Psychiatrists in Tubingen, He described a 50-year-old woman whom he had followed from her admission for paranoia, progressive sleep and memory disturbance, aggression, and confusion, until her death 5 years later. His report noted distinctive plaques and neurofibrillary tangles in the brain histology. It excited little interest despite an enthusiastic response from Kraepelin, who promptly included "Alzheimer's disease" in the 3ih edition of his text Psychiatrie in 1910. Alzheimer published three further cases in 1909 and a "plaque-only" variant in 1911, which reexamination of the original specimens in 1993 showed to be a different stage of the same process, Alzheimer died in 1915, aged 51, soon after gaining the chair of psychiatry in Breslau, and long before his name became a household word.     

Combination pharmacotherapy in Alzheimer's disease

Alzheimer's disease is a progressive, debilitating form of dementia affecting more than 18 million people worldwide. Without a cure, many patients and their families must turn to long-term care institutions during the later stages of the disease. Our current treatments only delay progression and help control behavioral symptoms. In recent years, research within this field has expanded to include many clinical trials on potential drug therapies. However, despite the numerous studies, the enigma of this disease remains. It is difficult yet necessary, to stay abreast of emerging information that may warrant changes in current therapy. Rationale for combination therapy becomes evident as we review the multiple neurochemical pathways common to the disease. This paper will review available information on Alzheimer's disease pharmacotherapy, and evaluate data on the use of combination drug therapy. Individual efficacy, possible synergistic effects, and the safety of combination therapy will also be addressed.     

Epidemiology of Alzheimer's disease: occurrence,determinants, and strategies toward intervention

More than 25 million people in the world today are affected by dementia, most suffering from Alzheimer''s disease. In both developed and developing nations, Alzheimer''s disease has had tremendous impact on the affected individuals, caregivers, and society. The etiological factors, other than older age and genetic susceptibility, remain to be determined. Nevertheless, increasing evidence strongly points to the potential risk roles of vascular risk factors and disorders (eg, cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions) and the possible beneficial roles of psychosocial factors (eg, high education, active social engagement, physical exercise, and mentally stimulating activity) in the pathogenetic process and clinical manifestation of the dementing disorders. The long-term multidomain interventions toward the optimal control of multiple vascular risk factors and the maintenance of socially integrated lifestyles and mentally stimulating activities are expected to reduce the risk or postpone the clinical onset of dementia, including Alzheimer''s disease.     

Early diagnosis of Alzheimer's disease: update on combining genetic and brain-imaging measures

Diagnosis of Alzheimer's disease is often missed or delayed in clinical practice; thus, methods to improve early detection would provide opportunities for early intervention, symptomatic treatment, and improved patient function. Emerging data suggest that the disease process begins years before clinical diagnostic confirmation. This paper reviews current research focusing on methods for more specific and sensitive early detection using measures of genetic risk for Alzheimer's disease and functional brain imaging. This approach aims to identify patients in a presymptomatic stage for early treatment to delay progressive cognitive decline and disease onset.     

Novel strategies for the prevention of dementia from Alzheimer's disease

As the world''s population continues to age, Alzheimer''s disease presents a homing public health crisis that left unchecked, threatens to overwhelm health care systems throughout the developed world, in order to significantly tackle the most catastrophic and devastating symptom of Alzheimer''s disease (AD)-dementia-we must be able to detect the disease prior to the onset of clinical symptoms, and be able to offer patients preventative treatments that block or significantly slow disease progression. This review summarizes a variety of the most promising early detection methods for Alzheimer''s disease (AD) and mild cognitive impairment (MCI) that could be used to identify those at high risk of developing the disease and used for monitoring disease progression and response to investigational treatments, in addition, treatment research programs that could be developed into disease-modifying treatments that significantly delay the development of dementia are highlighted. These potential treatments target many different pathways, and may one day be dosed in combination to increase efficacy and prevent cognitive deterioration in patients with AD. While we still face numerous challenges, AD researchers have made great progress in understanding disease mechanisms. As we have seen in the treatment of heart disease, even modest preventative treatments can have hugely significant clinical outcomes and drastically reduce disease prevalence on a population scale. Therefore, there is hope that the development of prophylactic treatments, combined with improved early detection methods, will provide dramatic relief for millions of aging individuals threatened by the specter of Alzheimer''s disease.     

Is dementia preventable?

Dementía is an important public health problem of increasing magnitude. At present, available therapies provide only minor and temporary relief, and attempts to find a cure have so far failed. Epidemiological studies have identified risk factors for dementía, particularly Alzheimer''s disease and vascular dementia. In principle, these findíngs provide an opportunity to intervene and prevent the dementía epidemic. Attention to nongenetic risk factors such as hypertension, hyperlipidemia, smoking, and obesity may thus not only prevent cardiovascular disease but also dementia, although it is difficult to prove the efficacy of these measures for dementía prevention.     

Behavioral and psychological signs and symptoms of dementia: a practicing psychiatrist's viewpoint

Alzheimer's disease typically presents with two often overlapping syndromes, one cognitive, the other behavioral. The behavioral syndrome is characterized by psychosis, aggression, depression, anxiety, agitation, and other common if less well-defined symptoms subsumed under the umbrella entity "behavioral and psychological symptoms of dementia" (BPSD), itself divided into a number of subsyndromes: psychosis, circadian rhythm (sleepwake) disturbance, depression, anxiety, and agitation, it is BPSD with its impact on care providers that ultimately precipitates the chain of events resulting in long-term institutional care. The treatment challenge involves eliminating unmet medical needs (undiagnosed hip fracture and asymptomatic urinary tract infection or pneumonia). Pharmacologic intervention relies on risperidone and, increasingly cholinesterase inhibitors for the control of psychosis (but with response rates of only 65% at tolerable doses), olanzapine and risperidone for anxiety, and carbamazepine and valproic acid for agitation. However, evidence increasingly favors nonpharmacologic interventions, to the extent that these should now be considered as the foundation of BPSD treatment. Problem behaviors are viewed as meaningful responses to unmet needs in the therapeutic milieu. Because the progression and impact of BPSD varies between patients, interventions must be explored, designed, implemented, and assessed on an individual basis. They include: family support and education, psychotherapy reality orientation, validation therapy, reminiscence and life review, behavioral interventions, therapeutic activities and creative arts therapies, environmental considerations (including restraint-free facilities), behavioral intensive care units, and workplace design and practices that aid the ongoing management of professional caregiver stress.     

Fleshing out the amyloid cascade hypothesis: the molecular biology of Alzheimer's disease

Alzheimer's disease (AD) is a disorder of two pathologies- plaques and tangles. The former have as a key constituent amyloid protein and the latter the microtubule-associaied protein tau. Genetics has demonstrated that changes in either protein are sufficient to cause dementia. The amyloid cascade hypothesis proposes that plaque-related changes precede tangle-related changes and positions amyloid as central to the degeneration of AD. All the evidence suggests this is correct, including evidence that presenil ins alter the processing of the amyloid precursor protein and evidence that disrupting the normal properties of tau underlies the related froniotemporal dementias. The amyloid cascade hypothesis has provided the basis for nearly a decade of intensive basic science - the skeleton of that hypothesis can now be fleshed out, and confidence is growing that this will result in useful disease-modifying therapies in the future.     

A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer's disease

Early research into Alzheimer's disease launched the cholinergic hypothesis, based on the correlation between central cholinergic deficiency and clinical measures of cognitive decline. This was epitomized in therapeutic strategies employing a variety of procholinergic agents, of which only the inhibitors of cholinesterase (ChE), the enzyme thai hydrolyzes acetylcholine in the synaptic cleft, have been proven clinically viable. Five such agents are reviewed: tacrine and donepezil, which act at the ionic subsite of acetylcholinesterase (AChE), and rivastigmine, galantamine, and metrifonate, which act at its catalytic esteratic subsite. Despite statistical evidence of efficacy from numerous well-controlled multicenter trials, important clinical utility issues remain outstanding: (i) number-needed-to-treat (NNT) analyses, quantifying the number of patients needing to be treated for one patient to show benefit, find values of 3 to 20; (ii) the pivotal trials themselves were conducted in nonrepreseniative populations, largely comprised of physically healthy outpatients with mildto-moderate Alzheimer's disease and a mean age of 72 years (thereby excluding over 30% of typical Alzheimer patients in State of California-funded clinics), treated for up to 6 months; and (Hi) tolerability is underreported and characterized by a positive correlation between dose, effect and cholinergic side effects - potentially serious adverse events include bradycardia, anorexia, weight loss and myasthenia with respiratory depression. Therapies thus require titration and constant monitoring. Nevertheless, acetylcholinesterase inhibitors (AChEls) constitute the first class of effective agents and are likely to remain so in the continuing absence of viable alternatives.