Age-associated Dementias Research Articles

Age-associated dementia among older people aging with HIV in the United States: a modeling study.

Almost 400 000 people with HIV (PWH) in the United States are over age 55 years and at risk for age-associated dementias (AAD), including Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID). We projected the cumulative incidence and mortality associated with AAD among PWH at least 60 years in the United States compared with the general population. Integrating the CEPAC and AgeD-Pol models, we simulated two cohorts of 60-year-old male and female individuals: PWH, and the general US population. We estimated AAD incidence and AAD-associated mortality rates. Projected outcomes included AAD cumulative incidence, life expectancy, and quality-adjusted life-years (QALYs). We performed sensitivity and scenario analyses on AAD-specific (e.g. incidence) and HIV-specific (e.g. disengagement from HIV care) parameters, as well as premature aging among PWH. We projected that 22.1%/16.3% of 60-year-old male individuals/female individuals with HIV would develop AAD by 80 years compared with 15.9%/13.3% of male individuals/female individuals in the general population. Accounting for age-associated and dementia-associated quality of life, 60-year-old PWH would have a lower life expectancy (QALYs): 17.4 years (14.1 QALYs) and 16.8 years (13.4 QALYs) for male and female individuals, respectively, compared with the general population [male individuals, 21.7 years (18.4 QALYs); female individuals, 24.7 years (20.2 QALYs)]. AAD cumulative incidence was most sensitive to non-HIV-related mortality, engagement in HIV care, and AAD incidence rates. Projected estimates of AAD-associated morbidity, mortality, and quality of life can inform decision-makers and health systems planning as the population of PWH ages. Improved AAD prevention, treatment, and supportive care planning are critical for people aging with HIV.

Development and validation of the age-associated dementia policy (AgeD-Pol) computer simulation model in the USA and Europe

ObjectiveTo develop and validate a novel, microsimulation model that accounts for the prevalence and incidence of age-associated dementias (AAD), disease progression and associated mortality.Design, data sources and outcome measuresWe developed...

Primary neuron and astrocyte cultures from postnatal Callithrix jacchus: a non-human primate in vitro model for research in neuroscience, nervous system aging, and neurological diseases of aging.

The ability to generate in vitro cultures of neuronal cells has been instrumental in advancing our understanding of the nervous system. Rodent models have been the principal source of brain cells used in primary cultures for over a century, providing insights that are widely applicable to human diseases. However, therapeutic agents that showed benefit in rodent models, particularly those pertaining to aging and age-associated dementias, have frequently failed in clinical trials. This discrepancy established a potential "translational gap" between human and rodent studies that may at least partially be explained by the phylogenetic distance between rodent and primate species. Several non-human primate (NHP) species, including the common marmoset (Callithrix jacchus), have been used extensively in neuroscience research, but in contrast to rodent models, practical approaches to the generation of primary cell culture systems amenable to molecular studies that can inform in vivo studies are lacking. Marmosets are a powerful model in biomedical research and particularly in studies of aging and age-associated diseases because they exhibit an aging phenotype similar to humans. Here, we report a practical method to culture primary marmoset neurons and astrocytes from brains of medically euthanized postnatal day 0 (P0) marmoset newborns that yield highly pure primary neuron and astrocyte cultures. Primary marmoset neuron and astrocyte cultures can be generated reliably to provide a powerful NHP in vitro model in neuroscience research that may enable mechanistic studies of nervous system aging and of age-related neurodegenerative disorders. Because neuron and astrocyte cultures can be used in combination with in vivo approaches in marmosets, primary marmoset neuron and astrocyte cultures may help bridge the current translational gap between basic and clinical studies in nervous system aging and age-associated neurological diseases.

Immunomodulation for prion and prion-related diseases

Prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformational change of a normal self protein called cellular prion protein to a pathological and infectious conformer known as scrapie prion protein (PrPSc). Currently, all prion diseases lack effective treatment and are universally fatal. Past experiences with bovine spongiform encephalopathy and variant Creutzfeldt–Jakob disease mainly in Europe, as well as the current epidemic of chronic wasting disease in North America, have highlighted the need to develop prophylactic and/or therapeutic approaches. In Alzheimer’s disease that, like prion disease, is a conformational neurodegenerative disorder, both passive and active immunization has been shown to be highly effective in model animals at preventing disease and cognitive deficits, with emerging data from human trials suggesting that this approach is able to reduce amyloid-related pathology. However, any immunomodulatory approach aimed at a self-antigen has to finely balance an effective humoral immune response with potential autoimmune toxicity. The prion diseases most commonly acquired by infection typically have the alimentary tract as a portal of infectious agent entry. This makes mucosal immunization a potentially attractive method to produce a local immune response that partially or completely prevents prion entry across the gut barrier, while at the same time producing modulated systemic immunity that is unlikely to be associated with toxicity. Our results using an attenuated Salmonella vaccine strain expressing the prion protein showed that mucosal vaccination can protect against prion infection from a peripheral source, suggesting the feasibility of this approach. It is also possible to develop active and/or passive immunomodulatory approaches that more specifically target PrPSc or target the shared pathological conformer found in numerous conformational disorders. Such approaches could have a significant impact on many of the common age-associated dementias.

The Molecular Genetics of the Risk Factors of Vascular Dementias*

Secondary prevention of the age-associated dementias requires clarification of the risk factors. Vascular dementia is mainly due to cerebral hypoxic or hemorrhagic infarcts as a consequence of cerebrovascular disease. For this reason attention must be paid to the risk factors of cerebrovascular diseases. Both environmental and genetic causes determine the manifestation of these risk factors, for example, factors related to cholesterol and glucose metabolism, regulation of blood pressure and inflammatory cascades. Disturbances of genetically driven processes increase the risk of a cerebrovascular event. In this respect candidate genes and their polymorphisms need to be considered. In contrast to Alzheimer's disease, relevant molecular genetic investigations into vascular dementia are rare. For this reason research findings related to stroke and neurodegenerative dementias need to be extended and discussed with regard to their relevance in vascular dementia. Primary prevention of vascular dementia is not possible at present; secondary prevention, using both medicinal therapy and lifestyle modifications, can counteract susceptibility to the risks.

Nicotinic Acetylcholine Receptor Distribution in Alzheimer's Disease, Dementia with Lewy Bodies, Parkinson's Disease, and Vascular Dementia: In Vitro Binding Study Using 5-[125I]-A-85380

Nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of neurological disorders. 5-Iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a novel nAChR marker, binding predominantly to the alpha4beta2 subtype. This in vitro autoradiography study describes the distribution of 5-[(125)I]-A-85380 binding in post-mortem brain tissue from normal elderly individuals and from cases with age-associated dementias of both neurodegenerative and vascular types. The binding distribution of 5-[(125)I]-A-85380 in normal brain tissue was found to be consistent with the reported distribution of other high-affinity nicotinic ligands. In addition to high thalamic and moderate striatal and temporal cortex density, moderate 5-[(125)I]-A-85380 binding was also seen in white matter tracts in cingulate, occipital, and temporal areas, indicating the presence of nAChRs along nerve fiber tracts, which has not been reported in other high-affinity nicotinic agonist distribution studies. In Parkinson's disease (PD), loss of striatal 5-[(125)I]-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-[(125)I]-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimer's disease (AD) reduced striatal 5-[(125)I]-A-85380 binding could be related to reduced cortical inputs. The reductions of nAChRs seen in AD, DLB, and PD were not apparent in vascular dementia (VaD). In conclusion, 5-I-A-85380 is clearly a useful ligand for both in vitro and in vivo single photon emission tomography human studies investigating disease symptoms and progression, response to acetylcholinesterase-inhibiting drugs and in differentiating primary degenerative dementia from VaD.

Cholinergic facilitation of trace eyeblink conditioning in aging rabbits

The hippocampus is importantly involved in learning and memory, and is severely impacted by aging. In in vitro hippocampal slices, both the post-burst afterhyperpolarization (AHP) and spike-frequency accommodation are reduced in hippocampal pyramidal neurons after hippocampally-dependent trace eyeblink conditioning, indications of increased cellular excitability. The AHP results from the activation of outward potassium currents, including sI AHP and muscarinesensitive I M. The AHP is significantly increased in aging hippocampal neurons, potentially contributing to age-associated learning deficits. Compounds which reduce the AHP and spike-frequency accommodation could facilitate learning in normal aging or in age-associated dementias such as Alzheimer's disease. The cholinesterase inhibitor metrifonate enhances trace eyeblink conditioning by aging rabbits and reduces the AHP and accommodation in hippocampal CA1 neurons in a dose-dependent manner. These reductions are mediated by muscarinic cholinergic transmission as they are blocked by atropine. Hippocampal neurons from metrifonate treated but behaviorally naive rabbits were more excitable and not desensitized to the effects of metrifonate since the AHP and accommodation were further reduced when metrifonate was bath applied to the neurons. These observations suggest that the facilitating effect of chronic metrifonate on acquisition of hippocampally dependent tasks is mediated at least partially by increasing the baseline excitability of CA1 pyramidal neurons. The issue of whether learning can be facilitated with muscarinic cholinergic agonists, in addition to cholinesterase inhibitors, was addressed by training aging rabbits during intravenous treatment with the M 1 agonist CI1017. A dose-dependent enhancement of acquisition was observed, with rabbits receiving 1.0 or 5.0 mg/ml CI1017 showing comparably improved learning rates as those receiving 0.5 mg/ml or vehicle. Sympathetic side effects, mainly excess salivation, were seen with the 5.0 mg/ml dose. Post-training evaluations suggested that the effective doses of CI1017 were enhancing responsivity to the tone conditioned stimulus. These studies suggest that muscarinic cholinergic neurotransmission is importantly involved in associative learning; that learning in aging animals may be facilitated by enhancing cholinergic transmission; and that the facilitation may be mediated through actions on hippocampal neurons.

Epidemiological Dementia Index: A Screening Instrument for Alzheimer’s Disease and Other Types of Dementia Suitable for Use in Populations with Low Education Level

Introduction: MMSE and CAMCOG are neuropsychological scales developed for use in everyday clinical practice and epidemiological surveys. Material and Methods: These two instruments were used as part of the assessment during an epidemiological survey in the municipality of Pylaia, Greece. The project was based on the World Health Organization Program for Research on Aging and Age-Associated Dementias (1992). It had two phases. During phase I, nursing students collected demographic data, risk factors, personal and family history data and they applied MMSE, CAMCOG and scales of everyday life functioning. During phase II, 4 physicians examined all subjects that manifested possible cognitive deterioration (MMSE<27), in order to reach a final diagnosis. The final diagnosis was made according to DSM-IV and NINCDS-ADRDA criteria. MMSE and CAMCOG were not taken into consideration in the diagnostic process. Three hundred and eighty subjects were initially screened. All were aged over 70 years. After the exclusion of subjects who were illiterate, blind, etc., the results of 277 subjects were finally analyzed. Subjects with 6 years of education or less accounted for 92.42% of the total study sample. Twelve of them (5.33%) suffered from Alzheimer’s disease, 7 from vascular dementia (2.52%) and 1 suffered from secondary dementia (0.36%). Results: MMSE exceeded 90% sensitivity at the level 22/23 and specificity at 14/15. The levels for CAMCOG were 56/57 and 43/44, respectively. This low performance of both tests is to a large extent due to the functional illiteracy of elderly individuals in Greece, to possible coexistence of mood disorders or simply to lack of cooperation. The analysis of data led to the development of an Epidemiological Dementia Index (EDI), with a scale ranging from 0 to 7. Nondemented subjects had a mean EDI of 5.12 (SD = 1.67) and demented patients had a mean EDI of 1.6 (SD = 1.92). At the level 4/5 sensitivity was 93.33. Specificity was 93.56 at the level 2/3.

Epidemiology of dementias.

The increasing and widespread interest in age-associated dementias originated because of the rapid aging of the world population. Considering the rapid demographic changes and current epidemiologic data indicating a steep increase in the frequency of dementia with advancing age, several authors have introduced the concept of an "epidemic of dementia". Epidemiological research gives the opportunity to provide both scientific data and background information for health policy makers. Information concerning the frequency of dementias, their geographical distribution, as well as related disability, is an essential requirement for cost-effective planning of health care services. At the same time, data from population-based surveys, and in particular from cross-national studies, may give clues to the etiology, diagnosis and treatment of the dementias.

Drug treatment of cognitive impairment and emotional disturbances in the elderly

Disorders with cognitive impairment in the elderly are age-associated memory impairment, pseudodementias, secondary dementias, vascular dementias, and primary dementias. Pharmacological treatment strategies concern the use of vasodilators, nootropics, acetylcholinergie drugs, monoaminergic drugs, neuropeptides and neuropeptide-like drugs, vitamin B12 substitution, ganglioside GM1, phosphatidylserine, and acetyl-I-carnitine. On the whole, drugs with vasodilator effects were unsuccessful in the past. However, new drugs have been introduced which also enhance the metabolism in the neurons. These drugs, the nootropics, often combine a vasodilator effect with the activation of brain metabolism and the protection of the brain from toxic effects. However, effects of nootropics have mainly been demonstrated in animal experiments. Acetylcholinergic drugs have attracted great interest in dementia treatment, but altogether the trials with these drugs have shown disappointing results. Studies of drugs affecting monoa...

The World Health Organization cross-national research program on age-associated dementias

The World Health Organization cross-national research program on age-associated dementias

Autoimmune mice as models for discovery of drugs against age‐related dementia

AbstractThe discovery and development of drugs to treat Alzheimer's disease and other age‐associated dementias constitute an important goal of research in the pharmaceutical industry. Suitable animal models are routinely sought to expedite the discovery and development processes. The current review proposes new animal models based upon research findings from both clinical and animal investigations which suggest a neuroimmunologic component in certain age‐associated dementias. Several clinical studies are discussed which suggest associations between dementia and brain‐reactive autoantibodies in patients with Alzheimer's disease. In addition, studies of mice suggest that neuroimmunological, neuropathological, and behavioral characteristics of aging are accelerated in genetically autoimmune‐prone mice. The learning and memory deficits of autoimmune mice are qualitatively similar to those of normal aged mice, and these deficits show similar sensitivity to pharmacologic interventions involving cholinergic and GABNbenzodiazepine systems. However, the appearance and progression of these changes with age occur more rapidly and with greater reliability in the autoimmune mice when compared with non‐autoimmune strains. The studies reviewed suggest that autoimmune mice may provide a useful animal model for identification and evaluation of new drugs against learning and memory dysfunctions. In addition, the accelerated decline of learning/memory in autoimmune mice may expedite evaluation of chemical interventions designed to prevent the occurrence or arrest the progress of Alzheimer's disease and other age‐associated dementias. The autoimmune models may be especially appropriate in identifying novel drugs with the immune system as a primary target.

Animal models of age-related dementia: neurobehavioral dysfunctions in autoimmune mice

The development of strategies for treatment of Alzheimer's disease and other age-associated dementias is an important goal of research in the neurosciences. It is suggested that advances in understanding of the etiology of those disorders would provide the most obvious avenues to development of preventative treatments. Research findings from both clinical investigations and studies of animal models are presented which suggest a neuroimmunologic component in age-associated dementia. Clinical studies suggest an association between dementia and brain-reactive autoantibodies in subsets of patients with Alzheimer's disease. Studies of mice suggest that: 1. 1) when compared with normal genotypes, mutant mice with accelerated autoimmunity show learning and memory impairments at earlier chronological ages 2. 2) the learning and memory deficits of autoimmune and normal mice are qualitatively similar 3. 3) the behavioral deficits of normal aged and autoimmune mice are sensitive to similar Pharmacologic interventions. Overall, these findings suggest that intervention strategies targeting the immune system might be useful in the treatment or prevention of aging-associated dementia. Autoimmune mice would be useful as models for the development and testing of such immune-based interventions.