Clinical Expression Of Dementia Research Articles

The impact of aging in dementia: It is time to refocus attention on the main risk factor of dementia

Alzheimer’s disease (AD) represents the most common form of dementia among old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved, and no cure is available. The amyloid hypothesis has been recently questioned due to the failure of amyloid-centered treatments. The fact that cognitively normal old age subjects have substantial amyloid deposition in the brain comparable to the levels observed in AD patients suggests that amyloid accumulation may enter into the normal process of aging and what really triggers neuronal death and clinical manifestation is the loss of function due to an energetic failure. With this viewpoint article, we aim to challenge the traditional view of amyloid as the leading cause of AD. Conversely, we propose the core feature of aging, that is the progressive brain energy decline, as the main risk factor for dementia in older persons. Thus, a bioenergetic deficit secondary to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. The optimization of brain energetics should become a key component in future strategies for preventing and treating dementia.

Cognitive Reserve in Midlife is not Associated with Amyloid-β Deposition in Late-Life.

We examined associations between cognitive reserve and late-life amyloid-β deposition using florbetapir positron emission tomography (PET). We used data from the Atherosclerosis Risk in Communities (ARIC) and ARIC-PET Study. 330 dementia-free participants underwent PET scans. Mean global cortical standardized uptake value ratio (SUVR) >1.2 was defined as elevated. Midlife cognition was significantly associated with late-life cognition, but not with late-life elevated SUVR; education was not associated with late-life SUVR, but was strongly associated with late-life cognition. Cognitive reserve may reduce dementia risk by mitigating the impact of Alzheimer's disease pathology on the clinical expression of dementia, rather than by altering its pathogenesis.

Brain Aging and Late-Onset Alzheimer's Disease: A Matter of Increased Amyloid or Reduced Energy?

Alzheimer's disease (AD) represents the most common form of dementia in old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved. The definition of AD has changed over the past years, offering an ever more detailed definition of pre-morbid and pre-clinical status, but without a similar strong emphasis on the role of aging as the main risk factor. In fact, while early-onset AD is a clear consequence of gene mutations, late-onset AD is more likely due to a gradual accumulation of age-related damages. The pathogenetic amyloid cascade hypothesis has been recently questioned due to multiple clinical failures. Furthermore, several studies reported that cognitively normal elderly have a high amyloid deposition in the brain comparable to the levels observed in old age subjects with AD. This suggests that amyloid accumulation enters into the normal process of aging and what really triggers neuronal death and clinical manifestation in late-onset AD still needs further explanation. In this context, 'normal brain aging' and AD might represent a different pathway of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes affecting the brain may be considered as biologic manifestations of increasing entropy. Bioenergetic deficits due to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. So, increased amyloid in the brain of old age subjects may represent the downstream event expression of a biological system that is cooling down because of its exhaustion and not the core causative factor of late-onset dementia.

Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: a post mortem study.

The association between the pathological features of AD and dementia is stronger in younger old persons than in older old persons suggesting that additional factors are involved in the clinical expression of dementia in the oldest old. Cumulative data suggests that neuroinflammation plays a prominent role in Alzheimer's disease (AD) and different studies reported an age-associated dysregulation of the neuroimmune system. Consequently, we sought to characterize the pattern of microglial cell activation and astrogliosis in brain post mortem tissue of pathologically confirmed cases of early and late onset AD (EOAD and LOAD) and determine their relation to age. Immunohistochemistry (CD68 and glial fibrillary acidic protein) with morphometric analysis of astroglial profiles in 36 cases of AD and 28 similarly aged controls. Both EOAD and LOAD groups had higher microglial scores in CA1, entorhinal and temporal cortices, and higher astroglial response in CA1, dentate gyrus, entorhinal and temporal cortices, compared to aged matched controls. Additionally, EOAD had higher microglial scores in subiculum, entorhinal and temporal subcortical white matter, and LOAD higher astrogliosis in CA2 region. Overall, we found that the neuroinflammatory pathological markers in late stage AD human tissue to have a similar pattern in both EOAD and LOAD, though the severity of the pathological markers in the younger group was higher. Understanding the age effect in AD will be important when testing modifying agents that act on the neuroinflammation.

Contribution of cognitive performance and cognitive decline to associations between socioeconomic factors and dementia: A cohort study.

BackgroundSocioeconomic disadvantage is a risk factor for dementia, but longitudinal studies suggest that it does not affect the rate of cognitive decline. Our objective is to understand the manner in which socioeconomic disadvantage shapes dementia risk by examining its associations with midlife cognitive performance and cognitive decline from midlife to old age, including cognitive decline trajectories in those with dementia.Methods and findingsData are drawn from the Whitehall II study (N = 10,308 at study recruitment in 1985), with cognitive function assessed at 4 waves (1997, 2002, 2007, and 2012). Sociodemographic, behavioural, and cardiometabolic risk factors from 1985 and chronic conditions until the end of follow-up in 2015 (N dementia/total = 320/9,938) allowed the use of inverse probability weighting to take into account data missing because of loss to follow-up between the study recruitment in 1985 and the introduction of cognitive tests to the study in 1997. Generalized estimating equations and Cox regression were used to assess associations of socioeconomic markers (height, education, and midlife occupation categorized as low, intermediate, and high to represent hierarchy in the socioeconomic marker) with cognitive performance, cognitive decline, and dementia (N dementia/total = 195/7,499). In those with dementia, we examined whether retrospective trajectories of cognitive decline (backward timescale) over 18 years prior to diagnosis differed as a function of socioeconomic markers. Socioeconomic disadvantage was associated with poorer cognitive performance (all p < 0.001). Using point estimates for the effect of age, the differences between the high and low socioeconomic groups corresponded to an age effect of 4, 15, and 26 years, for height, education, and midlife occupation, respectively. There was no evidence of faster cognitive decline in socioeconomically disadvantaged groups. Low occupation, but not height or education, was associated with risk of dementia (hazard ratio [HR] = 2.03 [95% confidence interval (CI) 1.23–3.36]) in an analysis adjusted for sociodemographic factors; the excess risk was unchanged after adjustment for cognitive decline but was completely attenuated after adjustment for cognitive performance. In further analyses restricted to those with dementia, retrospective cognitive trajectories over 18 years prior to dementia diagnosis showed faster cognitive decline in the high education (p = 0.006) and occupation (p = 0.001) groups such that large differences in cognitive performance in midlife were attenuated at dementia diagnosis. A major limitation of our study is the use of electronic health records rather than comprehensive dementia ascertainment.ConclusionsOur results support the passive or threshold cognitive reserve hypothesis, in that high cognitive reserve is associated with lower risk for dementia because of its association with cognitive performance, which provides a buffer against clinical expression of dementia.

The role of different languages and cultures in dementia

With the rising numbers of persons with dementia globally, the focus of research has shifted towards understanding potentially protective factors that may reduce its risk or delay its onset. Several lifetime experiences such as education, occupational complexity, social engagement and other cognitively stimulating activities are considered to improve cognitive reserve and enhance ability to withstand effects of disease pathologies. These factors are however known to vary widely between different countries and cultures. Recent evidence also suggests that the ability to speak more than one language (bilingualism) has a significant role to play in facilitating cognitive reserve. While several studies reported a delay in the onset of dementia in bilinguals, others found no effect or an effect confined to parts of the examined population, making this a topic of recent debate. In this talk, the role of different cultural and lifetime experiences such as bilingualism, education and occupation with respect to their potentially protective effects on dementia will be discussed, with particular reference to the context of India, a developing country. The mechanisms underlying this association will be discussed in a range of cognitive disorders, including Alzheimer’s disease, Frontotemporal dementia, stroke and mild cognitive impairment. In the background of a wide degree of sociocultural, educational and lingusitic mileau that exists globally, the role of these factors in clinical expression of dementia is likely to be significant.

Clinical-pathologic correlations in vascular cognitive impairment and dementia

The most common causes of cognitive impairment and dementia are Alzheimer's disease (AD) and vascular brain injury (VBI), either independently, in combination, or in conjunction with other neurodegenerative disorders. The contribution of VBI to cognitive impairment and dementia, particularly in the context of AD pathology, has been examined extensively yet remains difficult to characterize due to conflicting results. Describing the relative contribution and mechanisms of VBI in dementia is important because of the profound impact of dementia on individuals, caregivers, families, and society, particularly the stability of health care systems with the rapidly increasing age of our population. Here we discuss relationships between pathologic processes of VBI and clinical expression of dementia, specific subtypes of VBI including microvascular brain injury, and what is currently known regarding contributions of VBI to the development and pathogenesis of the dementia syndrome. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

A life-course study of cognitive reserve in dementia: Dementia incidence in inpatient registers and mmse test scores in a clinical study in sweden

Cognitive reserve helps mitigate the impact of pathology on the clinical expression of dementia. Education and occupational complexity are considered as contributors to reserve, although it has been argued that cognitive reserve is likely formed over the life-course. A life-course model of cognitive reserve in dementia risk has not yet been tested. We apply a life-course model and examine if school grades around age 10, formal educational attainment, and lifetime occupational complexity affect dementia incidence in inpatient registers.

O3-4.4 How does education affect associations between neuropathology and clinical dementia?

Almost everyone who dies in old age has some pathology in their brain at death, but does not necessarily die with dementia. Cognitive reserve factors such as education are thought to protect (“neuroprotection”) or provide resilience (“compensation”) against dementia-related pathology. We investigated the neuroprotection and compensation hypotheses in a large population-based cohort study (Epidemiological Clinicopathological Studies in Europe; EClipSE). EClipSE has harmonised longitudinal clinical data and neuropathology from three longstanding population-based studies that included post-mortem brain donation. These three studies started between 1985 and 1991. Number of years of education during earlier life was recorded at baseline in each study. Incident dementia was detected through follow-up interviews, complemented by retrospective informant interviews, death certificate data and linked health / social records (dependent on study) after death. Dementia-related neuropathologies were assessed in each study in a comparable manner based on the CERAD protocol. Eight hundred and seventy-two brain donors were included of whom 56% were demented at death. Longer years in education were associated with decreased dementia risk and greater brain weight but had no relationship with the burden of neurodegenerative or vascular pathologies. The associations between neuropathological variables and clinical dementia differed according to the “dose” of education such that more education reduced dementia risk largely independently of severity of pathology. In conclusion, more education in early life did not protect individuals from developing neurodegenerative and vascular neuropathology by the time they died but it did appear to mitigate the impact of pathology on the clinical expression of dementia before death.

Alzheimer's pathology, mixed pathologies and the clinical expression of dementia in the old and the oldest old

Recent studies have come to conflicting conclusions as to whether the relationship of Alzheimer's disease (AD) pathology and clinical dementia is the same in the oldest old as it is for persons below the age of 90. Most of these studies have not incorporated data on mixed pathologies. We assessed clinical and neuropathologic data from 638 persons aged 65-106 at death from the Rush Memory and Aging Project and the Religious Orders Study, two longitudinal studies of aging and dementia. Persons were evaluated on average 6 months prior to death using standard criteria for dementia. Brains were evaluated for a pathologic diagnosis of AD (NIA-Reagan criteria), Lewy bodies (LB) and infarcts, and whether they had one or mixed pathologies. We investigated the relationship of single and mixed pathologies and clinical dementia prior to death in persons age 90 and over compared to persons under age 90. We used logistic regression models adjusted for sex and education to test whether age at death modified the effect of pathology on the odds of dementia. There were 225 persons age 90 and over at death (mean = 94.1, SD = 3.1) and 413 persons under age 90 (mean = 83.5, SD = 4.9). The frequency of AD pathology and infarcts was higher in the oldest old compared to younger old (AD: 71.1% vs. 52.8%, p < 0.001; infarcts: 40.7% vs. 27.5%, p < 0.001). There was no significant difference between the two age groups for Lewy bodies (21.3% vs. 16.4%, p = 0.099). Mixed pathologies were present in 42.2% of the oldest-old compared to 23.1% of the old (p < 0.001). Both AD and mixed pathologies independently increased the odds of dementia in both the old and oldest old (all p-values <0.001). There was no difference in the relationship of AD or mixed pathologies to dementia in the oldest old compared to the younger old (p>0.2 for all interactions). The frequency of mixed pathologies increase with age. AD pathology, LB and infarcts all individually and in combination increase the odds of dementia in both younger and older elders. AD pathology has the same effect on clinical dementia in the old and oldest old when accounting for other pathologies.

Education, the brain and dementia: neuroprotection or compensation?

The potential protective role of education for dementia is an area of major interest. Almost all older people have some pathology in their brain at death but have not necessarily died with dementia. We have explored these two observations in large population-based cohort studies (Epidemiological Clinicopathological Studies in Europe; EClipSE) in an investigation of the relationships of brain pathology at death, clinical dementia and time in education, testing the hypothesis that greater exposure to education reduces the risk of dementia. EClipSE has harmonized longitudinal clinical data and neuropathology from three longstanding population-based studies that included post-mortem brain donation. These three studies started between 1985 and 1991. Number of years of education during earlier life was recorded at baseline. Incident dementia was detected through follow-up interviews, complemented by retrospective informant interviews, death certificate data and linked health/social records (dependent on study) after death. Dementia-related neuropathologies were assessed in each study in a comparable manner based on the Consortium to Establish a Registry for Alzheimer's Disease protocol. Eight hundred and seventy-two brain donors were included, of whom 56% were demented at death. Longer years in education were associated with decreased dementia risk and greater brain weight but had no relationship to neurodegenerative or vascular pathologies. The associations between neuropathological variables and clinical dementia differed according to the 'dose' of education such that more education reduced dementia risk largely independently of severity of pathology. More education did not protect individuals from developing neurodegenerative and vascular neuropathology by the time they died but it did appear to mitigate the impact of pathology on the clinical expression of dementia before death. The findings suggest that an understanding of the mechanisms leading to functional protection in the presence of pathology may be of considerable value to society.

Association between cardiovascular disease and dementia.

Longitudinal studies have shown association between cardiovascular risk factors and dementia. However, these studies are not capable of detecting asymptomatic cardiovascular alterations and thus may provide erroneous estimates of association. Autopsy studies could be more useful in elucidating these questions. The present clinicopathological study sought to examine the relationship between dementia, cardiovascular risk factors and disease.Methods603 subjects, who underwent autopsy, were classified regarding the presence of dementia, according to post mortem cognitive classification. Demographics, cardiovascular risk factors, and anatomically-proven cardiovascular disease (myocardial hypertrophy, cerebral and carotid atherosclerosis) were compared among cognitively normal persons and individuals with dementia.ResultsCognitive deficit was associated with advanced age, stroke, physical inactivity and low body mass index (p< 0.05). Circle of Willis atherosclerosis was greater in patients with dementia than in controls on univariate analysis (p=0.01). However, this association lost significance when adjusted by age and gender (p=0.61). Heart failure and anatomopathological cardiac parameters were more severe in the control group than in demented individuals (p< 0.05). Carotid artery atherosclerosis and intima-media thickness were similar in both groups.ConclusionAdvanced age, stroke, physical inactivity and low body mass index were linked to dementia. Circle of Willis atherosclerosis was associated with dementia only when age was not considered. Our results suggest that cerebral artery atherosclerosis was not directly associated with clinical expression of dementia.

Time Will Be of the Essence in Treating Alzheimer Disease

BackgroundDecreased cerebrospinal fluid (CSF) β-amyloid 42 (Aβ42) concentration, but not Aβ40 concentration, is a biomarker for Alzheimer disease. This Aβ42 concentration decrease in CSF likely reflects precipitation of Aβ42 in amyloid plaques in brain parenchyma. This pathogenic plaque deposition begins years before the clinical expression of dementia in Alzheimer disease. Normal aging and the presence of the apolipoprotein E (APOE*4) allele are the most important known risk factors for Alzheimer disease.ObjectiveTo estimate the interactive effects of normal aging and presence of the APOE*4 allele on CSF Aβ42 concentration in adults with normal cognition across the life span.DesignThe CSF was collected in the morning after an overnight fast using Sprotte 24-g atraumatic spinal needles. The CSF Aβ42 and Aβ40 concentrations were measured in the 10th milliliter of CSF collected by sandwich enzyme-linked immunosorbent assay. The APOE genotype was determined by a restriction digest method.SubjectsOne hundred eighty-four community volunteers with normal cognition aged 21 to 88 years.ResultsThe CSF Aβ42, but not the Aβ40, concentration decreased significantly with age. There was a sharp decrease in CSF Aβ42 concentration beginning in the sixth decade in subjects with the APOE*4 allele. This age-associated decrease in CSF Aβ42 concentration was significantly and substantially greater in subjects with the APOE*4 allele compared with those without the APOE*4 allele.ConclusionsThese CSF Aβ42 findings are consistent with acceleration by the APOE*4 allele of pathogenic Aβ42 brain deposition starting in later middle age in persons with normal cognition.

Age and Apolipoprotein E*4 Allele Effects on Cerebrospinal Fluid β-Amyloid 42 in Adults With Normal Cognition

Decreased cerebrospinal fluid (CSF) beta-amyloid 42 (A beta 42) concentration, but not A beta 40 concentration, is a biomarker for Alzheimer disease. This A beta 42 concentration decrease in CSF likely reflects precipitation of A beta 42 in amyloid plaques in brain parenchyma. This pathogenic plaque deposition begins years before the clinical expression of dementia in Alzheimer disease. Normal aging and the presence of the apolipoprotein E (APOE*4) allele are the most important known risk factors for Alzheimer disease. To estimate the interactive effects of normal aging and presence of the APOE*4 allele on CSF A beta 42 concentration in adults with normal cognition across the life span. The CSF was collected in the morning after an overnight fast using Sprotte 24-g atraumatic spinal needles. The CSF A beta 42 and A beta 40 concentrations were measured in the 10th milliliter of CSF collected by sandwich enzyme-linked immunosorbent assay. The APOE genotype was determined by a restriction digest method. Subjects One hundred eighty-four community volunteers with normal cognition aged 21 to 88 years. The CSF A beta 42, but not the A beta 40, concentration decreased significantly with age. There was a sharp decrease in CSF A beta 42 concentration beginning in the sixth decade in subjects with the APOE*4 allele. This age-associated decrease in CSF A beta 42 concentration was significantly and substantially greater in subjects with the APOE*4 allele compared with those without the APOE*4 allele. These CSF A beta 42 findings are consistent with acceleration by the APOE*4 allele of pathogenic A beta 42 brain deposition starting in later middle age in persons with normal cognition.

Visual memory predicts Alzheimer's disease more than a decade before diagnosis.

Recent studies have suggested that AD may reflect a chronic process that begins many years before the clinical expression of dementia. The current study examines premorbid Benton Visual Retention Test (BVRT) and Wechsler Adult Intelligence Scale-vocabulary (WAIS-voc) test scores in order to determine whether long-term deficits in these tests can predict the development of AD decades later in the Baltimore Longitudinal Study of Aging (BLSA). Participants are volunteers from the BLSA, a multidisciplinary study of normal aging conducted by the National Institute on Aging. A total of 1,425 BLSA participants who were older than 60 years were included in the analyses. Cox proportional hazards models were used to estimate the relative risk of developing AD associated with BVRT and WAIS-voc scores at different time periods up to 20 years before the diagnosis of AD. The relative risks for 6 or more BVRT errors vs less than 6 errors at 1 to 3, 3 to 5, 5 to 10, and 10 to 15 years before the diagnosis of AD were 5.69, 2.11, 1.76, and 1.83 (p < 0.05). The relative risk for 15 or more years before diagnosis was not significant (p > 0.10). WAIS-voc scores were not significantly associated with the risk of AD in any time period. A greater number of errors on the BVRT is associated with an increased risk of AD up to 15 years later. Poor visual memory performance may represent an early expression of AD years before diagnosis. This result suggests the need to continue to revise views on the natural history of AD and the possibility of an increased window of opportunity for preventive treatment before definitive diagnosis.

Alzheimer's disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities.

Alzheimer's disease (AD) can be diagnosed with a considerable degree of accuracy. In some centers, clinical diagnosis predicts the autopsy diagnosis with 90% certainty in series reported from academic centers. The characteristic histopathologic changes at autopsy include neurofibrillary tangles, neuritic plaques, neuronal loss, and amyloid angiopathy. Mutations on chromosomes 21, 14, and 1 cause familial AD. Risk factors for AD include advanced age, lower intelligence, small head size, and history of head trauma; female gender may confer additional risks. Susceptibility genes do not cause the disease by themselves but, in combination with other genes or epigenetic factors, modulate the age of onset and increase the probability of developing AD. Among several putative susceptibility genes (on chromosomes 19, 12, and 6), the role of apolipoprotein E (ApoE) on chromosome 19 has been repeatedly confirmed. Protective factors include ApoE-2 genotype, history of estrogen replacement therapy in postmenopausal women, higher educational level, and history of use of nonsteroidal anti-inflammatory agents. The most proximal brain events associated with the clinical expression of dementia are progressive neuronal dysfunction and loss of neurons in specific regions of the brain. Although the cascade of antecedent events leading to the final common path of neurodegeneration must be determined in greater detail, the accumulation of stable amyloid is increasingly widely accepted as a central pathogenetic event. All mutations known to cause AD increase the production of beta-amyloid peptide. This protein is derived from amyloid precursor protein and, when aggregated in a beta-pleated sheet configuration, is neurotoxic and forms the core of neuritic plaques. Nerve cell loss in selected nuclei leads to neurochemical deficiencies, and the combination of neuronal loss and neurotransmitter deficits leads to the appearance of the dementia syndrome. The destructive aspects include neurochemical deficits that disrupt cell-to-cell communications, abnormal synthesis and accumulation of cytoskeletal proteins (e.g., tau), loss of synapses, pruning of dendrites, damage through oxidative metabolism, and cell death. The concepts of cognitive reserve and symptom thresholds may explain the effects of education, intelligence, and brain size on the occurrence and timing of AD symptoms. Advances in understanding the pathogenetic cascade of events that characterize AD provide a framework for early detection and therapeutic interventions, including transmitter replacement therapies, antioxidants, anti-inflammatory agents, estrogens, nerve growth factor, and drugs that prevent amyloid formation in the brain.

Syndrome démentiel et pathologies intercurrentes chez les sujets âgés. Étude de 100 patients de plus de 75 ans en Unité de Médecine Interne Gériatrique

Elderly people with dementia are admitted in ever increasing number to Internal Medicine units for exploration of dementia and treatment of intercurrent diseases. The purpose of this prospective study of 100 demential subjects aged 75 or more (mean: 85.3 +/- 5.4 years) was to discover the cause of dementia, to investigate the associated diseases and to evaluate the effects of treatment of these pathologies on the patients' cognitive performance. The mean duration of stay in hospital was 25.5 +/- 14.5 days (extreme: 6-100 days); 69 returned home, 17 were institutionalized and 14 died. Dementia was degenerative and of the Alzheimer type (73%) with vascular lesions (24%) associated with brain tumours (2%) or normal-pressure hydrocephalus (1%). On average, 2 pathologies were associated with Alzheimer's dementia and 3.5 with dementia cum vascular brain lesions. Repeated evaluation of cognitive performance was carried out using Folster's Mini Mental Status (MMS), a global evaluation test. It showed that 18% of the patients were significantly improved while the other diseases were being treated. The hypothesis of regressive confusional elements superimposed on dementia is accepted by the authors as it fits the model of geriatric multipathology morbidity. Since there is no specific treatment for most types of dementia, particular attention must be paid to associated diseases likely to aggravate the clinical expression of dementia.