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Nutrition et démence chez les personnes âgées

Nutrition et démence chez les personnes âgées

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Nutrition et démence chez les personnes âgées

Conférencière : Carol Greenwood, Ph. D., professeure, département des sciences de la nutrition, Université de Toronto; chercheuse titulaire, unité de recherche appliquée Kunin-Lunenfeld, Baycrest Centre, Toronto (Ontario).

La Dre Greenwood a placé le thème de sa discussion sur la nutrition et la démence dans le contexte des considérations sur les influences environnementales constituant un risque de déclin cognitif et de démence. Même si la démence a d’importantes racines génétiques, les facteurs environnementaux jouent un rôle important dans son étiologie. Selon certaines études, ces facteurs sont associés à environ 60 % des cas de démence survenant après l’âge de 80 ans.

Habitudes alimentaires augmentant le risque de déclin cognitif
Pour bien comprendre le risque posé par les facteurs environnementaux, la Dre Greenwood a recommandé à ses auditeurs de porter attention au régime alimentaire sur une longue durée plutôt qu’à des cas particuliers d’apports alimentaires, bons ou mauvais. La connexion entre nutrition et démence repose sur l’idée sous-jacente que les neurones ont besoin d’apports nutritifs. Des changements nutritionnels entraînent des modifications du métabolisme neuronal. Une alimentation saine garantit la signalisation de l’insuline dans le cerveau, nécessaire à l’apprentissage et à la mémoire. Les cliniciens doivent encourager des habitudes alimentaires propres à maintenir les concentrations cérébrales de neurotrophines nécessaires à la plasticité synaptique impliquée dans la consolidation de la mémoire; de plus, une bonne alimentation et des apports nutritifs appropriés peuvent réduire l’inflammation et le stress oxydatif, et maintenir la capacité de la circulation cérébrale à fournir les nutriments essentiels au cerveau.

Des progrès dans ce domaine de recherche permettraient de contrer l‘isolationnisme qui marque parfois la perception des maladies chroniques. Le cerveau est fortement subordonné à la santé de l’organisme tout entier et une modification de l’alimentation peut exercer une influence directe sur des mala- dies liées au régime alimentaire, comme les maladies cardiovasculaires (MCV), le diabète de type 2 et la dépression.

De nombreuses études épidé-miologiques sur l’alimentation sont disponibles et indiquent qu’un apport calorique excessif engendre un stress oxydatif. La Dre Greenwood et ses collègues se sont penchés sur le rôle des apports en graisses. Un apport élevé en graisses, surtout saturées et polyinsaturées, accompagné d’un déficit en graisses oméga, est typique de l’alimentation nord-américaine. Des études ont montré que les régimes alimentaires faibles en fruits, en légumes, en céréales complètes et en huiles de poisson sont associés à un risque plus élevé de démence. Ce régime est également associé aux MCV, au diabète, à la dépression et à d’autres états pathologiques inflammatoires et chroniques. Les effets indésirables sur le cerveau ne sont pas simples, et il est probable que des mécanismes multiples sont impliqués; dissocier le rôle de la maladie chronique d’un impact direct sur la fonction cérébrale risque de donner une fausse idée de ces effets.

Les huiles de poisson constituent un bon exemple de la façon dont un nutriment particulier peut intervenir sur des voies neuronales multiples. Les études portant sur les huiles de poisson et le risque de démence ont eu du mal à isoler le rôle propre de ces huiles parce que, comme tous les nutriments, celles-ci ont de multiples effets sur l’organisme. Comme les graisses oméga font partie des recommandations alimentaires, la distinction entre le rôle soi-disant phy-siologique du nutriment et son rôle pharmacologique s’estompe. L’incorporation de graisses oméga dans un régime alimentaire holistique est une bonne approche, qui « stimule » le système. L’autre approche compte sur un impact pharmacologique important avec une stratégie de type « cibler et isoler » grâce à des suppléments alimentaires et un enrichissement nutritionnel (comme les œufs). Mais une telle approche néglige d’autres propriétés très précieuses des protéines de poisson.

De la même façon, des recherches sur les avantages cliniques associés à une exposition altérée aux antioxydants ont isolé des micronutriments et les ont fournis sous forme de suppléments alimentaires, ce qui a abouti à des données ambiguës. Cependant, on ne peut pas extrapoler les effets de cette consommation à ceux d’un régime alimentaire incorporant des micronutriments sur la base d’un apport nutritif mesuré en grammes par jour. L’approche ciblée oublie également que le cocktail nutritif complet est plus important (p. ex. : aspect synergique) que la consommation de chaque composé séparément. Les constituants alimentaires fonctionnent en bloc.

Il existe des enjeux pressants étant donnés les changements des marqueurs de santé à l’échelle de la population tout entière. Les personnes présentant une adiposité centrale (associée au développement du syndrome métabolique) sont des « bombes à retardement » de comorbidités. Les résultats de nouvelles études indiquent que l’obésité centrale autour de la cinquantaine augmente le risque de démence, indépendamment des comorbidités diabétiques et cardiovasculaires; les sujets présentant le degré le plus important d’obésité centrale triplent leur risque de déclin cognitif1.

Le régime alimentaire méditerranéen

L’approche clinique de tels patients doit inclure un changement d’habitudes alimentaires, et les données probantes proviennent principalement du régime méditerranéen (Figure 1). Les effets bénéfiques sont directement liés à l’augmentation des apports en fruits, en légumes et en poisson, et à la réduction de la consommation de viande rouge. De récentes données en faveur de cette approche ont été fournies par une étude prospective de 2 258 sujets non atteints de démence en milieu communautaire à New York; mieux le régime méditerranéen était suivi, plus le risque de maladie d’Alzheimer (MA) était faible2.

Le rôle du contrôle glycémique et du diabète de type 2
De plus en plus de données scientifiques laissent entendre que le diabète est en soi un facteur de risque de déclin cognitif, ce qui nécessite un contrôle glycémique draconien chez les patients hyperglycémiques.

Des études animales ont apporté des preuves de l’interrelation entre contrôle glycémique et démence, et la Dre Greenwood et ses collègues ont examiné l’effet des habitudes alimentaires typiquement nord-américaines sur la performance cognitive du rat, particulièrement sur l’apprentissage et la mémoire. Les bais-ses de performance étaient clairement associées à une consommation riche en graisses saturées : les rats soumis à ce régime étaient plus susceptibles d’avoir des performances aléatoires lors des tests.

Il reste à identifier quels aspects du régime riche en graisses saturées nuisent à la fonction cognitive, et à démêler ces effets de ceux du diabète. La Dre Greenwood a mentionné des études présentant les résultats d’une évaluation neuropsychiatrique habituelle de personnes âgées hyperglycémiques, qui examinait plus particulièrement la mémoire immédiate et différée (cette dernière faisant appel à la fonction hippocampique). Les résultats montrent que les personnes les plus insensibles à l’insuline réalisent la moins bonne performance. Avec l’âge, la perte de sensibilité à l’insuline est liée à une détérioration de la mémoire.

Maladie chronique et risque accru de démence
Les recherches actuelles indiquent de plus que la résistance à l’insuline peut excéder les effets de la consommation de graisses sur le déclin cognitif. Des études récentes s’appuyant sur l’imagerie structurelle éclairent la relation entre diabète et cognition. Une étude examinant la perte de la fonction hippocampique chez des sujets âgés non encore diagnostiqués pour un diabète de type 2, mais dont le contrôle glycémique est défaillant, a trouvé qu’un très mauvais contrôle glycémique était fortement associé à une atrophie hippocampique. De tels effets sont évidents chez les personnes dont le diabète est bien maîtrisé; à mesure que le diabète perdure et que les sujets perdent le contrôle métabolique et développent une hyper-cholestérolémie et une hypertension, l’atrophie se propage dans le cerveau et des lésions de la substance blanche se manifestent. Ce sont les composantes vasculaires du diabète, qui apparaissent plus tard au cours de l’évolution de la maladie.

La voie de signalisation de l’insuline est nécessaire à la mémorisation

La Dre Greenwood a fait observer que, bien que le cerveau ne soit généralement pas considéré comme un organe sensible à l’insuline, la densité cérébrale de récepteurs de l’insuline est élevée, et les voies de signalisation de l’insuline jouent un rôle intégral dans la consolidation de la mémoire. Ces voies sont perturbées chez les diabétiques. De telles associations avec les voies de signalisation de l’insuline sont importantes et peuvent expliquer les mauvaises performances de mémoire des personnes diabétiques par rapport à des non-diabétiques d’âge apparié, mais ce n’est pas une preuve irréfutable d’une contribution du diabète à la pathologie de la démence.

La Dre Greenwood a suggéré qu’une perturbation des voies de signalisation de l’insuline contribue sûrement à cette pathologie. L’enzyme de dégradation de l’insuline est l’enzyme clé impliquée dans la dégradation du peptide Ab, qui favorise le développement des plaques de la ma-ladie d’Alzheimer. Cette enzyme est régulée à la baisse dans le cerveau des diabétiques, ce qui ralentit la dégradation du peptide Ab. De plus, de fortes concentrations périphériques d’Ab entravent l’exportation d’Ab, et constituent donc un risque élevé d’accumulation du peptide Ab. Les diabétiques présentent également des niveaux élevés de cytokines inflammatoires, engendrant une accumulation pathologique du peptide Ab et des réponses inflammatoires correspondantes. La cascade inflammatoire du peptide Ab favorise la formation de plaques.

Des études portant sur des sujets au diabète bien maîtrisé, mais porteurs d’un polymorphisme génétique au niveau du gène codant pour le facteur de nécrose des tumeurs (TNFa), corroborent cette idée. Ces individus sont moins à même de fabriquer le TNFa et de déclencher des réponses inflammatoires. Les porteurs de SNP (polymorphisme nucléotidique) obtenaient de meilleurs résultats aux tests et leur baisse de performance était moindre. Le rôle des cytokines inflammatoires en terrain diabétique fait selon toute vraisemblance partie intégrante de l’entretien de la santé cérébrale, a déclaré la Dre Greenwood.

Des perturbations de la voie de signali-sation de l’insuline peuvent également contribuer à la formation des enchevêtrements neurofibrillaires. En particulier, le taux de GSK-3, une enzyme atténuée par la voie de signalisation de l’insuline, peut augmenter chez les diabétiques. La GSK-3 est importante, car elle augmente la phosphorylation de la protéine tau associée à la formation des enchevêtrements neurofibrillaires, et ces derniers sont plus nombreux en terrain diabétique ou obèse. L’accumulation d’enchevêtrements signale le passage d’une perte normale de fonction à une pathologie. En conséquence, certains ont avancé que la MA est la séquelle cérébrale du diabète, ce que réfute la Dre Greenwood, bien qu’elle pense que la maladie se manifeste plus rapidement dans ce contexte.

Habitudes alimentaires favorisant le bien-être cognitif

La principale recommandation alimentaire au patient diabétique doit être de consommer des aliments à faible indice glycémique. Les études portant sur la performance cognitive postprandiale ont constaté que les fonctions de mémorisation et de remémoration étaient altérées après une consommation d’aliments à glucides simples. Il semble que ce soit la sécrétion de cortisol induite par l’insuline, et non les modifications de la glycémie, qui est la clé de cette réponse. L’augmentation du cortisol entraîne des effets problématiques sur l’hippocampe, dont certains sont liés au stress oxydatif. En outre, les diabétiques bénéficiant d’un bon apport en antioxydants souffrent de baisses cognitives moindres. La clé réside dans un contrôle glycémique minutieux afin de minimiser l’agression diabétique répétée au cours de la journée.

Conclusion
La Dre Greenwood a fait observer que les modifications du régime alimentaire des personnes âgées peuvent s’interpréter comme une recommandation de perte de poids, et ce risque est souvent avancé comme objection aux modifications alimentaires. Aucune ligne directrice claire ne permet au médecin de décider quand cesser d’encourager la perte de poids, qui est corrélée à un risque de fragilité chez la personne âgée. La meilleure approche pour minimiser la fragilité, a-t-elle conseillé, c’est d’améliorer les apports nutritifs tout en faisant plus d’exercice physique. Une approche plus ferme des habitudes alimentaires est nécessaire, étant donné que l’incidence du diabète et du syndrome métabolique évolue, notamment en raison du vieillissement de la génération du baby-boom. La Dre Greenwood a averti son auditoire que les forces contribuant à l’augmentation de la démence sont largement sous-estimées, et qu’il est grand temps d’instaurer des modifications du mode de vie.

Bibliographie

  1. Whitmer RA, Gustafson DR, Barrett-Connor E, et al. Central obesity and increased risk of dementia three decades later. Neurology 2008;71:1057-64.
  2. Scarmeas N, Stern Y, Tang MX, et al. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 2006;59:912-21.

Nutrition and Dementia among Older Adults

Nutrition and Dementia among Older Adults

Teaser: 

Click here to view the entire report from the 28th Annual Scientific Meeting of the Canadian Geriatrics Society

Nutrition and Dementia among Older Adults

Speaker: Carol Greenwood, PhD, Professor, Department of Nutritional Sciences, University of Toronto; Senior Scientist, Kunin-Lunenfeld Applied Research Unit, Baycrest Centre, Toronto, ON.

Dr. Carol Greenwood contextualized her discussion’s theme of nutrition and dementia as contributing to considerations of the environmental influences posing risk for cognitive decline and dementia. While dementia has important genetic roots, a large causative factor is environmental exposure. In cases of disease onset at >80 years of age, studies have suggested that ~60% relates to this factor.

Dietary Patterns that Increase Risk of Cognitive Decline

To understand the risk mediated by environmental exposure, she recommended that listeners focus on chronic diet rather than on instances of good or poor intake. The connection between nutrition and dementia relates to the underlying idea that neurons require nutritional support; altered nutrition equates to altered neuronal metabolism. Sound nutrition maintains brain insulin signaling, needed for learning and memory. Clinicians should aim to promote dietary habits that maintain brain neurotrophin levels, which support synaptic plasticity needed for memory consolidation; further, good diet and appropriate nutrient intake can reduce inflammation and oxidative damage, and maintain the cerebrovasculature’s capacity to supply essential nutrients to the brain.

Advances in this area of research could help to remediate an isolationist philosophy that can pervade viewpoints on chronic disease. The brain is highly sensitive to the health of the body, and through dietary modification it is possible to exert direct impact on diet-associated conditions such as cardiovascular disease (CVD), type 2 diabetes, and depression.

Many epidemiologic studies on diet are available, indicating that excess caloric intake leads to oxidative stress. Dr. Greenwood and colleagues have examined the role of fat intake. High fat intake, particularly of saturated and polyunsaturated fats, along with a dearth of Omega fats, are typical of the North American diet. Studies have shown that diets low in fruits, vegetables, whole cereal grains, and low in fish oils are associated with higher risk of dementia. This diet profile also associates with CVD, diabetes, depression, and other inflammatory and chronic disease states. The adverse effects on the brain are not simple, and multiple mechanisms are likely involved; separating the role of chronic disease from a direct impact on brain function would distort the effects.

Fish oils exemplify how individual nutrients can modulate multiple neuronal pathways. Studies involving fish oils and dementia risk have found the individual role hard to isolate because they, as all nutrients, have multiple effects in the body. As the Omega fats are incorporated into dietary recommendations the so-called physiologic role of the nutrient versus the pharmacologic role blurs. Incorporating the Omega fats on a wholistic nutritional basis is the sound approach, one that “nudges” the system. The other seeks to exert a large pharmacological impact with a “targeting and isolating” approach through supplements or food enrichment (e.g., eggs). Such an approach overlooks other aspects of fish protein that are valuable.

Similarly, investigations of health outcomes associated with altered antioxidant exposure have isolated micronutrients and supplied them in supplemental form, producing equivocal data. However, measuring the effects of this consumption should not be extrapolated to the effects of a dietary pattern that incorporates micronutrients on a grams per day nutritional intake. The targeted approach also overlooks that the full nutritional cocktail is more important (e.g., the synergistic aspect) than consuming any one individual compound. Food constituents work together.
These are pressing issues given the population-wide changes in health markers. Individuals with central adiposity (associated with development of the metabolic syndrome) are a “time bomb” of comorbidities, she stated. New study results suggest that central obesity in midlife increases dementia risk independent of diabetes and cardiovascular comorbidities; individuals with the greatest degree of central obesity bear a threefold increase of cognitive decline.1

The Mediterranean Diet
The needed clinical approach for such patients supports changing eating patterns, and the burden of evidence points toward the Mediterranean diet (Figure 1). The beneficial effects relate directly to increased fruit, vegetable and fish intake and reduced red meat consumption. Recent evidence for the approach was provided by a prospective study of 2,258 community-based nondemented individuals in New York; those with higher adherence to the Mediterranean diet had lower risk for Alzheimer’s disease (AD).2

The Role of Type 2 Diabetes and Glycemic Control
Increasing evidence suggests that diabetes per se appears to be a risk factor for cognitive decline, necessitating aggressive glycemic control in hyperglycemic patients.

Evidence for the interrelationship of glycemic control and dementing illness has been drawn from animal studies, and Dr. Greenwood and colleagues have investigated the effect of typical North American dietary patterns on cognitive performance in rats, specifically on learning and memory. Performance decrements were clearly associated with high saturated fat consumption; rats fed this diet were most likely to show random/chance performance in testing.

The task is to identify which qualities of the high saturated fat diet compromise cognitive function, and to disentangle these effects from diabetes’ effects. Dr. Greenwood cited studies with standard neuropsychiatric assessment results of hyperglycemic older adults, looking specifically at immediate and delayed recall (the latter calls on hippocampal function). Results show those more insensitive to insulin exhibit worse performance. With age, lost insulin sensitivity relates to impaired memory function.

Chronic Disease and Enhanced Dementia Risk

Current research further suggests that insulin resistance may outweigh the effects of fat consumption on cognitive decline. Recent studies using structural imaging have cast light on the relationship between diabetes and cognition. One study investigating loss of hippocampal function in older individuals not yet diagnostic of type 2 diabetes but with compromised glucose control found that worse control strongly associated with hippocampal atrophy. Such effects are evident among well-controlled diabetic individuals; as diabetes endures, and individuals lose metabolic control and develop hypercholesterolemia and hypertension, atrophy disperses throughout the brain, and the presence of white matter lesions becomes evident. These are the vascular components of diabetes appearing later in its course.

Insulin Signaling Is Needed for Memory Processing

Dr. Greenwood observed that while the brain is not often considered an insulin-sensitive organ, it has a high density of insulin receptors, and insulin signaling pathways play an integral role in memory consolidation. These insulin signaling pathways become disrupted in the setting of diabetes. These associations with the insulin pathway are important and may explain why the diabetic individual has poor memory performance relative to an age-matched nondiabetic, but it is not clear indication that diabetes contributes to dementia pathology.

It likely does both, Dr. Greenwood argued. The key enzyme involved in degradation of Ab protein promoting development of AD plaques is the insulin degrading enzyme, which is down-regulated in the brains of those with diabetes, slowing Ab degradation. In addition, the Ab export is impaired due to high levels of Ab in the periphery, leaving them at high risk of Ab accumulation. Diabetics also have higher levels of inflammatory cytokines, producing a disease state of Ab accumulation and corresponding inflammatory responses. The Ab inflammatory cycle facilitates plaque formation.

Studies featuring individuals with well-controlled diabetes but carrying a genetic polymorphism to tumour necrosis factor (TNF)a support this view. Such individuals are less able to manufacture TNFa and launch inflammatory responses. Those carrying the single nucleotide polymorphism (SNP) have performed better on testing and showed fewer decrements in performance. The role of inflammatory cytokines in the context of diabetes is likely integral to the maintenance of brain health, Dr. Greenwood stated.

Disturbances to the insulin signaling pathway may also contribute to the development of neurofibrillary tangles. Specifically, GSK-3, an enzyme dampened by the insulin signaling pathway, may be increased in those with diabetes. GSK-3 is important because it increases phosphorylation of the tau protein associated with development of neurofibrillary tangles, which appear in greater levels in the diabetic/obese state. The accumulation of tangles signals the move from normal loss of function into pathology. Correspondingly, some have argued that AD is the brain sequelae of diabetes, and while Dr. Greenwood expressed her disagreement, she thinks the disease occurs more rapidly in this setting.

Dietary Patterns that Promote Cognitive Well-Being
The focus of dietary recommendations for the diabetic patient should be on low-glycemic index food intake. Studies that have investigated postprandial cognitive performance found that after consuming simple carbohydrate foods, degraded processing and recall function results. It appears that insulin-induced cortisol secretion, and not changes in blood glucose, are key to this response. Increased cortisol exerts problematic effects in the hippocampus, some of which relate to oxidative stress. Further, diabetic individuals with sound antioxidant intake experience fewer decrements in cognition. The key is careful glycemic control to minimize the diabetic insult occurring repeatedly throughout the day.

Conclusion
Dr. Greenwood observed that the risk of appearing to recommend weight loss to an older population is often raised as an objection to dietary modification. There are no clear guidelines as to when physicians should stop encouraging weight loss, which is correlated with frailty risk with advancing age. The best approach to minimizing frailty, she advised, is improved nutritional intake combined with increased exercise. A more aggressive approach to dietary patterns is required, given that the incidence of diabetes and the metabolic syndrome are changing, especially as baby boomers age. Dr. Greenwood advised listeners that the pressures driving dementia upward are vastly underestimated, and now is the time to implement lifestyle modifications.

References

  1. Whitmer RA, Gustafson DR, Barrett-Connor E, et al. Central obesity and increased risk of dementia three decades later. Neurology 2008;71:1057-64.
  2. Scarmeas N, Stern Y, Tang MX, et al. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 2006;59:912-21.

Assessment of Fitness-to-Drive in Persons with Dementia

Assessment of Fitness-to-Drive in Persons with Dementia

Teaser: 

Click here to view the entire report from the 28th Annual Scientific Meeting of the Canadian Geriatrics Society

Assessment of Fitness-to-Drive in Persons with Dementia

Speaker: Frank Molnar, MSC, MDCM, FRCP(C), Staff, Division of Geriatric Medicine, The Ottawa Hospital; Associate Professor, Department of Medicine, University of Ottawa; Affiliate Investigator, The Ottawa Health Research Institute; Scientist, The Elisabeth Bruyere Research Institute, Ottawa, ON.

Dr. Frank Molnar, a member of the network of interdisciplinary investigators for the Canadian Driving Research Initiative for Vehicular Safety in the Elderly (CanDRIVE), reviewed practical approaches to assessing fitness to drive in the setting of a dementia diagnosis.

CanDRIVE Research

The Canadian Institutes of Health Research (CIHR)-funded CanDRIVE research team has worked to produce substantive research and recommendations on fitness to drive via a two-pronged approach. First, the group has aimed at deriving and validating screening tools for this patient segment. This pillar of their work has involved building a national research team to examine medical aspects of fitness to drive in conjunction with an array of health professionals (leading to the development of tests with cut-offs based on group data), in order to pursue the second pillar of their purpose: facilitating networking and knowledge translation (leading to adjusting cut-offs and using specific findings to assess individual patients). CanDRIVE will conduct a large prospective cohort study that tracks fitness to drive among adults with dementing illness.

While the primary research is in its infancy, Dr. Molnar explained that the CanDRIVE research teams will focus on disseminating their acquired knowledge to physicians. Further, CanDRIVE aims to incorporate input from clinicians on what they should be looking at.

The Scope of the Problem
While older drivers are generally safer when compared to younger cohorts, the rate of motor vehicle crashes per km driven according to driver’s age increases beyond age 80. This shift, due primarily to the accumulation of medical illnesses in late age, means the net number of collisions and casualties will soar with an aging populace. Emergency rooms will treat an increasing number of older crash victims.

Projections through 2026 from Transport Canada show that crashes will rise primarily in older groups. An older person involved in a crash has a fourfold higher likelihood of being seriously injured or hospitalized; has a higher risk of becoming permanently disabled or dying; and takes longer to recover. Studies have shown that the majority of crash-injured seniors were driving the vehicle, and that most of the crashes involving older drivers are multivehicle and involve innocents. Dr. Molnar asked listeners to consider that they are not doing older drivers a favour by letting them drive when they reach the limit of their ability to do so safely.

The Problem Is not Age Alone

The vast majority of older drivers are safe drivers, Dr. Molnar insisted, and CanDRIVE is sensitive to the concern that their work contributes to ageism or alarmism about seniors at the wheel. He emphasized that medical conditions and medications are the primary cause of older drivers’ incompetence, and any medication can contribute to collision risk. Older people are affected disproportionately due to polypharmacy.

Dr. Molnar explicitly stated that no disease or chronic condition can be isolated as categorically risky. It is not the presence but severity and/or instability of conditions, plus high doses and/or changing doses of medications, that are perilous. While physicians cannot prevent every accident, they are well-placed to detect many persons who are at risk for unsafe driving. Qualities of medical conditions or medications most correlated with impaired driving capacity are those that alter physical, sensory, mental, or emotional abilities.

Driving recruits a complex set of cognitive capacities and behaviours, including operational, tactical, and strategic categories of action. Doctors cannot correctly assess impaired function 100% due to limitations of the physical exam (which is primarily designed to detect presence or absence of disease, not to assess function or safety) and the inadequate time available in front-line clinical settings. For example, tactical maneuvering is involved in decisions drivers make on the road—it supports real-time contextual decisions. Impairments in this category are often hard for doctors to catch. Strategic capacity refers to decisions made before getting on the road, which is difficult for doctors to assess. No screening tool will ever be completely effective for screening for all motor vehicle crashes. Most assessment protocols only test stable intrinsic features of driving ability. Doctors may miss new or fluctuating illness. Further, physicians cannot anticipate patients’ judgment of extrinsic factors such as weather, other drivers, road conditions, or a car’s safety.

Clinical Assessment: An Overview of the Issues

Assessment can be improved, however CanDRIVE seeks to galvanize attention on this issue as it is well-documented that cognitive impairment puts drivers at increased risk of at-fault crashes. A 2004 study found that currently there are tens of thousands of older drivers with dementing illnesses in Ontario; by 2028, the figure will approach 100,000.

A diagnosis of dementia does not automatically mean no driving, Dr. Molnar stated; however, a diagnosis of dementia means that the clinician must ask if the person is still driving, and driving safety must be assessed and documented. Provincial reporting requirements vary but uniformly state that the condition must be assessed and reported.

The Canadian Medical Association’s (CMA) guidelines, “Determining Medical Fitness to Operate Motor Vehicles” (7th ed.), joins international consensus statements that recognize the limitations of available data on assessment but recommend that: one, those with moderate to severe dementia should not drive (CMA: Moderate = 1 ADL or 2 IADLs impaired due to cognition); two, that individual assessment should be performed for those with mild dementia; three, that periodic follow-up is required (every 6-9 months); and four, the “gold standard” is comprehensive on-road assessment. Dr. Molnar opined that the CMA guidelines should go further in terms of ADLs—any single IADL impairment due to cognition should trigger an assessment of fitness to drive. Further, he finds the 6-9 month follow-up rule insensitive and advises an individualized approach (e.g., assessing every 3 months in the setting of rapidly progressing disease).

Dr. Molnar cautioned that while clear assessment protocols are given (e.g., for using the MMSE, Clock Drawing, Trails B), no guidance is provided as to how physicians should apply such tests. For example, how to respond to different scores, what cut-offs to use, and which errors equal automatic failure remain under debate. CanDRIVE has examined dozens of dementia and driving articles, and was unable to find one cognitive test that was analyzed via a validated cut-off. Clinicians are working in an evidence-based vacuum, Dr. Molnar stated.

An Approach to Assessing Fitness to Drive
Clinicians must inquire, “Do you drive?” Failure to verify has not protected clinicians in litigation, Dr. Molnar advised. Two, recall that driving capacity depends on a global clinical picture, including the patient’s cognition, function, physical abilities, medical conditions, behaviour, and driving record. Then, follow general questions with specific cognitive tests. Corroborative information from the family can help, and Dr. Molnar suggested several areas of inquiry that are best asked when the patient is not in the room (Table 1). Further, review medical conditions that when severe, poorly controlled, or changing rapidly can compromise capacity to drive (he suggested clinicians ask themselves, “Would I get in a car with this person based on these findings?”). Dr. Molnar recommended that the “3 Ds”— dementia, delirium, and depression— are most important to consider. He then reviewed medications that could affect driving (Table 2).

The key intervention is to test specific cognitive domains, as with the aforementioned protocols. Judgment is assessed by the test response to dangerous situations (e.g., fire); visuospatial ability is tested with the MMSE and clock drawing; executive function is assessed with Trails A and B, clock drawing, and 1-minute animal naming; and reaction time can be verified with the ruler drop test. In the case of overlapping/unclear cognitive scores, he argued for serial trichotomization (e.g., clearly unsafe, uncertain with further testing required, no concerns regarding safety), as shown in Figure 1.

He advised that the MMSE is the best place to start; patients scoring under 20 are likely unsafe to drive. All areas of testing mentioned yield valuable data; the ruler drop test, while not validated, is important in assessing reaction. Such tests are valuable because decrements of reaction time (which is not tested in the physical examination) often only become apparent outside of testing when lapses involve seconds. However, driving involves the need for reactions on a millisecond scale.

Conclusion
Dr. Molnar closed with emphasizing that if dementia is diagnosed, driving must be asked about, formally assessed, and documented. Physicians can perform a comprehensive driving safety clinical evaluation in approximately 15 to 20 minutes. If clinicians are unsure of safety, refer to specialized assessment or specialized on-road testing. In dementia, reassess driving safety every 6 to 9 months. Finally, he encouraged those with any ideas about driving assessment to bring them to the attention of CanDRIVE staff via their website (www.candrive.ca).

Poststroke Dementia among Older Adults

Poststroke Dementia among Older Adults

Teaser: 


Aleksandra Klimkowicz-Mrowiec, PhD, Department of Neurology, University Hospital Cracow, Poland.

Stroke and dementia are major health problems affecting older people. Cerebrovascular disease is the second-leading cause of dementia after Alzheimer’s disease, the third- leading cause of death, and one of 10 leading causes of physical disability. In parallel with the increased prevalence of stroke in aging populations and the decline in mortality from stroke, the rate of diagnosed poststroke dementia has increased, causing a growing financial burden for health care systems. This article discusses the epidemiology, etiology, and determinants of poststroke dementia and outlines the search for a suitable treatment.
Key words: dementia, stroke, cognition, risk factors, cognitive impairment.

Parkinson’s Disease Dementia versus Dementia with Lewy Bodies

Parkinson’s Disease Dementia versus Dementia with Lewy Bodies

Teaser: 


Catherine Agbokou, MD, MSc, Service de Psychiatrie Adulte, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.
Emmanuel Cognat, MD, Service de Psychiatrie et de Psychologie Médicale, Hôpital Saint-Antoine, Université Pierre et Marie Curie, Paris, France.
Florian Ferreri, MD, MSc, Service de Psychiatrie et de Psychologie Médicale, Hôpital Saint-Antoine, Université Pierre et Marie Curie, Paris, France.

Differentiating between Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) is a difficult issue for many clinicians. To date, these diseases share most of their clinical, neuropathological, and management features. Therefore, PDD and DLB are considered by some authors to be the two extremities of a single spectrum disease named Lewy body diseases. Nevertheless, specific diagnostic criteria now exist for each disease and specific diagnosis remains of interest in clinical practice. In this article, we summarize features and diagnostic criteria of both PDD and DLB, compare them, and examine their treatment options.
Key words: Parkinson’s disease dementia, dementia with Lewy bodies, Lewy body disease, movement disorders, dementia, treatment.

Dementia and Depression: The Importance of Recognizing their Relationship

Dementia and Depression: The Importance of Recognizing their Relationship

Teaser: 

Click here to view the entire report from the 4th Canadian Colloquium on Dementia

Dementia and Depression: The Importance of Recognizing their Relationship

Speaker: Dr. Kristine Yaffe, MD, Associate Professor, Department of Psychiatry, Neurology and Epidemiology; Co-director of the Clinical and Translational Sciences Training Program, University of California, San Francisco; San Francisco, CA, USA.

Dr. Kristine Yaffe, of the University of California, San Francisco and San Francisco VA Medical Center, sought to shed light on the co-occurrence of depression and dementia, which are commonly encountered by practitioners caring for aging adults. Cognitive impairment affects up to one-third of older adults. Similarly, depression appears frequently and can co-occur with dementia. Both affect quality of life, and contribute to increased morbidity and mortality among this population segment.

Why, Dr. Yaffe asked, might they go together? Patients presenting with symptoms of major depression often experience altered cognition as an effect of the mood disorder, and, similarly, depressive symptoms can accompany dementia as part of the disease. This is particularly the case in dementia with Lewy Bodies and frontotemporal dementia, but symptoms can appear in the setting of Alzheimer’s disease (AD) as well. Depression may not only be a reaction to cognitive problems but a risk factor for later cognitive impairment.

The depressive symptoms that tend to co-occur with deteriorating cognition include deficits in executive functioning and multitask domains, as well as inability to focus or retain new information. Processing speed is affected. However, on testing, memory impairment is often not registered and is not a hallmark of the paired conditions.

Dr. Yaffe stated that this constellation is recognized and tends to be termed pseudodementia. She questioned the value of the term, as the entity is not really “pseudo” and seems to call into question the validity and veracity of the patient’s experience. On the contrary, the symptoms are very real but not necessarily permanent. A careful cognitive evaluation is required; further, cognitive testing should be repeated subsequent to treating the depression.

Rather than thinking in terms of or aiming for clear-cut diagnosis, she encouraged listeners to think of patterns of disease expression. The focus must, however, remain on the particular individual and the uniqueness of his/her case.

Depressive Symptoms in the Setting of Cognitive Impairment
The general constellation Dr. Yaffe suggested that clinicians be aware of is marked by a general slowing down. She noted that typical depressive symptoms can differ in the setting of cognitive impairment; dysphoria, rather than major mood symptoms, is the hallmark. Other symptoms to watch for among older patients include loss of interest in usual activities and decreased social interaction.

Regarding the validity of currently available testing scales, Dr. Yaffe considered the commonly used dementia scales to be of value in the setting of mild and moderate dementia (Mini-Mental State Exam score ≥15). In advanced dementia, the scales are of diminished utility. Further, she claimed that the commonly used Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for depression are not very useful in this setting and advocated using the National Institutes of Mental Health Criteria for Depression in Alzheimer’s Disease (NIMH-dAD) criteria (Table 1). These are not dissimilar to DSM-IV but are less stringent—roughly, one major symptom is required, plus two others, for a positive diagnosis. She reminded listeners that the fifth revision of the DSM is forthcoming and new criteria are to be expected. Currently, the NIMH-dAD is a more sensitive scale and a better assessment tool when dealing with co-occurring dementia and depression.

Dr. Yaffe noted that many patients with dementia present with depressive symptoms. It is important to assess for depressive symptoms in dementia as they may bear on both the symptoms of and prognosis for the cognitive state. These patients are at double risk: they are vulnerable to greater functional decline and greater mortality. Neither condition is benign and both are treatable.
Depression may also be a risk factor per se for cognitive decline. Dr. Yaffe advocated watchfulness in the setting of geriatric depression, as patients should be monitored for signs of dementia. In her clinical practice, she will refer depressed older individuals for neuropsychiatric testing as they are at increased risk (by a factor of two to three times) for developing cognitive problems. Research has suggested that in the presence of three to five symptoms of depression, there is a doubling of risk of cognitive decline. This may be due to changes in cortisol; or, it could be an early symptom of neurodegeneration.

It is possible to see structural brain changes in imaging in dementia. Classically, three things appear: one, nothing, in some cases; two, numerous white matter changes, often in the frontal subcortical region, relating to the executive impairment (bringing vascular dementia to the fore); and three, hippocampal atrophy. Given the last, it is unsurprising, she stated, that individuals go on to develop cognitive difficulties. Functional imaging findings often include frontal hypometabolism (in depression), and classic temporal-parietal hypometabolism (in AD).

Treating Depression Co-Occurring with Dementia
As for treatment approaches, when treating geriatric depression in the setting of mild to moderate cognitive impairment, she noted that most pharmacotherapeutic options prescribed for younger adults, such as the selective serotonin reuptake inhibitors (Figure 1), also work in the older population, with the caveat that one must be vigilant regarding comorbidities and any relevant background medical conditions. Research has suggested that sertraline is of good utility in this patient segment. She noted that the sertraline studies and other relevant studies concerning the co-occurrence of the disorders have found that mood improves but the cognitive deficits tend to remain untouched. In her experience, Dr. Yaffe finds the impairment improves but does not disappear.
As for nonpharmacological treatments, cognitive behavioural therapy (CBT) can be helpful, even in vascular depression. The best strategy involves CBT plus pharmacological therapy. Among aging adults assisted by a caregiver, caregiver education is a key element of the therapy that should aim to redress any misconceptions or negative attitudes about the disorders from which the patient is suffering. Patient support groups are also of high value. While electroconvulsive therapy has been found to have efficacy in the setting of geriatric depression, note that it can cause increased confusion or other altered functioning.

Conclusion
Dr. Yaffe closed with some thoughts about the nature of the relationship between dementia and cognitive deficits. What stems from what, which of the two should be seen as a prodrome, and other key questions lack clear answers. What is clear, she noted, is that these conditions are not benign, they tend to co-occur, and recognizing this is among the key pearls she hoped to impart. Patients need to be followed closely, and their depression needs aggressive treatment.

Idiopathic Normal Pressure Hydrocephalus

Idiopathic Normal Pressure Hydrocephalus

Teaser: 

Click here to view the entire report from the 4th Canadian Colloquium on Dementia

Idiopathic Normal Pressure Hydrocephalus

Speaker: Dr. Norman Relkin, MD, PhD, Director, Cornell Memory Disorders Program; Associate Professor of Clinical Neurology and Neuroscience, Weill Cornell Medical College; Associate Attending Neurologist, NewYork-Presbyterian Hospital, New York, NY, USA.

Dr. Norman Relkin discussed idiopathic normal pressure hydrocephalus (NPH), a disease commonly termed “reversible dementia.” Dr. Relkin formally defined NPH as “a condition characterized by chronic nonobstructive enlargement of the cerebral ventricles in association with progressive disturbances of gait and balance, cognition, and/or urination.” These form the so-called classic triad of NPH disturbance (Figure 1).

Dr. Relkin suggested that the triad’s shortcoming lies in its lack of universality, as the qualitative and quantitative expression of these symptoms varies. Nonetheless, the entity is often regarded as an ideal diagnosis, given these symptoms’ general applicability. Further, NPH is detectable on imaging and responds to surgical treatment with generally good long-term outcomes. However, NPH also lacks a gold standard of pathological criteria and does not respond to drug therapy (acetazolamide has been tried unsuccessfully, Dr. Relkin noted). Further, response to surgery can be inconsistent, and treatment involves a high rate of morbidity.

Diagnosing Normal Pressure Hydrocephalus
The Classic Triad

Clinical signs and symptoms, supplemented by radiologic findings, are the primary means of identifying patients with NPH. Dr. Relkin observed that researchers are working to identify biological markers for the disease in enhanced quantitative brain imaging, but integrating biomarkers into the differential diagnosis remains a future possibility.

Dr. Relkin urged his audience to be aware that the NPH-associated clinical triad is likewise not ideally reliable. One study found that, on diagnosis, ~50% of patients had the classic triad. Gait is the most reliably recognized symptom of NPH. Given that the triad is an imperfect diagnostic construct, he advised clinicians to be aware of the partial presentation of these symptoms: for example, urinary urgency is more common than frank incontinence in early stages of the disease. Overall, NPH-related disturbances may be subtle and not obviously progressive, but should be persistent.

Radiographic Evidence
Controversy lingers regarding the value of radiographic results for NPH, and, overall, there are no completely reliable quantitative measurements. The primary finding associated with NPH is atrophy. However, atrophy findings do not allow the clinician to rule out lookalike syndromes when investigating for NPH; the syndrome most commonly confused with NPH is aqueductal stenosis. Imaging characteristics of NPH include disproportionate ventriculomegaly, increased callosal angle, doming of the lateral ventricle, enlargement of the temporal horns, and expansion of the diameter of the third ventricle, often with a bowed appearance of that ventricle.

Dr. Relkin advised that cerebrospinal fluid (CSF) flow void symptoms and brain diffusivity measurements are not clear diagnostic indicators. Currently, inspection is the standard. Dr. Relkin addressed whether there is a way to distinguish the enlargement of temporal horns in NPH from that enlargement seen in Alzheimer’s disease (AD)-associated hippocampal atrophy. The hippocampus and parahippocampal folds do become more prominent in AD and can help differentiate atrophy from hydrocephalus. These areas take on a smooth, rounded contour in AD, and this can be a useful sign in some patients for distinguishing these two entities. However, Dr. Relkin advised, these can be comorbid diseases.

Features of Gait Abnormality

Gait abnormalities (incorrectly called gait apraxia) remain the best feature for recognizing NPH. Dr. Relkin advised that clinicians be alert to signs of slowed movement, decreased step height, inadequate upward angulation of the foot, diminished stride length, reduced shoulder counter-rotation relative to the pelvis, as well as increased step width and foot rotation angles. Of particular note is that patients will require 3-4 steps to perform a 180-degree turn. He emphasized that a qualitative and quantitative evaluation of gait and posture should be carried out in every case of suspected NPH.

Urinary Disturbances

Urologic evaluation may assist in differential diagnosis. Urinary disturbance, he stated, is the least consistently observed component of the NPH triad. There will be increased urinary frequency and urgency, as well as urinary incontinence (but not fecal, he noted). It is important to ask if there is nocturia, claimed Dr. Relkin. The gait disorder may impede toileting.

Cognitive Impairment

On cognitive evaluation, the hallmarks of NPH are slowed cognition, dysexecutive syndrome, visuospatial deficits, and behavioural changes. Testing may assist in assessing baseline mental status and response to treatment.

Other Signs and Symptoms Associated with Normal Pressure Hydrocephalus

Other findings indicative of NPH include increased head circumference, syncopal episodes, altered sleep architecture, and the development of systemic hypertension. The latter may occur 1-2 years prior to the onset of frank symptoms.

Symptoms Not Associated with Normal Pressure Hydrocephalus
Findings one would not expect in the case of NPH include papilledema, meningismus, headache, seizures (except post-shunt), or lateralized deficits. Dr. Relkin reminded listeners that the differential diagnosis is lengthy, and NPH symptoms need to be considered in light of overlapping symptomatology with lookalike syndromes (Table 1).

Given the lack of clarity around the signs associated with NPH, Dr. Relkin and colleagues worked to develop consensus criteria that were published in 2005.1 They sought to define the probably, possible, and unlikely classifications for NPH based on history, brain imaging, clinical findings and physiologic criteria. Their recommendations appear in Table 2. The criteria given do not apply to a review of shunt responsiveness.

Dr. Relkin also discussed guidelines for cerebrospinal fluid drainage in the assessment of suspected NPH. The lumbar puncture tap test should involve the drawing of at least 40-50 cc’s of fluid. Gait and cognitive testing should follow within an hour of completing the tap. Continuous or intermittent draining will require hospital admission. Higher-volume drainage is more predictive of shunt responsiveness, he noted; further, a negative tap test does not preclude shunt reponsiveness.

Treatment
Programmable shunts are the new standard. They permit the opening pressure of the valve to be altered and can help to optimize treatment, but they add complication and cost. This cost is saved on the lower rates of re-operation. Complications of the shunt are the major drawback; the programmable shunt malfunction rate is 20%. Programmable shunts are part of an evolving and improving treatment process, Dr. Relkin claimed.

Conclusion
Dr. Relkin reminded listeners that NPH is one of the truly reversible causes of dementia if detected early. New technologies for diagnosis and treatment are improving disease outcomes.

Reference

  1. Marmarou A, Bergsneider M, Relkin N, et al. Development of guidelines for idiopathic normal-pressure hydrocephalus: introduction. Neurosurgery 2005;57(3 Suppl):S1-3.

Antiamyloid Immunotherapy: What Do the Blood Vessels Think?

Antiamyloid Immunotherapy: What Do the Blood Vessels Think?

Teaser: 

Click here to view the entire report from the 4th Canadian Colloquium on Dementia

Antiamyloid Immunotherapy: What Do the Blood Vessels Think?

Speaker: Steven M. Greenberg, MD, PhD, Director, Hemorrhagic Stroke Research Program, Massachusetts General Hospital; Associate Professor of Neurology, Harvard Medical School, Boston, MA, USA.

The final speaker, Dr. Steven Greenberg, focused on vascular issues related to antiamyloid immunotherapies.

Is Antiamyloid Therapy the Solution?
He began by addressing whether antiamyloid therapy might be considered a solution or might only contribute further to the problem of cognitive deterioration, as well as vascular pathology. As Dr. Relkin had discussed, earlier significant trials of the therapy resulted in a serious inflammatory response. What possible approaches might avoid this toxicity?

Historically, Dr. Greenberg observed, people taking anti-inflammatories to retard inflammation were thought to be at decreased risk for Alzheimer’s disease (AD), as inflammation was perceived as part of the cascade leading to AD-associated deterioration. That was turned on its ear in Dr. Dale Schenk’s work, as discussed by Dr. Relkin. Schenk’s work on immunization to beta-amyloid with mouse models appeared to generalize to humans. Indeed, individuals who have participated in immunization trials and who came to autopsy showed striking clearing of beta-amyloid deposition as a result of the therapy. The serious drawback of this treatment was the risk of meningoencephalitis, which led to initial discontinuation of the study.

The Toxicity of Antiamyloid Therapy
The adverse events included subacute cognitive decline, seizures, and white matter changes. These effects were reversible in some cases; however, two deaths were reported. The value of passive immunotherapy is still emerging-studies in which patients are receiving premade antiamyloid antibody therapies are ongoing, and some changes, reminiscent of the previous white matter changes on MRI, have been reported. Passive immunotherapies may not totally avoid toxicity and severe side effects.

Cerebral Amyloid Angiopathy and Inflammation
Dr. Greenberg stressed the connection between meningoencephalitis and cerebrovascular amyloid or cerebral amyloid angiopathy (CAA). This topic partners with the study of AD and amyloid. It involves essentially the same peptide, with a difference in Ab40 and Ab42 ratios. Dr. Greenberg showed an illustration of the life cycle of the amyloid peptide, a complex entity (Figure 1). Once formed, it might degrade, be deposited in the vessels, or pass out of the nervous system. There is a strong pathological overlap between Alzheimer’s and CAA. Research has uncovered the prevalence of vascular amyloid in almost every AD case. Dr. Greenberg also emphasized the presence of microbleeds which are, radiographically, a hallmark pathological feature found in a substantial set of AD patients. Such hemorrhages are also a cardinal feature of amyloid angiopathy, which tends to be worse in the parietal lobes where the hemorrhages are located. There is a nearly superimposable distribution of the hemorrhages when one examines individuals with AD; the microbleeds in AD patients occur in the same distribution as amyloid angiopathy. Bleeding in AD patients, Dr. Greenberg contended, suggests underlying amyloid angiopathy. There are virtually no AD patients without this associated vascular pathology.

Dr. Greenberg further considered what this vascular pathology present in AD patients has to do with the toxic response to beta-amyloid immunotherapy. The evidence comes from the pathology of vaccine-associated meningoencephalitis; the resemblance of iatrogenic toxicity to spontaneously occurring syndromes of amyloid angiopathy-related inflammation; and animal studies.
Dr. Greenberg showed brain pathology images from the two fatalities that occurred in the active vaccine study. Both autopsies revealed substantial clearing of amyloid plaques. However, the vascular amyloid remained present at an advanced stage, with evidence of vascular breakdown. There was significant inflammation around the vessels and an outpouring of inflammatory cells, mostly lymphocytes. Pathologically, it looked like there had been an inflammatory response to the vessels themselves. These results, he stated, are striking in light of spontaneously occurring syndromes of CAA-related inflammation: a sizeable subset of patients present with subacute cognitive changes or seizures. The pathology they exhibit is reminiscent of the changes seen in the active vaccine study-including advanced amyloid angiopathy and perivascular inflammation. There are focal cortical infarctions, possibly representing effects of inflammation. Their MRIs show subcortical changes in the white matter, extending to overlying grey matter. Radiographic as well as clinical data suggest similarities between the two processes. Dr. Greenberg compared the amount of white matter disease in study participants with spontaneously occurring CAA syndrome with patients with the iatrogenic pathology from the active vaccine study. Patients treated with anti-inflammatories improved clinically and showed corresponding improvement of white matter findings on MRI. There was a relapsing subgroup with bouts of spontaneously occurring CAA-people who came in with a second or third bout of the same syndrome-who showed repeated instances of return of the hyperintensities.

Studies of transgenic mice with robust plaque and vascular amyloid showed occurrences of hemorrhages in passive immunization. These findings with animal models represent another adverse occurrence and raise the question of what happens to vessels when amyloid is pulled from them.

So, Dr. Greenberg queried, if we suppose that vascular amyloid is the problem and is the trigger of adverse events in immune-based therapy, how is it avoided? Approaches to avoiding CAA-related toxicity might include better noninvasive detection of CAA; better identification of those at risk for CAA-related inflammation; and adjusting the mode of treatment.

Dr. Greenberg considered PET imaging for the noninvasive detection of amyloid angiopathy. He stated that Pittsburgh compound B (PIB) accumulates in regions with high levels of plaques. Because patients with amyloid angiopathy showed increased accumulation of this compound, he questioned whether this signifies that PIB binds to vascular amyloid. Dr. Greenberg argued that PIB predominantly accumulates in the occipital cortex, a region the most highly enriched in vascular amyloid. One may use a ratio of occipital to global PIB binding to determine how much amyloid would be present.

Talking about risk factors, Dr. Greenberg noted the overrepresentation of the APOE 4/4 genotype among patients with inflammatory CAA. This marker may represent susceptibility for CAA-related inflammation.

Finally, altered methods of treatment may minimize the risk of bad effects from vascular amyloid. Dr. Greenberg’s team has worked with multiphoton microscopy to look at the progression of vascular amyloid in living mice and mapped a predictable week-by-week progression of amyloid angiopathy in transgenic mice. The results were measured in a quantitative way across multiple imaging sessions. They wondered what would happen were they to directly apply beta amyloid antibodies to the surface of the brain in these transgenic mice. Results showed a decline in vascular amyloid. The direct application of antibodies to the surface of the brain reversed accumulation to the same extent vascular amyloid would tend to accumulate, with lack of toxicity. He stated that this suggests that beta-amyloid clearance can be done in a way that is protective of the vessels.

Conclusion
Dr. Greenberg concluded that the anti–beta-amyloid inflammatory response may be both beneficial when it is clearing amyloid, but harmful if it is causing tissue damage around it. There are clinical, radiological, animal, and other data suggesting that vascular amyloid contributes to vaccine-related toxicity. The possible approaches may involve altering the therapeutic approach, and determining who should be treated. Selecting subjects at low risk for adverse events may make antiamyloid immunotherapy a safer treatment.

The Pros and Cons of the Amyloid Hypothesis of Alzheimer’s Disease

The Pros and Cons of the Amyloid Hypothesis of Alzheimer’s Disease

Teaser: 

Click here to view the entire report from the 4th Canadian Colloquium on Dementia

The Pros and Cons of the Amyloid Hypothesis of Alzheimer’s Disease

Speaker: Andrea LeBlanc, PhD, Professor and McGill Dawson Scholar, Department of Neurology and Neurosurgery, McGill University; Project Director, Bloomfield Centre for Research
in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC.

Researcher Dr. Andrea LeBlanc addressed evidence for and against the amyloid beta (Ab) hypothesis of Alzheimer’s pathogenesis.

Historically, Alzheimer’s disease (AD) has been characterized by its pathological signs-namely, plaques. But AD pathology encompasses more than amyloid and tau, she stated. There are degenerating neurites within those plaques that are important, as well as neurofibrillary tangles, tau, and so forth. In AD, other features play a role: synaptic loss is obvious and related to dementia but is often not discussed. Also implicated in the degenerative process are glial activation and neuronal loss. The progressive cell loss in AD is not very obvious. So, Dr. LeBlanc questioned, is it neuronal loss, neuronal atrophy and/or neuronal dysfunction causing the cognitive decline?

Arguments Marshalled in Defense of the Amyloid-Beta Hypothesis
The hypothesis holds that the Ab peptide leads to synaptic degeneration, neuronal degeneration and formation of neurofibrillary tangles and thus to the cognitive losses observed. Progressive amyloid deposition is certainly greater in AD patients, Dr. LeBlanc granted. However, some noncognitively impaired individuals have a high plaque burden. Those who defend the hypothesis suggest that they may manufacture a nontoxic form of amyloid. The correlation between amyloid deposition and impairment levels is not clear-cut; for those who doubt the amyloid hypothesis, this finding seems to disprove it.

The second argument often offered by proponents of the Ab hypothesis is that genetic mutations or polymorphisms associated with AD lead to the overproduction of Ab peptide. This is definitely true, Dr. LeBlanc stated-the amyloid precursor protein (APP), presenilin-1 and presenilin-2 genes, and related mutations have been identified by Dr. Peter St.-George Hyslop and colleagues. All of these mutations lead to increased Ab peptide levels, an increase of Ab42 versus Ab40 ratios, or an increase in Ab aggregation in the absence of total increase in Ab. These features do influence the level of Ab or its ability to aggregate. The caveat Dr. LeBlanc added is that the increases are not large-they are statistically significant increases, but their biological significance is unclear since some brains from cognitively normal individuals contain higher levels of Ab.

The third argument offered in defense of the Ab hypothesis is that research has found that increased APP expression in Down Syndrome (Trisomy 21) is associated with AD pathology. There is AD pathology in Down Syndrome individuals. The primary evidence cited for this argument concerns the case of one individual with Down Syndrome but a diploid APP, who did not show AD pathology at death. Dr. LeBlanc granted that this would appear to strongly support the amyloid hypothesis. However, Dr. LeBlanc stated, the genetic region that is duplicated in Down Syndrome contains other genes than APP that could also play a role in AD pathology.

The fourth argument often cited in defense of the hypothesis is that presenilin is the active component of gamma [g]-secretase. Presenilin-1 is part of a complex that cleaves the C-terminus of the Ab peptide from the APP. However, the g-secretase complex cleaves many other proteins. This factor’s involvement in cognitive decline is not certain, however. The function of these proteins is difficult to determine. Dr. LeBlanc suggested that these polymorphisms also alter a normal function of the protein involved in normal cognition. Work on this is underexplored compared to amyloid-seeking work, she suggested.

Dr. LeBlanc described age-dependent stresses, traumatic brain injury, growth factor depletion, toxins, and mutant genes as leading to increased Ab peptide. She alleged that the peptide may just be a consequence of cellular dysfunction such as protein trafficking, organelle trafficking, and oxidative stress (Figure 1). A critical experiment, she proposed, would involve altering g-secretase sites of the APP and studying the consequence. She stated that mutant genes would need to be expressed in absence of amyloid production to determine that cells are not affected in an amyloid-independent manner by the genetic mutation.

The fifth argument concerns whether Ab is a neurotoxic peptide; Dr. LeBlanc granted that this is amply demonstrated. Cytotoxicity may be associated with a very particular form of Ab, the oligomer. However, Dr. LeBlanc countered by noting that in research, cytotoxosis is induced at much higher levels than physiological concentrations. In addition, cell death is not widely evident in brains of patients with AD and is not correlated with the level of dementia experienced. Dr. LeBlanc claimed that intracellular Ab is a more compelling potential cause of AD.

The sixth argument addresses the finding that genetically engineered and transgenic animals carrying mutant AD genes generate more amyloid and develop AD pathology and cognitive impairment. These problems have been reversed by anti-amyloid immunotherapy. However, Dr. LeBlanc noted that an APP transgenic mouse with an additional mutation at the caspase C-terminal site was found to not have any cognitive impairment, despite retaining the ability to make the same amount of Ab peptide.

The final argument for the hypothesis, supported by research, is that amyloid perturbs the synaptic function. Synaptic proteins are downregulated in AD, and soluble Ab is able to dysregulate synapses. As cited by Dr. Lovestone, an Ab oligomer injected directly in the brains of mice causes LTP problems. However, Dr. LeBlanc asserted that studies are required to prove that amyloid overproduction is preceding the synaptic problems and not the other way around.

An Alternative to the Amyloid-Beta Hypothesis: Is Amyloid Production a Consequence of the Disease?
Dr. LeBlanc asked, What if amyloid is a consequence of the disease and that age-dependent stresses cause amyloid beta peptide and neuritic plaque accumulation, neurofibrillary tangles, neuritic degeneration, and synapse loss?

This has been the focus of the research conducted by Dr. LeBlanc and her colleagues over the last 14 years. Working with primary cultures of human neurons, they removed the growth factors by serum deprivation. The cultures make two to four times more Ab peptide, dependent on caspase-6. Caspase-6 is a protease that degrades other proteins when activated; it is normally present in the brain but not activated unless there is an insult. Dr. LeBlanc and colleagues designed an antibody that would recognize only the active form of caspase-6 in the brain of AD patients and found that it is associated with all neuropathological markers. To prove the enzyme would be active in AD brain, they made a second antibody directed against the tau protein cleaved by caspase-6, and found that the cleaved tau is present in pretangles, extra- and intracellular tangles, and neurophil threads. Some patients, she noted, have carpets of these threads full of tau cleaved by caspase-6. They went on to study a series of cases to investigate whether there was a correlation with cognitive impairment levels. Among their findings was that active caspase-6 was abundantly present in mild, moderate, and severe AD. They also found evidence that among noncognitively impaired subjects, there can be a large amount of neurophil threads stained for tau cleaved with caspase-6. This occurs in the absence of hyperphosphorylation of tau; Dr. LeBlanc stated that it seems to precede the other markers of tau hyperphosphorylation.

Dr. LeBlanc concluded that since there is evidence that the amyloid hypothesis does not fully account for AD pathology, research should address what could be done in addition to stopping the Ab peptide to prevent cognitive impairment.

Curing Alzheimer’s Disease: The Case of Tau and GSK-3

Curing Alzheimer’s Disease: The Case of Tau and GSK-3

Teaser: 

Click here to view the entire report from the 4th Canadian Colloquium on Dementia

Curing Alzheimer’s Disease: The Case of Tau and GSK-3

Speaker: Dr. Simon Lovestone, PhD, MRCPsych, Professor, Old Age Psychiatry, MRC Centre for Neurodegeneration Research; Departments of Old Age Psychiatry and Neuroscience, King's College London, Institute of Psychiatry, London, England, UK.

The second speaker, Dr. Simon Lovestone, deemed the title of his presentation “inflammatory.” Given the complexity of AD therapeutics, can one really talk about “curing Alzheimer’s”?
Most AD treatments, Dr. Lovestone noted, are symptomatic. Disease modification therapies directed at the pathogenesis (i.e., the amyloid therapies) may or may not be curative. Dr. Lovestone explicitly defined curative treatments as those that may restore function.

Dr. Lovestone observed that most think that people with AD have symptoms because they are losing neurons. He granted the veracity of this hypothesis and that neuronal loss indeed causes symptoms. However, this notion offers little hope for people with AD, for no treatment restores neurons, short of stem-cell therapy-a therapy still in its infancy. Given this fact, and the fact that there may be no available therapy for years to come that is able to do more than slow disease progression, it would seem that there is little cause for optimism on the part of the public or researchers.

However, Dr. Lovestone rejected pessimism and suggested that treatments to restore function are within grasp. Dr. Lovestone claims that there are areas in the amyloid cascade hypothesis where restoring function is a meaningful objective-that is, from a pathogenic viewpoint, there is room to ask, could dementia symptoms result from a failure of neuronal function rather than a loss of neurons?

Tau Aggregation and Hyperphosphorylation in AD

One potential area Dr. Lovestone identified concerns tau. Neurofibrillary tangles are made of protein and tau. Tau is aggregated and phosphorylated in AD, and in neurodegenerative conditions—the tauopathies—the expression of the protein itself is altered. Dr. Lovestone advocated shifting attention from the role of the synapses and focusing instead on the protein machinery in the cell body. These proteins need to be transported to the synapse and elsewhere via axonal transport. The neurofilaments and microtubules facilitate the axonal transport needed for neuronal function. Vesicles, containing transported proteins, are held together by microtubular-associated proteins. Tau is an axonal-specific microtubular protein needed for normal neural function.
Dr. Lovestone described a hypothesis that when tau is hyperphosphorylated, or when phosphorylation is increased, tau tends to be removed. Microtubules tend to collapse and tau, under certain conditions, aggregates when not bound to microtubules. Presumably, Dr. Lovestone stated, that aggregation results in the neurofibrillary tangles of AD.

GSK-3 and Neuronal Function

Following this, Dr. Lovestone had four points to investigate: one, whether glycogen synthase kinase-3 (GSK-3) might be a tau kinase; two, whether GSK-3 might be altered in AD; three, whether there is any evidence that tau phosphorylation results in altered neuronal function; and four, whether GSK-3 might regulate neuronal function (Figure 1).

Research suggests that there is a range of kinases, including GSK-3, that will phosphorylate tau. Tau phosphorylation is switched off when the neurons are treated with a GSK inhibitor, as demonstrated in a study that used lithium. GSK-3 inhibition regulates tau phosphorylation in neurons, as a 1999 study showed.1

Regarding the second point, as to whether GSK-3 is altered in AD, Dr. Lovestone noted that it is difficult to test this hypothesis without accessing the brains of AD patients. Work by Pei et al. and Hye et al. has demonstrated that GSK-3 is increased in AD brains and that activity of GSK-3 correlates with damage. Dr. Lovestone and colleagues have investigated peripheral circulating cells; research suggests that GSK-3 is increased in white matter cells in AD.

As to whether GSK-3 protein is itself the best evidence for alteration in AD, Dr. Lovestone answers in the negative, saying evidence will likely come from understanding GSK regulation. It is inhibited by Wnt/wingless signaling and insulin signaling. Interestingly, insulin resistance is a strong risk factor for AD.

Going into the genetic evidence, Dr. Lovestone noted that a series of studies relevant to GSK, focusing on mediators of insulin signaling, have emerged from diabetes research. A diabetes study replicated with people with AD found association with a number of genes on the signaling pathway. There is further evidence from whole genome studies: according to one 2007 study, Gab2 alleles modify AD risk in APOE4 carriers, Dr. Lovestone stated. He further cited several chromosome studies showing association of mediators of insulin signaling with AD. Such studies have offered tentative evidence that regulation of GSK-3 through Wnt and/or insulin might be genetically associated with AD.

Regarding evidence that altering tau phosphorylation might be associated with altered neuronal function, Dr. Lovestone mentioned relevant drosophila studies modeling tauopathies. In such models, the addition of either human tau protein or GSK-3 affected axonal transport through clumping of the vesicles-some clumped and moved, while others were stationary. This affected neuronal function in larvae and adult flies. The phenotype effect was a massive increase of tau when they overexpressed GSK-3. The treatment of larvae with a series of GSK-3 inhibitors (i.e., lithium) reversed the phenotype in the tau-only expressing drosophila. There is a GSK-3 dependent tau phenotype in the absence of tau aggregation. In reviewing their results, they looked closely for tau aggregation, and found no evidence of it.

As to his final query-whether manipulating GSK-3 alters neuronal function-Dr. Lovestone again turned to evidence from animal studies regarding long-term potentiation (LTP), an increase in synaptic strength that follows the stimulation of the chemical synapse. In these studies of memory potentiation, they took mice with memory deficits overexpressing GSK and induced LTP. In their studies, when GSK-3 was inhibited following LTP; the memory potentiation lasted for hours. Dr. Lovestone described GSK-3 as “a gate that needs to be shut for memory to be preserved.” This may serve as early indication of the potential for treatments that restore function; however, Dr. Lovestone acknowledged, GSK-3 may prove a difficult target for pharmaceutical therapeutics to hit.

Reference

  1. Lovestone S, Davis DR, Webster MT, et al. Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations. Biol Psychiatr 1999;45:995-1003.