Alzheimer Disease: Zekry D

Zekry D, Duyckaerts C, Hauw JJ. · Laboratoire de neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, Paris (75). · Presse Med. · Pubmed #17553655 No free full text.

Abstract: The concept of vascular dementia has evolved over the past century to include multiple underlying pathophysiological mechanisms. Neuroimaging techniques offer new and better ways to identify the presence of cerebrovascular pathology, although they do not improve our ability to link these changes to the onset of clinical cognitive impairment. Clinical criteria for vascular dementia have also evolved but they remain imperfect. Most epidemiological studies define mixed dementia as the coexistence of Alzheimer's disease and vascular dementia. Clinicopathologic correlations show a clear association between the concomitant presence of vascular and Alzheimer lesions and the severity of cognitive impairment in mixed dementia and provide strong support for the validity of the mixed dementia concept. Mixed dementia is a very frequent disease that remains underdiagnosed, especially in the elderly. The diagnosis of vascular and mixed dementia remains a clinical challenge and cannot be improved without further studies of clinicopathological correlations and functional neuroimaging. Preventive therapeutic interventions include control of vascular risk factors and especially treatment of hypertension.

Zekry D, Duyckaerts C, Hauw JJ. · Laboratoire de neuropathologie, Hôpital de la Salpêtrière, Paris, France. · Psychol Neuropsychiatr Vieil. · Pubmed #16316816 No free full text.

Abstract: Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of dementia in the elderly. Although AD can be diagnosed with a very high degree of accuracy, the distinction between pure AD, VaD and mixed dementia (MD), where both pathologies co-exist in the same patient, remains a controversial issue and one of the most difficult diagnostic challenges. MD represents a very frequent pathology, especially in the elderly, as underlined by the neuropathological studies. However, the respective importance of degenerative and vascular lesions, their interaction in the genesis of dementia and the mere existence of mixed dementia are still debated. Accurate diagnosis of MD is of crucial significance for epidemiologic purposes and for preventive and therapeutic strategies. Until recently, pharmacological studies have generally focused on pure diseases, either AD or VaD, and have provided little data on the best therapeutic approach to MD. This review will provide an overview of neuropathological aspects of MD in the elderly, which appears to be one of the most common forms of dementia.

Zekry D, Epperson TK, Krause KH. · Department of Geriatrics, Geneva University Hospitals, Switzerland. · IUBMB Life. · Pubmed #12938732 No free full text.

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

Zekry D, Hauw JJ, Gold G. · Hôpitaux Universitaires de Genève, Thônex, Switzerland. · J Am Geriatr Soc. · Pubmed #12165002 No free full text.

Abstract: Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of dementia in older people. Although AD can be diagnosed with a considerable degree of accuracy, the distinction between isolated AD, VaD, and mixed dementia (MD), where both pathologies coexist in the same patient, remains a controversial issue and one of the most difficult diagnostic challenges. Although MD represents a very frequent pathology, especially in older people, as reported in neuropathological studies, the respective importance of degenerative and vascular lesions, their interaction in the genesis of dementia, and the mere existence of MD are still debated. Accurate diagnosis of MD is of crucial significance for epidemiological purposes and for preventive and therapeutic strategies. Until recently, pharmacological studies have generally focused on pure disease, AD or VaD, and have provided little information on the best therapeutic approach to MD. This article provides an overview of MD in older people. A retrospective review of the recent literature on prevalence, incidence, course, risk factors, diagnosis, and treatment of MD was performed. The article also emphasizes the need for further studies, including neuropsychological and functional evaluations, and neuroimaging and clinicopathological correlations to develop a better understanding of MD, which appears to be one of the most common forms of dementia.

Michel JP, Zekry D, Mulligan R, Giacobini E, Gold G. · Department of Geriatrics, Geneva University Hospitals, Switzerland. · Aging (Milano). · Pubmed #11442307 No free full text.

Abstract: Economic analyses of geriatric syndromes are seldom performed. However, demographic and epidemiological imperatives have led to significant interest in the evaluation of AD-related costs. Over 300 papers devoted to economic considerations of Alzheimer's disease have been published in peer-reviewed journals, within the last five years. In these papers, the chosen perspective (costs to society or to specific payers) is important. Analytical methods are still evolving and remain complex. Unresolved methodological issues will need to be addressed to further our understanding of long-term economic consequences. At present, it is clear that diagnostic and drug costs are low compared to the major cost of institutionalization. Thus, directing efforts at early diagnosis and delaying nursing home placement are two key cost-containment interventions. In this respect, the need to support informal care should not be underestimated.

Zekry D, Herrmann FR, Grandjean R, Meynet MP, Michel JP, Gold G, Krause KH. · Geneva University, Rehabilitation and Geriatrics Department, 3, chemin du Pont-Bochet, CH-1226, Thônex, Switzerland. · Age Ageing. · Pubmed #17971391 links to  free full text

Abstract: BACKGROUND: demented patients have been reported to be healthier than other old people of the same age. OBJECTIVES: to assess comorbid conditions, functional and nutritional status in medically ill hospitalised patients with normal cognition or affected by dementia of various causes and severities, or mild cognitive impairment (MCI). DESIGN AND SETTING: a prospective study was carried out, between January and December 2004, in the Rehabilitation and Geriatric Hospital (HOGER). METHODS: activities of daily living (ADL), instrumental activities of daily living (IADL) and mini nutritional assessment (MNA) scores were assessed as a function of the status of the patient two weeks before admission to hospital. On admission, cognitive status was assessed by a systematic battery of neuropsychological tests, comorbid conditions were assessed with the Charlson comorbidity index (CCI), and body mass index (BMI) and functional independence measure (FIM) were determined. BMI and FIM were also determined on discharge. RESULTS: we studied 349 patients (mean age 85.2 +/- 6.7; 76% women): 161 (46.1%) cognitively normal, 37 (10.6%) with MCI and 151 (43.3%) demented (61 Alzheimer's disease (AD), 62 mixed dementia (MD) and 17 vascular dementia (VaD)). ADL, IADL, FIM and MNA scores on admission decreased with cognitive status, regardless of the type of dementia. Functionality at discharge remained significantly lower in demented patients than in other patients. CCI was high and similar in all three groups (mean 4.6 +/- 2.7). Patients with VaD had poorer health than other demented patients, with a higher average comorbidity score, more frequent hypertension, stroke and hyperlipidaemia. Comorbidity did not increase with severity levels of dementia. CONCLUSIONS: in this cohort of very old inpatients, demented patients, non-demented patients and patients with MCI had similar levels of comorbidity, but demented patients had a poorer functional and nutritional status.

Zekry D, Duyckaerts C, Belmin J, Geoffre C, Moulias R, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, INSERM U 106 and 360, Association Claude Bernard, Pierre et Marie Curie University, 47 Bd de l'Hôpital, 75013 Paris, France. · Acta Neuropathol. · Pubmed #12898153 No free full text.

Abstract: Abeta peptide deposits are observed in brain cortical and leptomeningeal microvessels in a few families, in patients with Alzheimer's disease and in cognitively normal elderly subjects. These deposits, which cause Abeta amyloid angiopathy, are usually associated with other lesions induced by Abeta peptide and tau pathologies. To investigate the consequences of cerebral amyloid angiopathy on arterial morphology and search for correlations with the degree of cognitive impairment, we carried out a prospective clinicopathological and morphometric study in 29 institutionalized elderly patients cognitively normal or affected with sporadic dementia associated with Alzheimer-type lesions, cerebral infarcts or both. We measured the external and internal diameters of arteries 40-120 microm wide, containing moderate or severe Abeta deposits, and of unaffected arteries in the temporal and frontal lobes. We found no differences in the mean external diameters. In contrast, the mean internal diameters of vessels with moderate Abeta deposits were smaller than those of unaffected vessels. Conversely, the internal diameters of severely affected vessels were larger than those of unaffected vessels. This suggests that arterial walls become thicker during the early stages of amyloid angiopathy, and the diameter of the lumen decreases, whereas during advanced stages, the walls become thinner and the lumen becomes larger. In addition, we assessed the overall severity of amyloid angiopathy. This showed that thinner arterial walls and the severity of amyloid angiopathy were correlated to dementia. In a multivariate model that integrates the other macroscopic and microscopic lesions that may be implied in the mechanism of cognitive impairment, the severity of amyloid angiopathy per se explained 10% of the variability in the cognitive impairment.

Hauw JJ, Zekry D, Seilhean D, Forette B, Gallinari C, Laurent M, Moulias R, Piette F, Sachet A, Duyckaerts C. · Laboratoire de Neuropathologie R. Escourolle, INSERM U 106 et 360, Association Claude Bernard, Groupe Hospitalier Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75651 Paris. · J Mal Vasc. · Pubmed #12587216 No free full text.

Abstract: Neuropathological study of brain and brain vessels was performed in two series of 12 and 20 centenarians, focusing on the prevalence of small vessel lesions, infarction, Alzheimer's changes and mental status. These are discussed as a function of vascular risk factors. In the first series (12 cases), there was no correlation between the severity of small vessel lesions: hyalinosis (12/12), mineralisation (10/12), amyloid angiopathy (9/12), vascular risk factors (high blood pressure or diabetes), Alzheimer's lesions. However, there was a tendency for an association between amyloid angiopathy and high density of neurofibrillary tangles. In the second series (20 cases), small infarcts and lacunes were found in 9/20 cases, neurofibrillary tangles and diffuse deposits of A beta peptide were constant, senile plaques were very frequent (19/20). Five patients were demented (one vascular dementia, one Alzheimer dementia, and 3 mixed dementias). These data indicate that: 1) Lesions of the walls of small cerebral vessels do not seem linked to the vascular risk factors observed at the end of the life of centenarians. 2) Cerebral infarcts and lacunes are frequent in these patients, and are responsible, at least in part, for a high proportion of the cognitive dysfunctions. The study of larger series is needed for a better understanding of relationships between vascular and degenerative lesions in the oldest old.

Zekry D, Duyckaerts C, Belmin J, Geoffre C, Herrmann F, Moulias R, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, INSERM U 106 and 360, Association Claude Bernard, Pierre et Marie Curie University, Paris, France. · Neurobiol Aging. · Pubmed #12498955 No free full text.

Abstract: Vascular dementia appears rarer than previously thought, but the contribution of vascular lesions to cognitive impairment in Alzheimer's disease (AD) affected patients (mixed dementias) is now recognized as frequent. The role of strategic areas of the brain involved in the cognitive decline induced by vascular lesions and their relative contributions to the severity of the dementing process remain poorly understood. We determined the relationship between the severity of clinical dementia and the volume of different brain areas affected by infarcts in a prospective clinicopathological study in elderly patients. A volumetric study of the functional zones of Mesulam's human brain map affected by vascular lesions was made and correlations between quantified neuropathological data and the severity of dementia were performed in cases with large vascular lesions only, pure AD, and both lesions. The severity of cognitive impairment was significantly correlated with the total volume of infarcts but in a multi-variate model the volume destroyed in the limbic and heteromodal association areas, including the frontal cortex and in the white matter explained 50% of the variability in MMSE and GDS. The total volume of ischemic lesions explained only 0.1-5% of the variability in MMSE and GDS. Age only explained an extra of 0.1-1.6%. This study confirms that infarcts located in strategic areas have a role in the mechanism of cognitive impairment and brings a key for their quantification. It may be useful for developing neuropathological criteria in multi-infarct and mixed dementias.

Zekry D, Duyckaerts C, Belmin J, Geoffre C, Moulias R, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, 47-83, Bd de l'Hôpital, 75651, Paris, Cedex 13, France. · J Neurol. · Pubmed #12420093 No free full text.

Abstract: Clarifying the etiology of dementia is one of the most difficult diagnostic challenges, especially in the elderly. We examined the accuracy of clinical criteria to distinguish Alzheimer's disease (AD) and dementia associated with infarcts of the brain, either isolated (vascular dementia) or associated with degenerative lesions (mixed dementia). We carried out a prospective clinico-neuropathological study in a selected series of hospitalized patients. We evaluated the clinical aspects of 33 patients aged over 75 years by use of the criteria and scores of DSMIII, NINCDS-ADRDA, Loeb and Gandolfo, ADDTC and NINDS-AIREN and the Hachinski Ischemic Score. The neuropathological diagnosis was considered to be the gold standard. When comparing clinical criteria and neuropathology, the agreement was moderate for Hachinski's score (0.50) and Loeb's score (0.43) and substantial for the ADDTC (0.63) and the NINDS-AIREN (0.67). When mixed dementias were excluded, the agreement between all clinical criteria and scores and the pathological diagnosis rose to 0.88. Hachinski's score was the most sensitive (0.89) and the NINDS-AIREN the most specific (0.86) for the diagnosis of vascular dementia. In conclusion, all sets of clinical criteria distinguished pure AD from vascular dementia with a high accuracy whereas mixed dementia was clinically under-recognized. The NINDS-AIREN criteria were the most discriminating for the accurate identification of patients with mixed dementia.

Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, INSERM U 106 and 360, Association Claude Bernard, Pierre et Marie Curie University, 47 Bd de l'Hôpital, 75013 Paris, France. · Acta Neuropathol. · Pubmed #11935264 No free full text.

Abstract: The relative importance of vascular and Alzheimer's disease (AD) lesions, their interaction in the development of cognitive impairment and the very existence of mixed dementia induced by the potentiation of both mechanisms remain controversial. The aim of this study was to assess whether the patients with infarcts and lacunes have fewer plaques and tangles than those without vascular lesions, for similar severity of clinical dementia. We performed a prospective clinicopathological study in elderly patients of a long-stay care unit. The severity of clinical dementia was assessed by psychometry performed according to standardized methods less than 6 months before death. A volumetric study of cerebral vascular lesions was performed at post-mortem study of the brain. The density of neuritic plaques (SP), Amyloid beta focal deposits (A beta FD), and neurofibrillary tangles (NFT) in the temporal and frontal isocortex was quantified. According to DSM III criteria, 28 of the 33 patients for whom autopsies were performed had dementia. Twenty-four of the included patients had degenerative or vascular lesions, or both. The volume of infarcts and lacunes was significantly correlated with the severity of cognitive impairment. The density of SP, A beta FD and NFT in the temporal and frontal isocortex was significantly lower when vascular lesions were present. For similar clinical severity of dementia, there were fewer AD lesions in patients with vascular lesions than in those without vascular lesions.