In this thesis, the existence and uniqueness of gradient trajectories near an A2singularity are analysed. The A2-singularity is called a birth-death critical point in the real case. The birth-death critical point appears in a one-parameter family of functions. Such a family of functions has precisely two Morse critical points of index difference one, on the birth side. The result of the real case states that these two critical points are joined by a unique gradient trajectory up to time-shift. Here the gradient flow is defined with respect to any family of Riemannian metrics. This can be viewed as a converse to Smale’s cancellation theorem. We also look at the complex analogue of the result in Picard–Lefschetz theory. This analogue considers a holomorphic one-parameter family with an A2-singularity. Such a family has two critical Morse critical points near the singularity for every small non-zero parameter. We prove that the two Lagrangian vanishing cycles associated to these critical points intersect transversally in exactly one point in all regular fibres along a straight line. The result is obtained by analysing the gradient trajectories of the real part of these functions. Both proofs start with a normal form in local coordinates for such families of functions. The gradient equations in these coordinates can be rescaled into a fast-slow system of non-linear differential equation. Existence will rely on an adiabatic limit analysis whereas uniqueness follows from a Conley index pair construction. The latter construction will also show that connecting gradient trajectories cannot leave the local charts. Even though the proof of these two results follow from similar lines of argument, the real case cannot be reduced to the complex case and vice versa.

Doctoral Thesis by

https://hal.inria.fr/hal-00795739/document

Automatic classification of patients with Alzheimer's disease from structural MRI: A comparison of ten methods using the ADNI database

Background
Memantine, a low affinity antagonist to glutamate NMDA receptors, may prevent excitatory neurotoxicity in dementia.

Objectives
To determine efficacy and safety of memantine for people with Alzheimer's disease (AD), vascular (VD) and mixed dementia.

Search methods
The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 8 February 2006. This register contains references from all major healthcare databases and many ongoing trial databases and is updated regularly. In addition, the search engines Copernic and Google were used to identify unpublished trials through inspection of the websites of licensing bodies like the FDA , EMEA and NICE and of companies' websites (Lundbeck, Merz, Forest, Suntori etc) and clinical trials registries.

Selection criteria
Double-blind, parallel group, placebo-controlled, randomized trials of memantine in people with dementia.

Data collection and analysis
Data were pooled where possible. Intention-to-treat (ITT) and observed case (OC) analyses are reported.

Main results
1. Moderate to severe AD. Two out of three six month studies show a small beneficial effect of memantine. Pooled data indicate a beneficial effect at six months on cognition (2.97 points on the 100 point SIB, 95% CI 1.68 to 4.26, P < 0.00001), activities of daily living (1.27 points on the 54 point ADCS-ADLsev, 95% CI 0.44 to 2.09, P = 0.003) and behaviour (2.76 points on the 144 point NPI, 95% CI 0.88 to 4.63, P=0.004), supported by clinical impression of change (0.28 points on the 7 point CIBIC+, 95% CI 0.15 to 0.41, P < 0.0001). 
2. Mild to moderate AD. Pooled data from three unpublished studies indicate a marginal benefical effect at six months on ITT cognition (0.99 points on the 70 point ADAS-Cog, 95% CI 0.21 to 1.78, P = 0.01) which was barely detectable clinically (0.13 CIBIC+ points, 95% CI 0.01 to 0.25, P = 0.03) but no effect on behaviour, activities of daily living or OC analysis of cognition. 
3. Mild to moderate vascular dementia. Pooled data from two six month studies indicated a small beneficial effect of memantine on cognition (1.85 ADAS-Cog points, 95% CI 0.88 to 2.83, P = 0.0002), and behaviour (0.84 95% CI 0.06 to 0.91, P = 0.03) but this was not supported by clinical global measures. 
4. Patients taking memantine were slightly less likely to develop agitation (134/1739, 7.7% versus 175/1873, 9.3% OR 0.78, 95% CI 0.61 to 0.99, P = 0.04). This effect was slightly larger, but still small, in moderate to severe AD (58/506 [12%] vs 88/499 [18%]; OR = 0.6, 95% CI 0.42 to 0.86, P = 0.005). There is no evidence either way about whether it has an effect on agitation which is already present. 
5. Memantine is well tolerated.

Authors' conclusions
Memantine has a small beneficial effect at six months in moderate to severe AD. In patients with mild to moderate dementia, the small beneficial effect on cognition was not clinically detectable in those with vascular dementia and was detectable in those with AD. Memantine is well tolerated.

Memantine for dementia

The lesions of Alzheimer disease include accumulation of proteins, losses of neurons and synapses, and alterations related to reactive processes. Extracellular Aβ accumulation occurs in the parenchyma as diffuse, focal or stellate deposits. It may involve the vessel walls of arteries, veins and capillaries. The cases in which the capillary vessel walls are affected have a higher probability of having one or two apoe 4 alleles. Parenchymal as well as vascular Aβ deposition follows a stepwise progression. Tau accumulation, probably the best histopathological correlate of the clinical symptoms, takes three aspects: in the cell body of the neuron as neurofibrillary tangle, in the dendrites as neuropil threads, and in the axons forming the senile plaque neuritic corona. The progression of tau pathology is stepwise and stereotyped from the entorhinal cortex, through the hippocampus, to the isocortex. The neuronal loss is heterogeneous and area-specific. Its mechanism is still discussed. The timing of the synaptic loss, probably linked to Aβ peptide itself, maybe as oligomers, is also controversial. Various clinico-pathological types of Alzheimer disease have been described, according to the type of the lesions (plaque only and tangle predominant), the type of onset (focal onset), the cause (genetic or sporadic) and the associated lesions (Lewy bodies, vascular lesions, hippocampal sclerosis, TDP-43 inclusions and argyrophilic grain disease).

Classification and basic pathology of Alzheimer disease.

The authors assessed the association of smoking with dementia and cognitive decline in a meta-analysis of 19 prospective studies with at least 12 months of follow-up. Studies included a total of 26,374 participants followed for dementia for 2-30 years and 17,023 participants followed up for 2-7 years to assess cognitive decline. Mean study age was 74 years. Current smokers at baseline, relative to never smokers, had risks of 1.79 (95% confidence interval (CI): 1.43, 2.23) for incident Alzheimer's disease, 1.78 (95% CI: 1.28, 2.47) for incident vascular dementia, and 1.27 (95% CI: 1.02, 1.60) for any dementia. Compared with those who never smoked, current smokers at baseline also showed greater yearly declines in Mini-Mental State Examination scores over the follow-up period (effect size (beta)=-0.13, 95% CI: -0.18, -0.08). Compared with former smokers, current smokers at baseline showed an increased risk of Alzheimer's disease (relative risk=1.70, 95% CI: 1.25, 2.31) and an increased decline in cognitive abilities (effect size (beta)=-0.07, 95% CI: -0.11, -0.03), but the groups were not different regarding risk of vascular dementia or any dementia. The authors concluded that elderly smokers have increased risks of dementia and cognitive decline.

Smoking as a Risk Factor for Dementia and Cognitive Decline: A Meta-Analysis of Prospective Studies

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.

Mixed Dementia: Epidemiology, Diagnosis, and Treatment

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 β focal deposits (Aβ 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, Aβ 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

Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly.

The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy.

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.

Cerebral amyloid angiopathy in the elderly: vessel walls changes and relationship with dementia

Frailty has long been considered synonymous with disability and co-morbidity, to be highly prevalent in old age and to confer high risk for falls, hospitalization, and mortality. However it is becoming recognized that frailty may be a distinct clinical syndrome with a biologic basis. The frailty process appears as a transitional state in the dynamic progression from robustness through to functional decline. During this process, total physiological reserves decrease, and become less likely to be sufficient to maintain and repair the ageing body. The lack of consensus on the definition of frailty is partially related to the widespread use of the expression for different aspects of the condition. Longitudinal studies have demonstrated that slow gait, fatigue, exhaustion, anorexia, unintentional weight loss and reduced muscle strength should all be considered as major symptoms of frailty. At the stage of frailty, clinicians can easily distinguish frail from non-frail older adults using factors such as appearance (consistent or not with age), nutritional status (thin, weight loss), subjective health rating (health perception), performance (cognition, fatigue), sensory/physical impairments (vision, hearing, strength), and current care (medication, hospital). The process of “becoming frail” is silent and insidious. A better understanding of these clinical changes and their underlying mechanisms, beginning with the pre-frail state, may confirm the impression held by many geriatricians, that increasing frailty is distinguishable from ageing, and in consequence is potentially reversible. We therefore provide an update of the physiopathology and clinical, and biological characteristics of the frailty process, and speculate on possible preventive approaches.

Dina Zekry

Papers

Mixed Dementia: Epidemiology, Diagnosis, and Treatment

Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly.

The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy.

Cerebral amyloid angiopathy in the elderly: vessel walls changes and relationship with dementia

The frailty process: update of the phenotype and preventive strategies