Prof Marc Verny
email: marc.verny@aphp.fr

Charles Duyckaerts

Cognitive deficit, and neuropathological correlates, in the oldest-old

Keywords: dementia, cerebral amyloid angiopathy, TDP-43 inclusions, Lewy body, multiple brain lesions

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Cognitive deficit, when occurring in the oldest old, raises specific questions. The signs and symptoms are difficult to evaluate. The clinical history is usually hard to obtain in the absence of a next of kin. Comorbidities are the rule. Neurosensory deficits make testing difficult. Neuropsychological standards are rarely validated for patients over 80 years old. For a given socio-economic level, older people have often received less education. Clinical-pathologic studies, which have rarely involved this population, have generally demonstrated the existence of diseases specific for older age and have emphasized the frequency of brain co-lesions. Comorbidities partly explain why it is so difficult to identify a specific clinical pattern of known disorders. It has also been shown that the strength of clinic-pathological correlations is weaker in the oldest old than in younger patients. In this population, positive diagnosis of major neurocognitive disorders is frequently challenging (see table 1 of [START_REF] Gardner | Dementia in the oldest old: a multi-factorial and growing public health issue[END_REF]). This paper will describe the most common causes of cognitive impairment in the oldest old and their specific characteristics in this population.

Alzheimer disease

Alzheimer disease (AD) is the most common cause of intellectual deficit in the oldest old. In the elderly population, AD accounts for 60 to 70 % of all cases of intellectual deficit [START_REF] Pierce | Late-Onset Alzheimer Disease[END_REF]. Most epidemiological studies have dealt with dementia (all causes included). There has been some controversy concerning the incidence of dementia and AD, the incidence of AD reaching a plateau in the eldest population [START_REF] Miech | Incidence of AD may decline in the early 90s for men, later for women: the Cache County study[END_REF]. Most studies, however, indicate that the incidence of all-cause dementia is still increasing at advanced age [START_REF] Corrada | Dementia incidence continues to increase with age in the oldest old: The 90+ study[END_REF] even if the rate of increase could decelerate in the oldest old (see fig 2 of [START_REF] Pierce | Late-Onset Alzheimer Disease[END_REF]). By contrast, AD-related neuropathological changes seen at post-mortem examination peak at 95, and decline thereafter, while other causes of dementia become more prevalent, particularly in combination [START_REF] Farfel | Alzheimer's disease frequency peaks in the tenth decade and is lower afterwards[END_REF].

Low level of education, low level of physical activity, and poor physical performance were associated with dementia at older age ( [START_REF] Gardner | Dementia in the oldest old: a multi-factorial and growing public health issue[END_REF][START_REF] Bullain | Sound body sound mind? Physical performance and the risk of dementia in the oldest-old: The 90+ Study[END_REF]. The strong association between the risk of AD and the ApoE4 allele is not found in the oldest old [START_REF] Juva | APOE epsilon4 does not predict mortality, cognitive decline, or dementia in the oldest old[END_REF]. The ApoE4 allele is also less prevalent in this population, probably because of a detrimental effect of the E4 allele on survival [START_REF] Corrada | Apolipoprotein E genotype, dementia, and mortality in the oldest old: The 90+ Study[END_REF]. Surprisingly in a study involving individuals over 85 years of age, the authors showed that "ε4 did not predict dementia, but did predict AD-or amyloid-related pathologies; ε2 predicted dementia, but it was protective against amyloid and neuropathological AD; and ε3ε3 was protective against dementia, neurofibrillary tangles, and cerebral amyloid angiopathy (CAA)." High blood pressure known to increase the risk of dementia and AD in the younger population appears to be protective after the age of 85 years [START_REF] Euser | The effect of age on the association between blood pressure and cognitive function later in life[END_REF]. Finally, good or optimal health (i.e., no history of serious illness, vitamin deficiencies, head injury or substance abuse) at 85 years of age or older was associated with delayed onset of cognitive deficit or AD [START_REF] Mc Neal | Predictors of healthy brain aging[END_REF].

The common clinical feature is the gradual onset of a deficit involving episodic memory (as in the typical form of AD in younger patients). The deficit progresses over several years involving other cognitive functions with an impact on the subject's ability to perform activities of daily living (ADL) [START_REF] Pierce | Late-Onset Alzheimer Disease[END_REF]. Mean age of onset of atypical AD (logopenic, posterior or frontal variants) is younger than the mean age of onset observed in the typical form. At the initial stage (mild neurocognitive disorders), certain psychiatric symptoms are frequent such as apathy, anxiety and depression. Later, paranoid delusions and agitation may appear. Sleep disorders with circadian rhythm deregulation are frequent [START_REF] Pierce | Late-Onset Alzheimer Disease[END_REF]. Neuropsychological differences depending on the age of onset have been emphasized [START_REF] Tellechea | Early-and late-onset Alzheimer disease: Are they the same entity?[END_REF][START_REF] Joubert | Early-onset and late-onset Alzheimer's disease are associated with distinct patterns of memory impairment[END_REF]. However, to the best of our knowledge, no study has dealt specifically with the oldest old population.

The neuropathological diagnosis of AD relies on the presence of extracellular Aβ deposits and intraneuronal tau aggregation [START_REF] Montine | National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach[END_REF][START_REF] Hyman | National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease[END_REF]. The senile plaque is made of a core of amyloid Aβ surrounded by a corona of tau-positive neurites. Aggregation of tau in the soma of the neuron defines the neurofibrillary tangle (Fig. 1, a &b). Aβ deposition usually occurs also in the vessel walls (cerebral amyloid angiopathy) and affects the large vessels with or without capillary involvement (Fig. 1,c).

The course of AD has been considered as more aggressive in case of younger age and seems slower after 80 years old [START_REF] Barnes | Disease course varies according to age and symptom length in Alzheimer's disease[END_REF], but this point remains debated [START_REF] Eldholm | Progression of Alzheimer's disease: A longitudinal study in Norwegian memory clinics[END_REF]. The ratio between the density of neurofibrillary tangles in the cortex and in the hippocampus has been used to distinguish three types of AD: typical (25 th -75 th percentile), hippocampal sparing (<25 th percentile) and limbic predominant (>75 th percentile). Cases with hippocampal sparing are characterized by severe cortical symptoms; the mean age of death is 73. The memory deficit is prevalent in limbic predominant type; the mean age of death is older (86 y) [START_REF] Murray | Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study[END_REF]. The relationship between AD neuropathological changes (mainly tau pathology) and the cognitive deficit is usually strong before the age of 75, but tends to decrease in the very old population. There is almost a nine-times greater chance of developing dementia when neuritic plaques of the neocortex are present at age 75; this chance is only 2.48-times higher at age 95 [START_REF] Savva | Age, neuropathology, and dementia[END_REF]. In the "religious orders study" -a prospective and longitudinal clinical-pathological study involving religious communities -about 90% of the cases diagnosed as AD had a high density of AD changes (mean age at death: 86.6 years). But half of the cases with a diagnosis of mild cognitive impairment and one-third of the cases with normal cognitive function also met the neuropathological criteria of AD used at that time [START_REF] Bennett | Overview and findings from the religious orders study[END_REF]. The predominance of the amnestic syndrome in those cases has been emphasized [START_REF] Bennett | Overview and findings from the religious orders study[END_REF]. The relative sparing of cognitive abilities despite AD lesions has been interpreted as due to "resilience" in relation with a cognitive reserve [START_REF] Negash | Cognition and neuropathology in aging: multidimensional perspectives from the Rush Religious Orders Study and Rush Memory And Aging Project[END_REF].

Vascular diseases

Multiple large cerebral infarcts (total volume > 200 ml [START_REF] White | Recent clinical-pathologic research on the causes of dementia in late life: update from the Honolulu-Asia aging study[END_REF]), strategic infarcts (most often bilateral thalamic infarcts) or subcortical vascular encephalopathy are the classical causes of vascular cognitive impairment (that does not always fully qualify for the term vascular dementia) [START_REF] Thal | Vascular dementia: Different forms of vessel disorders contribute to the development of dementia in the elderly brain[END_REF]. Emphasis has been put on "microinfarcts" [START_REF] White | Recent clinical-pathologic research on the causes of dementia in late life: update from the Honolulu-Asia aging study[END_REF]. The definition of microinfarcts is not yet fully settled. They are basically infarcts that are not visible to the naked eye [START_REF] Van Veluw | Detection, risk factors, and functional consequences of cerebral microinfarcts[END_REF]. A maximal diameter of 5 mm has been proposed but it may be as small as 100 µm. Their number may be high (values of hundreds or even thousands per case have been given). They may be cortical or subcortical. Cortical microinfarcts are associated with an increased risk of dementia [START_REF] Arvanitakis | Microinfarct pathology, dementia, and cognitive systems[END_REF]. Diabetes and hypertension are not risk factors of cortical microinfarcts while CAA is [START_REF] Corrada | Microinfarcts are common and strongly related to dementia in the oldest-old: The 90+ study[END_REF][START_REF] Tanskanen | Population-based analysis of pathological correlates of dementia in the oldest old[END_REF]. Only a subset of microinfarcts are visible with magnetic resonance imaging (MRI) that is able to cover a larger volume of the brain, while neuropathology is able to detect microinfarcts of all sizes and in the acute as well as in the chronic stage, but neuropathological analysis barely covers 0.01% of the total volume of the brain [START_REF] Van Veluw | Detection, risk factors, and functional consequences of cerebral microinfarcts[END_REF]. Microinfarcts are uniformly distributed throughout the cortex. The presence of microinfarcts was found in 51% of the cases and was associated with lower educational level and history of transient ischemic attack [START_REF] Corrada | Microinfarcts are common and strongly related to dementia in the oldest-old: The 90+ study[END_REF] in a cohort of patients over 90. Microinfarcts frequently coexisted with larger infarcts. The microinfarcts in frontal, parietal and temporal cortical regions were strongly related to dementia. Similar results were obtained in a cohort of patients over 85 years of age [START_REF] Tanskanen | Population-based analysis of pathological correlates of dementia in the oldest old[END_REF]. Cortical microinfarcts in a population of patients, presenting with "eligible" cerebral amyloid angiopathy (aged 70 on average at inclusion), were found in 39% of the cases on MRI.

Microinfarcts are associated with lower total brain volume and cortical superficial siderosis but not with the volume of white matter hyperintensities or the number of lobar cerebral microbleeds [START_REF] Xiong | Cerebral cortical microinfarcts on magnetic resonance imaging and their association with cognition in cerebral amyloid angiopathy[END_REF].

Brain MRI often shows cortical microbleeds in patients with cognitive impairment (up to 20% of the cases). Microbleeds raise the possibility of CAA. In neuropathological series, the frequency of CAA increases with age to reach 16% after 85 years [START_REF] Robinson | Non-Alzheimer's contributions to dementia and cognitive resilience in the 90+ Study[END_REF]. Not all the microbleeds detected at MRI correspond to CAA. In the study of Robinson et al., only half (8%) of the 16% of neuropathologically diagnosed CAA cases had moderate to severe amyloid angiopathy; in8 %, the angiopathy was considered as mild [START_REF] Robinson | Non-Alzheimer's contributions to dementia and cognitive resilience in the 90+ Study[END_REF]. Finally, while up to 80% of AD cases have CAA of various degrees of severity, only 20% present with associated vascular lesions.

Hippocampal sclerosis

Hippocampal sclerosis (HS) is found in multiple conditions such as epilepsy, anoxia or frontotemporal lobar degeneration 43kDa TAR DNA-binding protein (FTLD-TDP). It may also be associated with aging with or without AD lesions (HS-aging or HS-dementia [START_REF] Onyike | Hippocampal sclerosis dementia: An amnesic variant of frontotemporal degeneration[END_REF]). The neuropathological definition of HS-aging includes neuronal loss in the CA1 sector of the hippocampus, associated -necessarily [START_REF] Robinson | Non-Alzheimer's contributions to dementia and cognitive resilience in the 90+ Study[END_REF] or not [START_REF] Hokkanen | Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population[END_REF] with neuronal loss in the subiculum. The CA2, CA3 and CA4 sectors and the dentate gyrus are spared. The lesion may be segmental [START_REF] Ighodaro | Hippocampal sclerosis of aging can be segmental: Two cases and review of the literature[END_REF], unilateral or bilateral but then often asymmetric [START_REF] Amador-Ortiz | Neuropathology of hippocampal sclerosis[END_REF]. Neuronal loss is accompanied by severe gliosis.

Increased awareness of HS-aging has caused an increase in its apparent prevalence from approximately 0% to over 18% in the National Alzheimer's Coordinating Center (NACC) data [START_REF] Brenowitz | Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both alzheimer's disease and non-tauopathic frontotemporal lobar degeneration[END_REF]. HS-aging prevalence increases with age [START_REF] Brenowitz | Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both alzheimer's disease and non-tauopathic frontotemporal lobar degeneration[END_REF]: present in 5/49 (10%) centenarians in the Georgia centenarian study [START_REF] Tanprasertsuk | Cliniconeuropathological findings in the oldest old from the Georgia Centenarian Study[END_REF], they were found in 35/642 (5%) cases in the "CC75C and CFAS" cohorts (mean age at death: 89 years) [START_REF] Hokkanen | Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population[END_REF], and in 28/185 (15%) [START_REF] Robinson | Non-Alzheimer's contributions to dementia and cognitive resilience in the 90+ Study[END_REF] or 31/183 (17%) [START_REF] Kawas | Multiple pathologies are common and related to dementia in the oldest-old[END_REF] cases in the 90+ study. The prevalence of the lesion is lower when "ischemic events" or epilepsy are excluded (as in [START_REF] Hokkanen | Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population[END_REF]). HS-aging and AD neuropathological changes are frequently associated, given the age of the patients -but the presence of AD neuropathological changes does not increase the risk of HS-aging [START_REF] Hokkanen | Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population[END_REF], see table 4 in [START_REF] Nag | Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease[END_REF]. One study has specifically focused on the risk factors of HS in the oldest old [START_REF] Trieu | Risk factors of hippocampal sclerosis in the oldest old[END_REF]. The authors stressed the potential role of two autoimmune conditions (rheumatoid arthritis and thyroid disease; OR 3.15; 95% CI 1.30-7.62; p = 0.011) in the development of HS in their cohort. Lewy body pathology was the only condition that increased the likelihood of HS (OR 5.70; 95% CI 1.22-26.4; p = 0.027).

Isolated bilateral lesions of the hippocampus of various origins have been known for long to cause a pure amnestic syndrome. The clinical picture in HS-aging is however more complex, and difficult to distinguish from the signs and symptoms of AD, or, when behavioral symptoms are prominent, from FTD -hence the term of HS-dementia that has been sometimes used [START_REF] Onyike | Hippocampal sclerosis dementia: An amnesic variant of frontotemporal degeneration[END_REF]. Its progression is slower than AD. Semantic and visuospatial tests are more affected in AD cases even if the global cognitive impairment is similar. Executive functions are similarly altered in HS and AD patients [START_REF] Smirnov | Trajectories of cognitive decline differ in hippocampal sclerosis and Alzheimer's disease[END_REF]. The large spectrum of cognitive deficits already suggests a disorder that is not limited to the hippocampus. Indeed, TDP-43 immunohistochemistry confirms the broader scope of the modifications. TDP-43 inclusions are the hallmark lesions of FTLD-TDP (which include mutations of granulin (GRN) genes, and hexanucleotide repeats in the C9ORF72 gene). TDP-43 inclusions (Fig. 1, d &e) are commonly found in HS: 8/11 (73%) cases in pure HS, 33/44 (75%) cases in HS associated with AD and in 5/10 (50%) cases of HS associated with other pathologies [START_REF] Amador-Ortiz | TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease[END_REF] and up to 100% of the cases in [START_REF] Hokkanen | Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population[END_REF]. The inclusions are found in areas that may include the hippocampus but may also involve more limited or larger areas -limbicpredominant age-related TDP-43 encephalopathy (LATE) (see below). The involvement of the hippocampus now appears as a stage of a more extensive pathology defined by TDP-43 inclusions: HSaging becomes but a part of a larger disorder thought to be FTLD-TDP [START_REF] Hatanpaa | Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia[END_REF] or more recently a specific disease of old age, called limbic-predominant age-related TDP-43 encephalopathy (LATE) [START_REF] Nelson | Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report[END_REF].

Limbic-predominant age-related TDP-43 encephalopathy (LATE)

In all groups of patients with neurocognitive disorders dying after 80 years, TDP-43 inclusions (now defined as belonging to LATE neuropathological changes: NC) appear as important contributors (> 20%). Clinically, the patients present at onset with an amnestic syndrome that mimics AD. It can evolve to a multidomain cognitive impairment with an alteration of ADL. At neuropathological examination, TDP-43 inclusions are found in the amygdala (stage 1), in the amygdala and hippocampus (stage 2), and finally also in the frontal cortex (stage 3).

The correlative studies indicate that patients with relatively preserved verbal fluency (corticallydependent), despite profound deficiency in word list delayed recall (hippocampal-dependent) are at risk for LATE-NC. Neuropathological stages 2 and 3 of LATE-NC are responsible for mild cognitive impairment or dementia in respectively 81 and 92% of cases. In cases of pure neuropathological lesions of LATE-NC, the course of the disease is more gradual than in cases of pathological association with AD lesions. Cooccurrence of LATE and AD may be responsible for an increased risk of agitation and aggression [START_REF] Sennik | Risk factors and pathological substrates associated with agitation/aggression in Alzheimer's disease: A preliminary study using NACC Data[END_REF]. The concept of LATE is recent; its existence as distinct from FTLD-TDP has been criticized [START_REF] Josephs | LATE to the PART-y[END_REF]. The clinicalpathologic correlations are still under investigation.

Lewy bodies

Lewy bodies are inclusions that are found in the cell body of the neuron, principally made of aggregated phosphorylated alpha-synuclein. Lewy bodies are confined to the brainstem usually in cases presenting with Parkinson disease. They are found in the cerebral cortex (Fig. 1,f) usually in patients with dementia (either Parkinson disease dementia or dementia with Lewy bodies when the cognitive deficit develops less than one year after the motor symptoms).

Clinical criteria of Lewy body dementia (LBD) as described in the fourth consensus report of dementia with Lewy bodies includes, besides the symptoms of dementia, "core clinical features": fluctuating cognition with pronounced variations in attention and alertness, recurrent visual hallucinations that are typically well formed and detailed, REM sleep behavior disorders which may precede cognitive decline, one or more cardinal features of parkinsonism (bradykinesia, rest tremor, rigidity). The diagnostic criteria also include supportive features (such as severe sensitivity to antipsychotic agents, severe autonomic dysfunction or hypersomnia and hyposmia), and indicative or supportive biomarkers. The fourth consensus report does not include any specific modification of the criteria with advanced age [START_REF] Mckeith | Diagnosis and management of dementia with Lewy bodies[END_REF]. The wide variability in the estimates of disease incidence and prevalence is the consequence of the difficulty of the clinical diagnosis. In a meta-analysis collecting clinical papers, incidence ranged from 0.5 to 1.6 persons / year and prevalence from 0.02 to 63.5 / 1000 persons [START_REF] Hogan | The prevalence and incidence of dementia with Lewy Bodies: a systematic review[END_REF]. In this meta-analysis, the prevalence of LBD increased with age and accounted for about 5% of all dementia cases in older populations. Other data indicate however a decrease in the oldest old [START_REF] Kane | Clinical prevalence of Lewy body dementia[END_REF].

The difficulty of the diagnosis is underlined by the neuropathologic studies. They show the high prevalence of Lewy bodies: in a clinical-pathologic study involving a population of oldest old [START_REF] Robinson | Non-Alzheimer's contributions to dementia and cognitive resilience in the 90+ Study[END_REF], Lewy bodies were found in 17% of the cases, 6% in the brainstem, 9% in the brainstem and limbic cortex and 1% in the neocortex. They also demonstrated that the cortical topography of the Lewy bodies has an impact on cognition. Lewy-related pathology, when it involved the neocortex, had a strong and significant association with dementia [START_REF] Tanskanen | Population-based analysis of pathological correlates of dementia in the oldest old[END_REF]. The analysis of the data of the National Alzheimer's Coordinating Center (NACC) showed the low sensitivity of clinical diagnosis (32.1% for pure LBD and 12.1% for AD + LBD) contrasting with good specificity (>95%) [START_REF] Nelson | Low sensitivity in clinical diagnoses of dementia with Lewy bodies[END_REF].

Among 345 patients with clinically diagnosed as Parkinson disease -disease onset ≥80 years in 90 and pathological diagnosis in 75 (comorbid conditions in 54) -the rate of dementia was 80% [START_REF] Jellinger | Very old onset parkinsonism: A clinical-pathological study[END_REF]. Fifty percent of the patients developed dementia when only Lewy pathology was found at post mortem. The association with vascular pathology did not modify the prevalence of dementia; by contrast, the frequent association with Alzheimer pathology was always associated with it. DOPA reactivity was positive only in half of the cases. Disease course and survival were shorter than in younger patients.

Aging-related tau astrogliopathy (ARTAG)

Neuropathological assessment of autopsy series of old patients has shown that phosphorylated tau could accumulate in astrocytes, in specific regions of the brain: below the ependymal, around the vessels or in the gray matter [START_REF] Kovacs | Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy[END_REF]. Clinical-pathologic correlations indicate that gray matter tau astrogliopathy may contribute to the cognitive impairment [START_REF] Robinson | Non-Alzheimer's contributions to dementia and cognitive resilience in the 90+ Study[END_REF]. The frequency of ARTAG increases with age and could be of interest in about half of the brains examined, according to some authors [START_REF] Robinson | Non-Alzheimer's contributions to dementia and cognitive resilience in the 90+ Study[END_REF].

Multiple pathologies in the brain

The main message from multiple pathologies studies of dementia in the oldest old is the correlation of cognitive impairment with associations of neuropathological lesions of different diseases [START_REF] Gardner | Dementia in the oldest old: a multi-factorial and growing public health issue[END_REF][START_REF] Robinson | Non-Alzheimer's contributions to dementia and cognitive resilience in the 90+ Study[END_REF][START_REF] White | Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies[END_REF][START_REF] Neltner | Brain pathologies in extreme old age[END_REF]. The most prevalent lesions are AD neuropathological changes and vascular changes; the importance of TDP 43 proteinopathy (LATE) including hippocampal sclerosis has been stressed more recently [START_REF] Nelson | Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report[END_REF]. As previously seen, the importance of Lewy body pathology is debated in this population. From a clinical point of view, the frequent association of multiple types of lesions causes complex symptoms and signs that may suggest different disorders or be too unspecific to be related to one single disease.

Consequences of general health on cognitive status

The reduction of cognitive reserve with age and the presence of multiple types of brain alterations make the cognitive status of patients more sensitive to systemic disorders. These disorders, commonly well tolerated in the young may, in the oldest old, disrupt a delicate balance. The disequilibrium can cause acute delirium or induce chronic cognitive dysfunction. The smaller the cognitive reserve, the less noxious the precipitating cause of delirium [START_REF] Inouye | Delirium in elderly people[END_REF]. The most frequent precipitating factors are infectious diseases, drugs, metabolic disorders and surgery (notably in emergency cases). The slope of cognitive decline in AD patients is accelerated after delirium [START_REF] Fong | Delirium accelerates cognitive decline in Alzheimer disease[END_REF]. Systemic disorders can lead to a loss of cognitive function sufficient to compromise previously spared autonomy. Chronic extra-neural pathologies such as atrial fibrillation [START_REF] Kalantarian | Cognitive impairment associated with atrial fibrillation[END_REF], obesity [START_REF] Cardoso | Diabesity and brain disturbances: A metabolic perspective[END_REF], diabetes [START_REF] Moheet | Impact of diabetes on cognitive function and brain structure[END_REF], chronic heart failure [START_REF] Ampadu | Heart failure and cognitive dysfunction[END_REF]… have a demonstrated role in cognitive impairment. Toxics can worsen cognitive impairment: this is observed, for instance, with alcohol consumption (even when low but regular) or with anticholinergic drugs [START_REF] Jaïdi | Reduction of the anticholinergic burden makes it possible to decrease behavioral and psychological symptoms of dementia[END_REF]. Appropriate analysis and treatment of all the multiple components interfering with cognitive functions is fundamental to improve the patient's cognitive status.

Conclusions

Neuropathology studies of large series of old patients have identified a few common diseases such as Alzheimer disease, Lewy body disease, vascular disorders and more recently TDP-43 accumulation. They have also shown that these pathological conditions were rarely pure but commonly associated -an association that makes their clinical diagnosis complex.

In the context of age-related diminution of cognitive reserve, together with the above-mentioned lesions, systemic disorders may lead to rapid worsening of the intellectual deficit and impaired activities of daily living. Some of the involved disorders may be amenable to treatment and are thus crucial to detect. Simple actions may then dramatically improve the patient's cognitive status.

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