Thibault Teissier

Eric Boulanger

Vincent Deramecourt

Normal ageing of the brain: histological and biological aspects

All the hallmarks of ageing are observed in the brain, and its cells, especially neurons, are characterized by their remarkably long lifetime. Like any organ or system, the brain is exposed to ageing processes which affect molecules, cells, blood vessels, gross morphology and, uniquely for this organ, cognition. The preponderant cerebral structures are characterized by the cellular processes of neurons and glial cells and while the quantity of cerebral interstitial fluid is limited, it is now recognized as playing a crucial role in maintaining cerebral homeostasis. Most of our current knowledge of the ageing brain derives from studies of neurodegenerative disorders. It is interesting to note that common features of these disorders, like Tau, phosphoTau and amyloid peptide accumulation, can begin relatively early in life as a result of physiological ageing and are present in subclinical cases while also being used as early-stage markers of neurodegenerative diseases in progression. In this article, we review tissue and cellular modifications in the ageing brain. Commonly described macroscopic, microscopic and vascular changes that in the ageing brain are contrasted with those seen in neurodegenerative contexts. We also review the molecular changes that occur with age in the brain, such as modifications in gene expression, insulin/insulin-like growth factor 1 signalling dysfunction, post-translational protein modifications, mitochondrial dysfunction, autophagy and calcium conductance changes.

Introduction

The histological architecture of the brain is remarkably complex. Grey and white brain matter are both characterised by the processes of tightly-interspersed neurons and glial cells. Despite its small volume, the interstitial fluid is now known to play a crucial role in maintaining the homeostasis of such a complex cellular system. Its composition is highly regulated by the blood-brain barrier. It also plays an important role in protecting the brain against neurotoxic compounds and in clearing metabolic and peptidic waste, such as the amyloid peptide, from the brain to perivascular spaces. Thus, it is sometimes considered to be an equivalent of the lymphatic system in the central nervous system, and has come to be known as the glymphatic system [START_REF] Iliff | A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β[END_REF]. Brain cells, and especially neurons, are remarkable for their long lifetime. Once mature, most of our neurons last our entire lifetime and show a high potential for plasticity in order to continuously modulate and adapt their complex synaptic network to changing conditions. Like any organ or system, the brain is exposed to the ageing process which affects molecules, cells, blood vessels, gross morphology. Unlike other organs, however, the ageing process in the brain can significantly affect cognition. Changes in the brain with age have been studied since the 19 th century -the exact nature and precise mechanisms of these changes nevertheless remain, for the most part, poorly defined. Furthermore, it remains difficult to define the boundary between "normal" changes due to ageing and the early stages of common, neurodegenerative diseases such as Alzheimer's disease (AD) seen in elderly people.

In this article, we review the macroscopic, structural and molecular changes that occur with ageing, the main neuropathological lesions commonly found in normal ageing brains, and discuss how ageing affects neuroplasticity.

Tissue and cell modifications in the ageing brain

Macroscopic brain changes with age

The volume and the weight of the human brain exhibits significant interindividual variability. There also exists a cohort bias since the mean weight of the human brain has significantly increased over the 20 th century (about 1g/y) [START_REF] Miller | Evidence for a secular increase in human brain weight during the past century[END_REF]. Early post-mortem studies, later confirmed by neuroimaging longitudinal studies, have shown that brain weight loss is very subtle between 20 and 60 years of age (about 0.1% per year) [START_REF] Dekaban | Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights[END_REF]. The progressive atrophy may be more rapid thereafter, particularly over the age of 70 [START_REF] Ho | Analysis of brain weight. I. Adult brain weight in relation to sex, race, and age[END_REF], [START_REF] Svennerholm | Changes in weight and compositions of major membrane components of human brain during the span of adult human life of Swedes[END_REF], with an annual rate of weight loss between 2 and 5%. The reasons for this progressive loss of brain weight with age are not clear. The most commonly reported explanations are the decline in volume of pyramidal neurons (rather than their number or density) and a decrease in their dendritic and axonal arborizations [START_REF] Anderson | The effect of advanced old age on the neurone content of the cerebral cortex. Observations with an automatic image analyser point counting method[END_REF]. This decrease is quite diffuse in white matter, but the shrinkage of grey matter is less uniform with the frontoparietal cortex more affected than the temporo-occipital [START_REF] Resnick | Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain[END_REF]. As a consequence of this reduced brain volume, the ventricular system expands and the subarachnoid space enlarges (Fig. 1A andB).

Microscopic brain changes with age

The issue of neuronal loss has long been a matter of controversy. Initial studies, from the 1950s, overestimated the loss of neurons with age because their density was only evaluated in two-dimensions -the cerebral cortex and hippocampus were thought to be particularly affected. However, different conclusions were arrived at with the use of modern, stereologically-based quantification in three dimensions [START_REF] West | Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias[END_REF]- [START_REF] Gómez-Isla | Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease[END_REF]. Neuronal loss with ageing is now considered as either undetectable or not exceeding 10% over our life span [START_REF] Pakkenberg | Neocortical neuron number in humans: effect of sex and age[END_REF], [START_REF] West | Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease[END_REF]. In some parts of the brain such as the locus coeruleus (LC), however, up to 25% of LC neurons are lost in the elderly (between the fourth and ninth decade) [START_REF] Mann | The locus coeruleus and its possible role in ageing and degenerative disease of the human central nervous system[END_REF]. Grey matter volume also significantly reduces over time, with the most severe losses in the insula, superior parietal gyri, central sulci, and cingulate sulci while amygdala, hippocampi, and entorhinal cortex are relatively well preserved [START_REF] Good | A Voxel-Based Morphometric Study of Ageing in 465 Normal Adult Human Brains[END_REF], [START_REF] Resnick | Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain[END_REF]. However, grey matter shrinkage does not necessarily result from neurodegeneration: it is rather suggested that it is mainly caused by extensive dendritic regression [START_REF] Dickstein | Changes in the structural complexity of the aged brain[END_REF]. A decline in white matter volume and integrity has also been reported [START_REF] Marstaller | Aging and largescale functional networks: white matter integrity, gray matter volume, and functional connectivity in the resting state[END_REF]- [START_REF] Drayer | Imaging of the aging brain. Part I. Normal findings[END_REF], notably in the prefrontal cortex [START_REF] Hedden | Insights into the ageing mind: a view from cognitive neuroscience[END_REF]. Therefore, normal cellular brain ageing is characterized more by subtle changes than a large-scale loss of cells. In the hippocampus, dendritic extents may increase in the dentate gyrus [START_REF] Flood | Dendritic extent in human dentate gyrus granule cells in normal aging and senile dementia[END_REF] while remaining stable in the 1 and 3 areas of the cornu ammonis (CA) and in the subiculum [START_REF] Hanks | Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease. I. CA1 of hippocampus[END_REF]- [START_REF] Flood | Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease. II. Subiculum[END_REF]. Similarly, no change in spines' density with age has been reported in the human hippocampus [START_REF] Williams | Age-related changes in Down syndrome brain and the cellular pathology of Alzheimer disease[END_REF], [START_REF] Curcio | Stability of synaptic density and spine volume in dentate gyrus of aged rats[END_REF]. On the other hand, frontal cortex and cingulate pyramidal neurons show a decrease in dendritic branching in rats [START_REF] Grill | Age-related and laminar-specific dendritic changes in the medial frontal cortex of the rat[END_REF], [START_REF] Markham | Aging and sex influence the anatomy of the rat anterior cingulate cortex[END_REF] which has also been found in the human medial prefrontal cortex [START_REF] De Brabander | Layer-specific dendritic regression of pyramidal cells with ageing in the human prefrontal cortex[END_REF]. In areas 10 and 18 of the human cortex, a 46% reduction in spine number and density has been reported in persons over 50 years [START_REF] Jacobs | Life-span dendritic and spine changes in areas 10 and 18 of human cortex: a quantitative Golgi study[END_REF]. In macaques, spine density in the neocortex decreased significantly with ageing [START_REF] Kabaso | The electrotonic structure of pyramidal neurons contributing to prefrontal cortical circuits in macaque monkeys is significantly altered in aging[END_REF], [START_REF] Duan | Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys[END_REF] and was associated with a loss of synapses [START_REF] Morrison | The Aging Cortical Synapse: Hallmarks and Implications for Cognitive Decline[END_REF]. Overall dendritic spine changes with age have been well described elsewhere [START_REF] Morrison | The Aging Cortical Synapse: Hallmarks and Implications for Cognitive Decline[END_REF], [START_REF] Dickstein | Dendritic spine changes associated with normal aging[END_REF]. These results reflect well the differences in grey matter shrinkage found between the various brain regions, as mentioned above. Myelinated nerve fibres from the white matter are also affected by normal ageing. While a part of them are lost, another part loses its myelin sheath which is incompletely remyelinated by oligodendrocytes, the number of which increases with ageing, negatively affecting the conduction velocity along nerve fibres [START_REF] Peters | The Effects of Normal Aging on Myelinated Nerve Fibers in Monkey Central Nervous System[END_REF], [START_REF] Peters | The effects of normal aging on myelin and nerve fibers: a review[END_REF]. Thus, there is a constitutive myelination activity, potentially explaining the increase in the expression of genes involved in myelination function during ageing [START_REF] Bishop | Neural mechanisms of ageing and cognitive decline[END_REF], [START_REF] Tripathi | New cellular and molecular approaches to ageing brain[END_REF], [START_REF] Bae | Decipher reliable biomarkers of brain aging by integrating literature-based evidence with interactome data[END_REF]. Paradoxically, the sheath thickness of some nerve fibres is continuously increasing because of this sustained activity [START_REF] Peters | The Effects of Normal Aging on Myelinated Nerve Fibers in Monkey Central Nervous System[END_REF], [START_REF] Stahon | Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter[END_REF]. As these changes seem to occur quite early in life, some authors suggest that myelin is the most susceptible part of the brain to ageing [START_REF] Xie | Effects of normal aging on myelin sheath ultrastructures in the somatic sensorimotor system of rats[END_REF]. On the other hand, glial cells' activity and number both increase with age [START_REF] Esiri | Ageing and the brain[END_REF]- [START_REF] Finch | Neurons, glia, and plasticity in normal brain aging[END_REF] and most upregulated genes in the brain are of glial origin [START_REF] Erraji-Benchekroun | Molecular aging in human prefrontal cortex is selective and continuous throughout adult life[END_REF]. In the main, microglia activation is recognized as sustaining a pro-inflammatory environment [START_REF] Cribbs | Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study[END_REF], [START_REF] Norden | Review: microglia of the aged brain: primed to be activated and resistant to regulation[END_REF] which could increase neurons' susceptibility to neurodegeneration [START_REF] Colonna | Microglia Function in the Central Nervous System During Health and Neurodegeneration[END_REF] and loss of synapses [START_REF] Hao | Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity[END_REF], [START_REF] Stranahan | Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats[END_REF]. Finally, neurogenesis is also impaired with ageing. While most neurons in the adult brain are produced during embryogenesis or very early in life, adult neurogenesis has been identified in the hippocampus, the sub-ventricular zone and in the olfactory bulb of the mammalian brain [START_REF] Baptista | Adult Hippocampal Neurogenesis: Regulation and Possible Functional and Clinical Correlates[END_REF], [START_REF] Riddle | Neurogenesis in the Adult and Aging Brain[END_REF]. Although data are still lacking, neurogenesis seems to decline with advancing age, with an already significant decline by middle age, particularly in the hippocampus [START_REF] Baptista | Adult Hippocampal Neurogenesis: Regulation and Possible Functional and Clinical Correlates[END_REF]- [START_REF] Galvan | Neurogenesis in the aging brain[END_REF]. However, the significance of this decline is not fully understood yet [START_REF] Baptista | Adult Hippocampal Neurogenesis: Regulation and Possible Functional and Clinical Correlates[END_REF].

AD-related changes

Neurofibrillary tangles (NFT) and senile plaques (SP), the two main neuropathological lesions associated with the definitive diagnosis of AD, are frequently observed in the brains of elderly individuals with normal cognitive functions. This very common occurrence has led to the currently unresolved question as to what extent the presence of non-pathological, AD-related lesions should be considered as normal ageing (i.e. preclinical AD). NFT are characterized by the intracellular accumulation of abnormally-hyperphosphorylated Tau proteins into filamentous inclusions known as paired helicoidal filaments [START_REF] Grundke-Iqbal | Microtubule-associated protein tau. A component of Alzheimer paired helical filaments[END_REF]. Many studies have confirmed the consistency of their localization: the entorhinal cortex and the CA1 field of the hippocampus are the first brain regions where NFT occur, while only sparse lesions are present in the adjacent temporal neocortex or frontal neocortex (Figure 1C). NFT predominate in layer II, and to a lesser extent III and V, of the entorhinal cortex. This typical distribution of NFT is now widely recognized as the initial stages I and II (of VI) in the hierarchical and progressive spreading of neurofibrillary pathology described 30 years ago by Braak and Braak [START_REF] Braak | Neuropathological stageing of Alzheimer-related changes[END_REF]. More recent neuropathological studies, focusing on subcortical and brainstem nuclei, have even showed that the first NFT may appear in teenagers in the locus coeruleus. Some authors, mostly from the US, consider the early and mid-stages of this neurofibrillary pathology to be a specific pathological process, independent of AD pathology, and potentially associated with cognitive decline. They coined the term "PART" (Primary Age-Related Tauopathy) to describe this neuropathological phenotype [START_REF] Crary | Primary age-related tauopathy (PART): a common pathology associated with human aging[END_REF], but the concept has not attained a widespread, international consensus and remains controversial [START_REF] Duyckaerts | PART is part of Alzheimer disease[END_REF].

SP result from the extracellular aggregation of Aβ peptides [START_REF] Glenner | Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein[END_REF]. Several Aβ peptides, of between 38 and 42 amino acids, derive from a larger transmembrane protein APP (amyloid precursor protein) after a complex cleavage process involving three main secretases (α, β, and γ). The microscopic aspect of amyloid deposits in brain tissue is heterogeneous. Classically, neuropathologists distinguish between diffuse amyloid deposits, characterized by their ill limited extent and their lack of affinity for "amyloid" specific stains such as Congo-Red, and dense amyloid deposits that are usually well defined and comprise a dense amyloid core surrounded by a corona of dystrophic neurites. Amyloid deposits associated with ageing are mostly diffuse (Fig. 1D). Their topographical extent usually includes the orbitofrontal, occipital and precunei cortex, the hippocampus, and the basal ganglia. In other words, such amyloid deposits correspond to Thal phases 1 to 3 (of 5) [START_REF] Thal | Phases of A beta-deposition in the human brain and its relevance for the development of AD[END_REF].

Figure 2 summarises the estimated prevalence of amyloid deposits, hippocampal neurofibrillary pathology (Braak stages I and II), and extensive neocortical neurofibrillary pathology (Braak V and VI) according to the age of the subjects [START_REF] Duyckaerts | Prevalence, incidence and duration of Braak's stages in the general population: can we know?[END_REF]. These data come from large autopsy cohorts, especially from Braak and Braak (more than 2660 brains grouped into age classes) [START_REF] Braak | Diagnostic criteria for neuropathologic assessment of Alzheimer's disease[END_REF]. Despite the fact that such post-mortem, epidemiological studies lack clinical information and are potentially biased owing to the possibility of unrecorded, underlying pathologies which can affect brain ageing, it is interesting to notice that the median age for the presence of hippocampal NFT is around 45 years of age. Almost all subjects aged over 80 years present hippocampal neurofibrillary pathology. The median age for cortical amyloid pathology is about 75, but the prevalence curve of amyloid deposits does not seem to reach 100%, even in centenarians. The prevalence of high Braak stages for neurofibrillary pathology is close to that of AD in elderly patients. Such data are important to keep in mind when interpreting biological and imaging biomarkers of AD in cohorts of elderly people.

Other neurodegenerative lesions in the ageing brain

Various other pathologies have been described in the ageing brain, among them argyrophilic grains (Fig. 1E), characterized by the synaptic accumulation of Tau protein isoforms with four microtubule-bonding domains, mostly in the pyramidal layer of the hippocampus. Grains are known to be age-related [START_REF] Ding | Argyrophilic grain disease: frequency and neuropathology in centenarians[END_REF], [START_REF] Josephs | Argyrophilic grains: a distinct disease or an additive pathology?[END_REF] and were consistently observed in the brains of a group of 29 centenarians [START_REF] Pham | Tau-positive grains are constant in centenarians' hippocampus[END_REF]. TDP-43 pathology has also been observed in almost 20% of aged controls [START_REF] Mcaleese | TDP-43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing[END_REF]; once again, the hippocampus was the most vulnerable structure for TDP-43 accumulation.

Cerebrovascular changes

The microvascular system of the brain consists of pre-capillaries and capillaries, devoid of smooth muscle cells, forming a three-dimensional network within the brain parenchyma. This network is perfused by penetrating arterioles which represent the termini of brain vasculature. The absence of functional shunts between the penetrating arteries explains the vulnerability of the brain to ischaemia in case of thrombosis or global hypoperfusion. Normal ageing affects both the macro-and microvascular systems of the brain, resulting in altered cerebral blood flow in elderly people [START_REF] Brown | Review: cerebral microvascular pathology in ageing and neurodegeneration[END_REF]. The arterioles supplying the deep white matter have the longest course through the brain and they often become tortuous with age: Hassler found that they were sparse in subjects under the age of 60, but common after the age of 70 [START_REF] Hassler | Arterial deformities in senile brains. The occurrence of the deformities in a large autopsy series and some aspects of their functional significance[END_REF]. Akima et al. found them to appear in the 5 th decade and to occur in all specimens above 80 years old [START_REF] Akima | A study on the microvasculature of the cerebral cortex. Fundamental architecture and its senile change in the frontal cortex[END_REF]. Capillary loss in normal ageing was evaluated as between 15 and 50%, according to the cortical or subcortical region [START_REF] Abernethy | Microvascular density of the human paraventricular nucleus decreases with aging but not hypertension[END_REF], [START_REF] Buée | Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders[END_REF]. The high frequency of leukoaraisosis in elderly people may be explained by these changes in brain vasculature.

Molecular ageing of the brain

Modifications in gene expression

One of the main hallmarks of ageing is the modification of genes' expression [START_REF] López-Otín | The hallmarks of aging[END_REF] and an increasing number of genes becomes upregulated or downregulated as we grow older. These changes in expression are mostly explained by epigenetic alterations which include several kinds of DNA and histone modifications that alter transcription [START_REF] Handy | Epigenetic Modifications: Basic Mechanisms and Role in Cardiovascular Disease[END_REF]. The importance of these modifications led to the publication of a recent multi-omic atlas of the brain's frontal cortex during ageing providing data on DNA mutations, changes in RNA and miRNA expression, and in DNA methylation and Histone 3 Lysine 9 acetylation [START_REF] Jager | A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research[END_REF]. With ageing, DNA becomes globally hypomethylated but the hypermethylation of 353 CpG sites is one of the best markers of ageing and has even been proposed as an "epigenetic clock" [START_REF] Horvath | DNA methylation age of human tissues and cell types[END_REF]- [START_REF] Hernandez | Distinct DNA methylation changes highly correlated with chronological age in the human brain[END_REF]. While there is no significant change in the expression of most genes in the brain, more than 150 do undergo a significant modification of their expression with age with a high degree of conservation between cohorts [START_REF] Bishop | Neural mechanisms of ageing and cognitive decline[END_REF], [START_REF] Sibille | Molecular aging of the brain, neuroplasticity, and vulnerability to depression and other brain-related disorders[END_REF]. Contrary to most other tissues where genes' expression is mainly upregulated with ageing, changes in gene expression in the human brain are predominantly shifts towards downregulation [START_REF] Bishop | Neural mechanisms of ageing and cognitive decline[END_REF]. Genes which are downregulated in the brain are associated with the functions of mitochondria, neural plasticity/synapses, inhibitory interneurons and the ubiquitin-proteasome system (UPS). On the contrary, genes associated with stress response, immune/inflammatory response, metal ion homeostasis, myelin-related functions and glia tend to be upregulated [START_REF] Bishop | Neural mechanisms of ageing and cognitive decline[END_REF], [START_REF] Tripathi | New cellular and molecular approaches to ageing brain[END_REF]. These trends are well conserved between rhesus macaques and humans but discrepancies exist in rodents where most changes are characterized by an upregulation of genes' expression, notably of those participating in neuronal functions [START_REF] Bishop | Neural mechanisms of ageing and cognitive decline[END_REF], [START_REF] Loerch | Evolution of the aging brain transcriptome and synaptic regulation[END_REF]. Accordingly, a recent study identified that genes involved in immunity, and more precisely in the complement system, in synaptic transmission and in myelination were very good biomarkers of brain ageing. Genes involved in synaptic transmission were negatively correlated with the genes related to immunity while genes involved in myelination showed a positive correlation with immunity-related genes (Table 1) [START_REF] Bae | Decipher reliable biomarkers of brain aging by integrating literature-based evidence with interactome data[END_REF]. It is possible that the increased immune reactions with ageing are in fact drivers of the downregulation of the expression of genes involved in synaptic transmission [START_REF] Berchtold | Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease[END_REF]- [START_REF] Lu | Gene regulation and DNA damage in the ageing human brain[END_REF]. This involvement of immunity in brain ageing is perfectly in line with the concept of inflammaging, defined as a chronic, sterile and low-grade inflammation which actively contributes to ageing and is considered a very good predictor of successful ageing [START_REF] Franceschi | Inflamm-aging. An evolutionary perspective on immunosenescence[END_REF]- [START_REF] Arai | Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians[END_REF].

Because of modulations in gene expression with ageing, a number of mRNAs and proteins essential to brain function are affected. The mRNA levels of brain-derived neutrophic factor (BDNF) and its receptor tyrosine kinase B (trkB), key modulators of brain plasticity, seem to be affected by ageing in specific areas of the brain. While BDNF levels remained stable over time in the hippocampus, the expression of its receptor was significantly decreased with age [START_REF] Webster | BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan[END_REF]. More changes were found in the prefrontal cortex, notably in the Brodmann area 9, as both BDNF and trkB showed a decreased expression with ageing [START_REF] Erraji-Benchekroun | Molecular aging in human prefrontal cortex is selective and continuous throughout adult life[END_REF], [START_REF] Webster | BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan[END_REF], [START_REF] Tapia-Arancibia | New insights into brain BDNF function in normal aging and Alzheimer disease[END_REF]. Interestingly, β-amyloid peptides, which accumulate even during normal ageing [START_REF] Piccini | beta-amyloid is different in normal aging and in Alzheimer disease[END_REF], [START_REF] Rodrigue | β-Amyloid burden in healthy aging[END_REF], were shown to impair BDNF signalling [START_REF] Tong | Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons[END_REF]. As a consequence of decreased BDNF or impaired signalling, the expression of many essential genes is compromised, mainly in gamma aminobutyric acid (GABA) neurons [START_REF] Glorioso | Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood[END_REF], which results notably in alterations in both inhibitory and excitatory synapses [START_REF] Oh | The Role of BDNF in Age-Dependent Changes of Excitatory and Inhibitory Synaptic Markers in the Human Prefrontal Cortex[END_REF]. Other neuropeptides such as somatostatin, neuropeptide Y or cortistatin, which can be produced in subtypes of GABA interneurons and target dendrites of pyramidal dendrites, are also significantly reduced with ageing [START_REF] Sibille | Molecular aging of the brain, neuroplasticity, and vulnerability to depression and other brain-related disorders[END_REF], [START_REF] Oh | The Role of BDNF in Age-Dependent Changes of Excitatory and Inhibitory Synaptic Markers in the Human Prefrontal Cortex[END_REF]. Post-synaptic GABA receptors were also decreased in older subjects, further impairing the functioning of GABA neurons [START_REF] Oh | The Role of BDNF in Age-Dependent Changes of Excitatory and Inhibitory Synaptic Markers in the Human Prefrontal Cortex[END_REF]. Such variations in expression or functionality are also found in other receptors such as nicotinic and muscarinic acetylcholine receptors [START_REF] Utkin | Aging Affects Nicotinic Acetylcholine Receptors in Brain[END_REF], [START_REF] Schliebs | The cholinergic system in aging and neuronal degeneration[END_REF], metabotropic glutamate receptors [START_REF] Griego | Metabotropic Glutamate Receptors at the Aged Mossy Fiber -CA3 Synapse of the Hippocampus[END_REF], [START_REF] Hernandez | Age-Related Declines in Prefrontal Cortical Expression of Metabotropic Glutamate Receptors that Support Working Memory[END_REF], N-methyl-D-aspartate (NMDA) receptors [START_REF] Zhao | The Effects of Aging on NMDA Receptor Subunits in the Synaptic Membrane and Relationships to Long-term Spatial Memory[END_REF]- [START_REF] Kumar | Alteration in NMDA receptor mediated glutamatergic neurotransmission in the hippocampus during senescence[END_REF], serotonin receptors [START_REF] Banerjee | Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine[END_REF] or dopamine receptors [START_REF] Karrer | Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: a meta-analysis[END_REF].

Insulin/insulin-like growth factor 1 signalling

Insulin/insulin-like growth factor 1 (IGF-1) signalling (IIS) has also been implicated in brain ageing. This pathway is involved in protein synthesis, proliferation and cell survival, notably acting through the rapamycin (mTOR) pathway, and is highly conserved through evolution [START_REF] O'neill | Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease[END_REF]- [START_REF] Vitale | ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians' Perspective[END_REF]. Its inhibition, through various means, importantly leads to increased lifespan in multiple species [START_REF] Kenyon | A C. elegans mutant that lives twice as long as wild type[END_REF]- [START_REF] Austad | Is antagonistic pleiotropy ubiquitous in aging biology?[END_REF]. Interestingly, and paradoxically, the IIS pathway has been shown to be neuroprotective and IGF-1 acts as a neurotrophic agent [START_REF] Van Der Heide | Insulin signaling in the central nervous system: learning to survive[END_REF], [START_REF] Sonntag | Insulin-like growth factor-1 in CNS and cerebrovascular aging[END_REF] but its repression can reduce the consequences of AD in murine models [START_REF] Van Der Heide | Insulin signaling in the central nervous system: learning to survive[END_REF], [START_REF] Cohen | Reduced IGF-1 signaling delays age-associated proteotoxicity in mice[END_REF]. It has been suggested that IGF-1 plays an essential role in cell proliferation during recovery after acute events such as strokes, while its inhibition of stress-resistance or autophagy becomes detrimental in situations like ageing where cellular debris and damage may accumulate [START_REF] Gubbi | 40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain[END_REF]. Interestingly, growth hormone (GH), produced by the pituitary, is a major regulator of IGF-1 secretion and limitation of pituitary development significantly increased lifespan in murine models [START_REF] Bartke | Life extension in the dwarf mouse[END_REF]- [START_REF] Flurkey | Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production[END_REF]. This suggests an interplay between these components.

Post-translational protein modifications

In addition to the changes described above, major protein modifications occur in the brain during normal ageing and participate in the accumulation of cellular debris. The ubiquitination of proteins is a process required for degradation of damaged, misfolded proteins by the UPS; however undegraded, ubiquitinated proteins are found to accumulate in the brain with ageing [START_REF] Pappolla | The "normal" brain. "Abnormal" ubiquitinilated deposits highlight an age-related protein change[END_REF]- [START_REF] Graham | Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia[END_REF], suggesting an impairment of the UPS and resulting in the accumulation of these detrimental proteins [START_REF] Hegde | Perturbations of Ubiquitin-Proteasome-Mediated Proteolysis in Aging and Alzheimer's Disease[END_REF]- [START_REF] Keller | The proteasome in brain aging[END_REF]. In addition, non-enzymatic modifications such as oxidation, notably produced when proteins react with reactive oxygen species (ROS), are also increased during normal brain ageing [START_REF] Grimm | Protein oxidative modifications in the aging brain: consequence for the onset of neurodegenerative disease[END_REF], [START_REF] Smith | Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease[END_REF]. Iron accumulation with ageing is also an important contributor to oxidation [START_REF] Jacobs | Life-span dendritic and spine changes in areas 10 and 18 of human cortex: a quantitative Golgi study[END_REF], [START_REF] Ward | The role of iron in brain ageing and neurodegenerative disorders[END_REF]. This leads to a change in proteins' function and modified proteins can accumulate with other intracellular molecular debris to form lipofuscin, which accumulates in brains over time [START_REF] Moreno-García | An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration[END_REF], [START_REF] Grune | Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and "aggresomes" during oxidative stress, aging, and disease[END_REF]. The number of corpora amylacea (spherical polyglucosan bodies which may contain cell debris) also increases with age [START_REF] Jacobs | Life-span dendritic and spine changes in areas 10 and 18 of human cortex: a quantitative Golgi study[END_REF], [START_REF] Augé | New perspectives on corpora amylacea in the human brain[END_REF]. Products of glycation, another non-enzymatic reaction between nucleophiles and carbonyl compounds and favoured by oxidation, also accumulate in ageing brains [START_REF] Frimat | Kidney, heart and brain: three organs targeted by ageing and glycation[END_REF]. These modifications all produce significant changes in proteins' structure, leading to their degradation or, on the contrary, to their aggregation. Cross-links can occur, forming uncontrolled complex structures with important consequences on protein function and leading, for example, to increased vascular stiffness [START_REF] Kohn | Age-related vascular stiffening: causes and consequences[END_REF]- [START_REF] Janda | Vascular Effects of Advanced Glycation End-Products: Content of Immunohistochemically Detected AGEs in Radial Artery Samples as a Predictor for Arterial Calcification and Cardiovascular Risk in Asymptomatic Patients with Chronic Kidney Disease[END_REF]. In addition, advanced glycation end-products (AGEs) can interact with the receptor for AGEs (RAGE), whose expression in the brain is increased with age, producing a vicious circle of signalling and activation that contributes to chronic, low-grade inflammation [START_REF] Teissier | The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging[END_REF], [START_REF] Osgood | Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier[END_REF]. Amyloidosis, an aggregation of insoluble and misfolded fibrils more widely studied in the context of AD which can be promoted by glycation [START_REF] Iannuzzi | Differential effects of glycation on protein aggregation and amyloid formation[END_REF], is also increased in brains of elderly people without cognitive impairment [START_REF] Aizenstein | Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly[END_REF], [START_REF] Haller | Amyloid Load, Hippocampal Volume Loss, and Diffusion Tensor Imaging Changes in Early Phases of Brain Aging[END_REF]. Overall, such loss of proteostasis can notably promote the unfolded protein response, lead to apoptosis or induce senescence, all of which are particularly detrimental in a tissue in which cell renewal is limited [START_REF] Schröder | ER stress and the unfolded protein response[END_REF]- [START_REF] Martínez | Endoplasmic reticulum proteostasis impairment in aging[END_REF].

Mitochondrial dysfunction

Together with muscles, the brain has a higher metabolic activity than all other organs, hence the brain may be more susceptible to mitochondrial dysfunction, a key hallmark of ageing [START_REF] López-Otín | The hallmarks of aging[END_REF], [START_REF] Mattson | Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States[END_REF]. With time, mitochondria accumulate mutations which are associated with homoplasmy and, as mentioned earlier, a diminished expression of mitochondrial proteins. As a consequence of such modifications, electron leakage occurs throughout the respiratory chain producing ROS and, in turn, increasing cell and mitochondrial damage [START_REF] Harman | THE FREE RADICAL THEORY OF AGING: EFFECT OF AGE ON SERUM COPPER LEVELS[END_REF]- [START_REF] Yao | Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence[END_REF]. Disruption of the electron transport chain also results in mitochondria with depolarized membranes [START_REF] Lores-Arnaiz | Brain cortex mitochondrial bioenergetics in synaptosomes and non-synaptic mitochondria during aging[END_REF]. Of note, since brain metabolism requires high oxygen consumption, the probability of producing ROS may be further increased. It is also important to note that while large amounts of ROS are detrimental, lower levels can stimulate a pro-survival response [START_REF] López-Otín | The hallmarks of aging[END_REF], [START_REF] Payne | Mitochondrial dysfunction in aging: Much progress but many unresolved questions[END_REF], [START_REF] Trifunovic | Mitochondrial dysfunction as a cause of ageing[END_REF]. Decline in mitochondrial function provokes a decline in nicotinamide adenine dinucleotide (NAD + ) levels, notably affecting the activity the NAD + -dependent sirtuins [START_REF] Braidy | Mapping NAD(+) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence[END_REF], [START_REF] Fang | NAD+ in Aging: Molecular Mechanisms and Translational Implications[END_REF]. This dysfunction may also lead to increased inflammation, as well as altered apoptosis and disrupted crosstalk among organelles [START_REF] Green | Mitochondria and the autophagyinflammation-cell death axis in organismal aging[END_REF], [START_REF] Kroemer | Mitochondrial membrane permeabilization in cell death[END_REF], [START_REF] Raffaello | Mitochondrial longevity pathways[END_REF]. The importance of mitochondrial dysfunction in ageing is underlined by an innovative study showing that mitochondrial removal from senescent cells diminished pro-ageing features of senescence [START_REF] Correia-Melo | Mitochondria are required for pro-ageing features of the senescent phenotype[END_REF]. More specific to the brain, projection neurons rely upon energy production by mitochondria to support ion fluxes and axonal transport, making them particularly vulnerable to mitochondrial dysfunction [START_REF] Mandal | Axonal Transport and Mitochondrial Function in Neurons[END_REF], [START_REF] Guo | Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications[END_REF]. With decreased energy production by mitochondria, a reduction in metabolic activities has been reported in the subiculum and dentate gyrus [START_REF] Small | Imaging hippocampal function across the human life span: is memory decline normal or not?[END_REF], a finding which was confirmed in another study in rats where the activities of both mitochondrial complexes and nitric oxide synthase were significantly reduced in the hippocampus and, to a lesser extent, in the cortex [START_REF] Navarro | Hippocampal mitochondrial dysfunction in rat aging[END_REF].

Autophagy

Autophagy is a process which permits cells to produce nutrients for themselves when extracellular nutrient concentrations are low, or under conditions of stress, and involves degrading cell components (mainly damaged cell debris) in autolysosomes formed by the fusion of an autophagosome with a lysosome. The mTOR pathway is an inhibitor of autophagy and, as mentioned earlier, is stimulated by IGF-1. Thus, sustained IGF-1 and mTOR signalling may prevent the autophagic recycling of damaged proteins and facilitate their aggregation and subsequent detrimental consequences. A similar process, mitophagy, exists for the degradation of damaged mitochondria. Impairment of both of these processes as a result of ageing accelerates the deleterious effects of cytotoxic cellular and organellederived components. Hence, suppression of autophagy has been identified as a cause of neurodegeneration [START_REF] Nixon | The role of autophagy in neurodegenerative disease[END_REF]- [START_REF] Komatsu | Loss of autophagy in the central nervous system causes neurodegeneration in mice[END_REF] while its enhancement ameliorates cognitive functions [START_REF] Yang | Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits[END_REF]- [START_REF] Lopez | A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction[END_REF]. In murine hippocampus, autophagic activity is decreased with ageing but this observation was not explained by an overactivated mTOR signalling, therefore other parameters must be responsible for this decline [START_REF] Yang | mTOR and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits[END_REF]. The decrease in BECN1 expression in older human brains, a key regulator of autophagy, [START_REF] Shibata | Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1[END_REF] suggests that autophagy may also decline with age in humans, but as extensively reviewed elsewhere, there is currently insufficient data on autophagy evolution during normal human brain ageing to definitively conclude on this matter [START_REF] Loeffler | Influence of Normal Aging on Brain Autophagy: A Complex Scenario[END_REF].

Calcium conductance

Correct Ca 2+ conductance and homeostasis are essential for signal propagation in the brain and their alteration might result in a deterioration of inter-neuronal communication. These changes in Ca 2+ signalling in the ageing brain have been extensively reviewed elsewhere [START_REF] Chandran | Cellular calcium signaling in the aging brain[END_REF]- [START_REF] Toescu | Altered Calcium Homeostasis in Old Neurons[END_REF]. Mainly, Ca 2+ conductance is increased in aged neurons as shown in the hippocampus where there is an increase in L-type, voltage-dependent Ca 2+ channels' density and activity in pyramidal cells [START_REF] Thibault | Increase in single L-type calcium channels in hippocampal neurons during aging[END_REF], [START_REF] Thibault | Elevated postsynaptic [Ca2+]i and Ltype calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity[END_REF]. The release of Ca 2+ from intracellular organelles is also altered by ageing as the endoplasmic reticulum calcium releasing channels, the inositol trisphosphate receptor (IP3R) and ryanodine receptor (RyR) all show an increased activity over time, partly mediated by ROS oxidation [START_REF] Gant | Early and Simultaneous Emergence of Multiple Hippocampal Biomarkers of Aging Is Mediated by Ca2+-Induced Ca2+ Release[END_REF], [START_REF] Feissner | Crosstalk signaling between mitochondrial Ca2+ and ROS[END_REF]. On the other hand, Ca 2+ buffering is impaired as the activities of both the sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) and the plasma membrane Ca 2+ ATPase (PMCA) pumps are decreased, potentially because of a reduction in available ATP and oxidation as consequences of mitochondrial dysfunction [START_REF] Feissner | Crosstalk signaling between mitochondrial Ca2+ and ROS[END_REF]- [START_REF] Michaelis | Decreased plasma membrane calcium transport activity in aging brain[END_REF]. Diminished mitochondrial Ca 2+ buffering capability has also been reported [START_REF] Xiong | Changes in Mitochondrial Status Associated with Altered Ca2+ Homeostasis in Aged Cerebellar Granule Neurons in Brain Slices[END_REF]. In addition, calcium-binding proteins such as calbindin 1 are overwhelmingly downregulated with age in the prefrontal cortex [START_REF] Erraji-Benchekroun | Molecular aging in human prefrontal cortex is selective and continuous throughout adult life[END_REF], [START_REF] Geula | Loss of calbindin-D28k from aging human cholinergic basal forebrain: relation to neuronal loss[END_REF], further impairing Ca 2+ signalling.

Conclusion

All the hallmarks of ageing are observable in the ageing brain and its structures [START_REF] Mattson | Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States[END_REF]. Most of the current knowledge of the ageing brain derives from studies of neurodegenerative disorders. It is interesting to recognize that changes like Tau, phosphoTau and amyloid peptide accumulation can begin in early life as a result of physiological ageing and are present in subclinical cases while also being used as early-stage markers of neurodegenerative diseases in progression. It will be important to increase research of normal ageing to better understand pathological ageing of the brain. Identification of new biomarkers, and progress in the field of functional neuroimaging, will help to better distinguish normal from pathological brain ageing and contribute to diagnosing the latter as early as possible.

Figure 1 :

 1 Figure 1: Illustration of common histological changes during normal brain ageing

Figure 2 :

 2 Figure 2: estimated prevalence of amyloid deposits and neurofibrillary pathology according to the age of the subjects

Table 1 .

 1 Gene expression changes over time in the ageing human brain

Disclosure of interest

The authors declare no conflict of interest.

Acknowledgements

We are grateful to Mike Howsam for his contribution of editorial assistance and English proofreading.


Major changes occur at the cerebral level with aging. Cerebral atrophy develops progressively. Multiple lesions related to small vessel diseases are detected in association with cerebral atrophy including white-matter hyperintensities, lacunes, microbleeds, dilated perivascular spaces and cerebral, including cortex, atrophy. The clinical impact and predictive value of these Imaging makers were examined.

Introduction

In the brain, the microvasculature is in close contact with the neural tissue. After large and medium-sized arteries, blood flow is distributed to arterioles which have one or two layers of smooth muscle cells in their media and thereafter to capillaries of less than 10 microns in diameter and that do not have contractile cells in their wall [START_REF] Macvicar | Neuroscience: controlled capillaries[END_REF]. These latter are surrounded by pericytes whose role is not fully understood yet [START_REF] Peppiatt | Bidirectional control of CNS capillary diameter by pericytes[END_REF]. Venules follow the capillary bed for collecting blood after oxygen consumption in larger veins and sinuses. Major changes occur with aging in the microvasculature in association with the progressive loss of the main neural components of cerebral tissue [START_REF] Balbi | Dysfunction of mouse cerebral arteries during early aging[END_REF]. All individuals do not present similar changes and various factors including genetic and vascular risk factors can largely influence the effects of aging on the cerebral microvasculature.

During the past two decades, the development of magnetic resonance imaging (MRI) has revolutionized the study of cerebral aging [START_REF] Fazekas | Pathologic correlates of incidental MRI white matter signal hyperintensities[END_REF][START_REF] Grafton | Comparison of postmortem magnetic resonance imaging and neuropathologic findings in the cerebral white matter[END_REF][START_REF] Ferrer | Arteriolosclerotic leucoencephalopathy in the elderly and its relation to white matter lesions in Binswanger's disease, multi-infarct encephalopathy and Alzheimer's disease[END_REF]. Multiple epidemiological studies obtained with MRI showed frequent signal changes in the cerebral tissue related to aging. Particularly, accumulating evidence supports that aging is frequently associated with the occurrence of white-matter hyperintensities on T2 or FLAIR images, covert infarcts, microbleeds, dilated perivascular spaces and cerebral atrophy resulting from microvessels' alterations [START_REF] Hilal | Prevalence, risk factors and consequences of cerebral small vessel diseases: data from three Asian countries[END_REF]. The exact pathophysiology of these different lesions is not understood [START_REF] Joutel | Pathogenesis of white matter changes in cerebral small vessel diseases: beyond vessel-intrinsic mechanisms[END_REF]. However, their clinical value and possible consequences at individual level are now progressively deciphered.

Because of the multiple eponyms and terms used for describing these MRI lesions observed in the literature up to the beginning of the 21 st century, an important effort was made in 2013 for proposing common terms in the literature for reporting cerebrovascular lesions detected so frequently on MRI with aging. The STandards for ReportIng Vascular changes on nEuroimaging or STRIVE criteria were proposed for defining white-matter hyperintensities, recent small subcortical infarcts, lacunes, perivascular spaces and cerebral microbleeds [START_REF] Wardlaw | Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration[END_REF]. The terms of leukoaraiosis, of lacunar infarction or of microhemorrhages should no longer be used and totally abandoned because they are not only confusing but also inaccurate [START_REF] Wardlaw | Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration[END_REF].

T2 or FLAIR white-matter hyperintensities (WMH)

During the eighties, at time of the first clinical MRI investigations in humans, clinicians were surprised to detect so frequently WMH on their elderly patients' images, often in the total absence of clinical manifestations. Only in the nineties, the prevalence and incidence of these lesions was properly investigated in large cohorts obtained in the general population. Large studies such as the Rotterdam study [START_REF] De Leeuw | Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study[END_REF], the Cardio-Vascular Health Study , the Atherosclerosis Risk in Community (ARIC) study [START_REF] Graff-Radford | Neuroimaging Correlates of Cerebral Microbleeds: The ARIC Study (Atherosclerosis Risk in Communities)[END_REF] and in France, the Three City (3C) study [START_REF] Godin | Joint effect of white matter lesions and hippocampal volumes on severity of cognitive decline: the 3C-Dijon MRI study[END_REF] provided key information concerning the risk factors and clinical correlates of such lesions developing with aging [START_REF] Longstreth | Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study[END_REF]. In parallel to these studies, a profusion of small or large cross-sectional and longitudinal studies was reported in elderly individuals in various clinical contexts particularly after stroke, cognitive complaints or decline [START_REF] Pantoni | Leukoaraiosis predicts hidden global functioning impairment in nondisabled older people: the LADIS (Leukoaraiosis and Disability in the Elderly) Study[END_REF] or even after the occurrence of dementia [START_REF] Ferrer | Arteriolosclerotic leucoencephalopathy in the elderly and its relation to white matter lesions in Binswanger's disease, multi-infarct encephalopathy and Alzheimer's disease[END_REF].

The results of all of these epidemiological MRI studies showed that WMH are frequently detected in elderly people. Their prevalence is variable according to the imaging criteria used for their definition, to the selection criteria used for elderly individuals included in the different cohorts and their clinical status at entry, to the country and also to the magnet strength and MRI sequences [START_REF] De Guio | Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease[END_REF]. However, globally, the prevalence of WMH varies from 50 to 90% in the different studies with a huge age-related increase between 60 and 90 years [START_REF] Vermeer | Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study[END_REF][START_REF] Kuller | White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study[END_REF][START_REF] Wong | Cerebral white matter lesions, retinopathy, and incident clinical stroke[END_REF] }. Most importantly, the extent of WMH appears to dramatically increase according to age in these different cohorts. This was initially established using various semi-quantitative scales, the most famous of which is that validated by Fazekas and collaborators [START_REF] Prins | Measuring progression of cerebral white matter lesions on MRI: visual rating and volumetrics[END_REF]. Thus, the frequency of confluent WMH seems to vary from less than 5% before age 60 years up to 30-40% at 80 years both in European as well as in Asian populations [START_REF] Hilal | Prevalence, risk factors and consequences of cerebral small vessel diseases: data from three Asian countries[END_REF].

This variable extent of WMH in elderly populations was repeatedly investigated. In the literature, multiple vascular risk factors were found associated with the extent of WMH in elderly individuals. High blood pressure appears clearly as the most consistently related to the amount of WMH [START_REF] Dufouil | Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy[END_REF][START_REF] Godin | Antihypertensive treatment and change in blood pressure are associated with the progression of white matter lesion volumes: the Three-City (3C)-Dijon Magnetic Resonance Imaging Study[END_REF]. Both the level of systolic blood pressure, the level of diastolic blood pressure, the mean blood pressure, the use of an antihypertensive treatment as well as the blood pressure variability were found independently related to the volume of WMH in cross-sectional studies [START_REF] Avet | Leukoaraiosis and ambulatory blood pressure load in a healthy elderly cohort study: the PROOF study[END_REF][START_REF] Klarenbeek | Ambulatory blood pressure in patients with lacunar stroke: association with total MRI burden of cerebral small vessel disease[END_REF][START_REF] Liu | Different impacts of blood pressure variability on the progression of cerebral microbleeds and white matter lesions[END_REF][START_REF] Conijn | Microbleeds, lacunar infarcts, white matter lesions and cerebrovascular reactivity --a 7 T study[END_REF][START_REF] Poels | Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study[END_REF][START_REF] Schwartz | Association of ambulatory blood pressure with ischemic brain injury[END_REF][START_REF] Gomez-Angelats | Blood pressure variability and silent cerebral damage in essential hypertension[END_REF]. The clinical impact of WMH has been also largely analyzed. However, in most studies, interpretation of results remains difficult because of the frequent association of WMH with covert infarcts, microbleeds or cerebral atrophy whose impact was not often discerned. Moreover, WMH on T2-weighted images do not have the same value as WMH observed on FLAIR images. Particularly, lacunes that correspond to cerebral holes resulting from focal ischemic insults appear hyperintense as other categories of tissue lesions on T2-weighted images whereas they are easily separated from other types of WMH using FLAIR images [START_REF] Viswanathan | Impact of MRI markers in subcortical vascular dementia: a multi-modal analysis in CADASIL[END_REF]. Pathological data have also confirmed the wide variety of tissue lesions underlying WMH (gliosis, demyelination, axonal loss, edema, incomplete infarction, complete infarction) which may also explain the variable clinical correlates of these MRI lesions [START_REF] Erkinjuntti | Diffuse vacuolization (spongiosis) and arteriolosclerosis in the frontal white matter occurs in vascular dementia[END_REF][START_REF] Akiguchi | Alterations in glia and axons in the brains of Binswanger's disease patients[END_REF][START_REF] Jones | Characterization of white matter damage in ischemic leukoaraiosis with diffusion tensor MRI[END_REF]. When brain atrophy, the number of cerebral small cavities and microbleeds are also considered, the clinical weight of WMH appears mainly related to their extent, location and to the presence of associated lesions [START_REF] Viswanathan | Impact of MRI markers in subcortical vascular dementia: a multi-modal analysis in CADASIL[END_REF]. Several authors previously observed that WMH located in the periventricular areas might have more effects on cognition and disability in elderly individuals than other types of WMH. Today, accumulating evidence suggests that WMH in periventricular areas may have different clinical consequences than WMH distant from the ventricles. Recent results obtained in a genetic model of cerebral small vessel disease suggest even that not only their clinical consequences but also their underlying pathophysiology might largely differ [START_REF] Duchesnay | Different Types of White Matter Hyperintensities in CADASIL[END_REF][START_REF] De Guio | Different types of white matter hyperintensities in CADASIL: Insights from 7-Tesla MRI[END_REF]. In this rare disorder, periventricular WMH were found related to cerebral atrophy and accumulation of lacunes suggesting that they may result from chronic hypoperfusion [START_REF] Duchesnay | Different Types of White Matter Hyperintensities in CADASIL[END_REF][START_REF] De Guio | Different types of white matter hyperintensities in CADASIL: Insights from 7-Tesla MRI[END_REF]. In contrast, WMH under the cortex appeared clinically benign and associated with brain inflation. Whether distinct mechanisms are also involved in WMH frequently detected in elderly subjects remains undetermined. However, clearly, multiple types of WMH can co-exist with distinct clinical effects combined to the effect of age, cerebral atrophy or associated lesions [START_REF] Jouvent | Brain atrophy is related to lacunar lesions and tissue microstructural changes in CADASIL[END_REF][START_REF] Jouvent | Cerebral atrophy in cerebrovascular disorders[END_REF].

At the cognitive level, WMH are often associated with decreased cognitive speed. The increased time to complete a cognitive task might be among the earliest clinical manifestation of these lesions [START_REF] Jouvent | Reaction Time is a Marker of Early Cognitive and Behavioral Alterations in Pure Cerebral Small Vessel Disease[END_REF][START_REF] Duering | Identification of a strategic brain network underlying processing speed deficits in vascular cognitive impairment[END_REF]. WMH have also been repeatedly related to performances in attention, concentration, and in multiple executive functions [START_REF] Jokinen | Longitudinal cognitive decline in subcortical ischemic vascular disease--the LADIS Study[END_REF][START_REF] Prins | Cerebral smallvessel disease and decline in information processing speed, executive function and memory[END_REF][START_REF] Peters | The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia[END_REF]. The location of WMH might explain these effects at the cognitive level. Particularly, there is accumulating evidence suggesting that WMH located in the frontal lobes close to the ventricles are able to interrupt or alter the connectivity through the forceps minor of the frontal cortices [START_REF] Duering | Identification of a strategic brain network underlying processing speed deficits in vascular cognitive impairment[END_REF][START_REF] Duering | Strategic white matter tracts for processing speed deficits in age-related small vessel disease[END_REF][START_REF] Righart | Impact of regional cortical and subcortical changes on processing speed in cerebral small vessel disease[END_REF]. WMH in the frontal lobe may also affect the thalamo-cortical fibers and slow down cognitive processing by interrupting or reducing the connectivity between basal ganglia and the cortex [START_REF] Duering | Strategic white matter tracts for processing speed deficits in age-related small vessel disease[END_REF]. Interestingly, in the CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts) model where cerebral atrophy appears very late during the course of the disease, WMH were found associated with executive dysfunction, reduced cognitive processing, and attention changes but could not account alone for severe cognitive change or dementia [START_REF] Benisty | White-Matter Lesions Without Lacunar Infarcts in CADASIL[END_REF]. In addition to executive dysfunction, WMH in elderly people were found strongly related to some motor disturbances. Particularly, gait and balance disorders can be observed in presence of extensive WMH. Walking speed, the time and ability to stand up from a chair or the time for maintaining a single-leg stance have been found strongly related to the extent of WMH in the LADIS study in non-disabled elderly subjects consulting at hospital [START_REF] Blahak | Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross sectional results from the LADIS study[END_REF][START_REF] Baezner | Association of gait and balance disorders with age-related white matter changes: the LADIS study[END_REF].

In elderly individuals, WMH should be considered also as an important risk marker. In longitudinal studies obtained in various populations, mostly in western countries, WMH is clearly an independent risk factor of stroke [START_REF] Vermeer | Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study[END_REF]. This was reported in all large cohorts including more recently in the 3C study with a follow-up of more than 10 years [START_REF] Kaffashian | Differential Effect of White-Matter Lesions and Covert Brain Infarcts on the Risk of Ischemic Stroke and Intracerebral Hemorrhage[END_REF]. Thus, the risk of stroke more than doubles at 10 years after taking into account multiple potential confounders when WMH are extensive. In elderly populations, the presence of such lesions on MRI was also found repeatedly associated with cognitive decline after a long follow-up [START_REF] Longstreth | Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study[END_REF][START_REF] Kaffashian | Long-Term Clinical Impact of Vascular Brain Lesions on Magnetic Resonance Imaging in Older Adults in the Population[END_REF]. The presence of confluent WMH at baseline is also an independent risk factor of dementia in elderly populations [START_REF] Kaffashian | Long-Term Clinical Impact of Vascular Brain Lesions on Magnetic Resonance Imaging in Older Adults in the Population[END_REF]. This risk appears independent from that related to associate lesions such as lacunes. Finally, not only are WMH associated with covert infarcts, lacunes, microbleeds or perivascular spaces which are the other major MRI markers of cerebral small-vessel disease in multiple cross-sectional studies, their extent was also found repeatedly related to cerebral atrophy in studies performed before the era of FLAIR images in elderly subjects [START_REF] Jouvent | Cerebral atrophy in cerebrovascular disorders[END_REF].

Covert infarcts and lacunes

With the widespread diffusion of MRI, small cavities presumably resulting from focal ischemic lesions are often detected in healthy individuals in the absence of stroke events. These lesions were initially called "silent infarcts" before these terms were challenged due to subtle but real consequences of these lesions, particularly at the cognitive level [START_REF] Vermeer | Prevalence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study[END_REF]. The term "covert infarct" [START_REF] Longstreth | Incidence, Manifestations, and Predictors of Brain Infarcts Defined by Serial Cranial Magnetic Resonance Imaging in the Elderly The Cardiovascular Health Study[END_REF] is now preferred to describe these MRI lesions. Covert infarcts are particularly frequent in elderly subjects [START_REF] Longstreth | Incidence, Manifestations, and Predictors of Brain Infarcts Defined by Serial Cranial Magnetic Resonance Imaging in the Elderly The Cardiovascular Health Study[END_REF][START_REF] Black | Vascular cognitive impairment: epidemiology, subtypes, diagnosis and management[END_REF]. In the largest epidemiological studies, their prevalence appears largely variable but always increasing with aging. Between 5 and 30% of individuals considered as healthy subjects may harbor a covert infarct or a lacune on their MRI at age 80 years [START_REF] Vermeer | Silent brain infarcts and the risk of dementia and cognitive decline[END_REF][START_REF] Mosley | Cerebral MRI findings and cognitive functioning: the Atherosclerosis Risk in Communities study[END_REF].

Accumulating evidence suggests that the vascular risk factors of stroke are also those of these small lesions which are however mostly detected incidentally. Hypertension, diabetes or hypercholesterolemia were found associated with their frequency in elderly populations [START_REF] Vermeer | Silent brain infarcts: a systematic review[END_REF]. Most importantly, these lesions are associated with an increased risk of incident stroke in elderly individuals. Interestingly, covert infarcts are not only associated with a larger incidence of ischemic stroke but also with an increased risk of hemorrhagic stroke. With combined data from the Cardio-Vascular Health Study and the ARIC study, Folsom et al. observed that the risk of intracerebral hemorrhage more than tripled in presence of more than three covert infarcts than in the total absence of such lesions [START_REF] Folsom | Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts[END_REF].

The potential long-term impact of these lesions according to their location was initially studied in the Rotterdam study. Unsurprisingly, lacunes in basal ganglia and particularly in the thalamus were found associated with altered performances in executive tests while those outside were found more related to memory performances [START_REF] Vermeer | Silent brain infarcts and the risk of dementia and cognitive decline[END_REF][START_REF] Vermeer | Silent brain infarcts: a systematic review[END_REF]. These findings were confirmed later in the LADIS study comprising nondisabled elderly subjects from neurology clinics [START_REF] Benisty | Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related whitematter changes: the LADIS study[END_REF]. Some results also support that covert infarcts may also be associated with an increased risk of cognitive decline [START_REF] Jokinen | Incident lacunes influence cognitive decline: the LADIS study[END_REF]. However, this was not always confirmed. Recently, in the 3C study in which lacunes were carefully separated from dilated perivascular spaces based on the 3D shape of MRI lesions and using millimetric slices, lacunes were not found to increase the risk of subsequent dementia after more than 10 years of follow-up [START_REF] Kaffashian | Long-Term Clinical Impact of Vascular Brain Lesions on Magnetic Resonance Imaging in Older Adults in the Population[END_REF]. The results were contrasting with the obvious risk of cognitive decline brought by confluent WMH [START_REF] Kaffashian | Long-Term Clinical Impact of Vascular Brain Lesions on Magnetic Resonance Imaging in Older Adults in the Population[END_REF]. However, whatever these considerations, the accumulation of such lesions (which differs from the risk related to a single lesion) appears clearly deleterious to brain functioning. In the CADASIL model of an accelerated and pure ischemic small-vessel disease, accumulation of these lesions were found significantly associated with increasing cognitive decline and disability over three years [START_REF] Chabriat | Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Prospective Cohort Study[END_REF]. The impact of these lesions might also differ according to the presence or absence of associated lesions. We can hypothesize that recovery of subtle cerebral dysfunction is more likely at an early stage when the rest of the brain is undamaged than at a late stage, in presence of multiple associated cerebral lesions.

Microbleeds

Microbleeds correspond to small areas of signal void (less than 10 mm in diameter) associated with blooming effects on all MRI sequences highly sensitive to magnetic heterogeneity which produces large artifacts in presence of iron (T2* or susceptibility-weighted-imaging sequences) [START_REF] Wardlaw | Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration[END_REF]. The term of microbleeds is now adopted at the international level although this term remains questionable. Actually, these signal abnormalities correspond to tattoos of iron deposits and not really to "true" bleeding. The prevalence of these signal abnormalities in the general population is about 5%, it increases considerably in stroke patients who present these lesions on MRI in about one-third of cases and in more than twothirds of hemorrhagic cases [START_REF] Cordonnier | Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting[END_REF]. In the Rotterdam study, the incidence of microbleeds was investigated longitudinally in 831 elderly individuals, half of whom had microbleeds at baseline. Incident microbleeds over 3.4 years was detected in about 10% of individuals, half of whom presented with more than two incident lesions [START_REF] Poels | Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study[END_REF]. Predictors of incident microbleeds in this cohort were age, the presence and number of microbleeds at baseline, the level of systolic blood pressure and pulse pressure [START_REF] Poels | Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study[END_REF]. While severe hypertension was found related to incident deep and infratentorial microbleeds, Apo ε4/ε4 was found associated with lobar microbleeds in line with the preferential accumulation of these lesions in lobar areas in presence of cerebral amyloid angiopathy [START_REF] Charidimou | Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis[END_REF].

The potential predictive value of microbleeds has been evaluated in multiple studies. First, in patients with intracerebral hemorrhages, the number of microbleeds in cortical lobar regions was found strongly related to the risk of hemorrhage recurrence in elderly people [START_REF] Greenberg | Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage[END_REF]. When microbleeds are presumably related to cerebral amyloid angiopathy, observed only in lobar regions without any obvious identified cause and after age 55 years, the risk of recurrence appears more than seven times higher than in presence of microbleeds located in the deepest cerebral areas and in presence of hypertension [START_REF] Charidimou | Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis[END_REF]. The number of microbleeds has been also found associated with the risk of ischemic stroke in patients with cerebral small-vessel diseases (figure 1) and who had a previous lacunar stroke suggesting that microbleeds are related to the severity of the vessel disease after an ischemic event [START_REF] Shoamanesh | Microbleeds in the Secondary Prevention of Small Subcortical Strokes Trial: Stroke, mortality, and treatment interactions[END_REF].

More recently, the increased risk of intracerebral hemorrhage in presence of such lesions has also been confirmed in patients who had an ischemic stroke related to thromboembolism [START_REF] Wilson | Outcome of intracerebral hemorrhage associated with different oral anticoagulants[END_REF]. However, accumulating data strongly suggest that the increased risk of hemorrhage in presence of microbleeds does not exceed the absolute risk of ischemic stroke, even in presence of multiple lobar microbleeds. Thus antithrombotic treatments in occlusive vascular disorders or atrial fibrillation should not be interrupted only based on the presence of such MRI lesions [START_REF] Wilson | Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies[END_REF]. Moreover, the presence and number of microbleeds should not alter decisions of acute stroke treatment based on thrombolytics or thrombectomy [START_REF] Turc | Microbleed Status and 3-Month Outcome After Intravenous Thrombolysis in 717 Patients With Acute Ischemic Stroke[END_REF][START_REF] Choi | Impact of Microbleeds on Outcome Following Recanalization in Patients With Acute Ischemic Stroke. Stroke; a journal of cerebral circulation[END_REF].

Interestingly, some pathological data recently suggested that microbleeds do not necessarily occur after the rupture of the microvessel wall but can also result from transient leakage of blood cells through the blood brain barrier [START_REF] Chang | Brain Endothelial Erythrophagocytosis and Hemoglobin Transmigration Across Brain Endothelium: Implications for Pathogenesis of Cerebral Microbleeds[END_REF] possibly passing through pericytes [START_REF] Fisher | Cerebral microbleeds in the elderly: a pathological analysis[END_REF] or can even occur after very small thrombosis [START_REF] Van Veluw | Heterogeneous histopathology of cortical microbleeds in cerebral amyloid angiopathy[END_REF]. Preclinical results in a mouse model with COL4A1 mutation and prone to develop cerebral hemorrhages also support that microbleeds may occur predominantly at the capillary level while true hemorrhages may result from the loss of smooth-muscle cells and structural defects of arterioles [START_REF] Ratelade | Severity of arterial defects in the retina correlates with the burden of intracerebral haemorrhage in COL4A1related stroke[END_REF] Altogether, these data emphasize that the pathophysiological and clinical significance of this imaging marker is finally much more complex than previously thought.

Perivascular spaces

In daily clinical practice, with the development of high-resolution MRI and increasing use of 3 Teslas MRI devices, identification of perivascular spaces is frequent [START_REF] Pollock | Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes[END_REF]. They correspond to fluid-filled spaces that follow the typical course of a vessel and having a signal intensity similar to the cerebrospinal fluid on all sequences. Because they follow the course of penetrating vessels, they appear linear when imaged parallel to the course of the vessel, and round or ovoid, with a diameter generally smaller than 3 mm, when imaged perpendicular to the course of the vessel. In elderly people their prevalence is 100% but the number and extent of perivascular spaces on MRI varies considerably among individuals [START_REF] Zhu | Frequency and location of dilated Virchow-Robin spaces in elderly people: a population-based 3D MR imaging study[END_REF]. There are different methods for evaluating the extent and number of the corresponding signal changes. In basal ganglia, perivascular spaces can appear dilated and very numerous leading to the so-called "etat criblé" which is detected in 1.3% of individuals aged more than 65 years in the 3 Cities cohort study [START_REF] Zhu | Frequency and location of dilated Virchow-Robin spaces in elderly people: a population-based 3D MR imaging study[END_REF].

Accumulating data support that the number and extent of dilated perivascular spaces increases with age, male sex and increased level of blood pressure, both hypertension, systolic blood pressure, diastolic blood pressure or the use of and antihypertensive agent [START_REF] Zhu | Frequency and location of dilated Virchow-Robin spaces in elderly people: a population-based 3D MR imaging study[END_REF]. The extent of dilated perivascular spaces on MRI also appears related to the severity of the other MRI markers of small-vessel disease suggesting that the visibility of perivascular spaces on MRI is related to the development of alterations in the microvasculature [START_REF] Cumurciuc | Dilation of Virchow-Robin spaces in CADASIL[END_REF]. Some recent data also suggest that dilated perivascular spaces within the white matter may be related to the development of amyloid deposits in perforating cerebral vessels [START_REF] Van Veluw | Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces[END_REF][START_REF] Van Rooden | Early Magnetic Resonance Imaging and Cognitive Markers of Hereditary Cerebral Amyloid Angiopathy[END_REF]. There are also results in the literature indicating that extensive dilated perivascular spaces in the white matter may increase the risk of degenerative dementia [START_REF] Zhu | High degree of dilated Virchow-Robin spaces on MRI is associated with increased risk of dementia[END_REF] and are associated with an increased risk of intracerebral hemorrhage in probable cerebral amyloid angiopathy [START_REF] Boulouis | Hemorrhage recurrence risk factors in cerebral amyloid angiopathy: Comparative analysis of the overall small vessel disease severity score versus individual neuroimaging markers[END_REF].

Cerebral Atrophy

The decrease of brain volume with aging may start between age 30 and 40 years. The atrophy rate is moderate at 40 years an estimated about 0.2% per year, it accelerates progressively with aging reaching after 70 years of age about 0.5%/year [START_REF] Peters | Ageing and the brain[END_REF]. At age 75 years, the brain volume is estimated about 10% lower than that measured at 30 years. Brain atrophy during normal aging seems to predominate in the prefrontal cortex and hippocampal regions [START_REF] Peters | Ageing and the brain[END_REF]. In pathological states, the atrophy rate appears much larger and the atrophy process develops differently at the regional level according to the underlying pathology.

In Alzheimer's disease patients, atrophy starts in the medial temporal lobes at the cortical level and can exceed 1% per year. Annual hippocampal atrophy rates between 4 and 5% have already been measured at advanced stage of the disease [START_REF] Pini | Brain atrophy in Alzheimer's Disease and aging[END_REF]. In patients with only mild cognitive impairment, an annual atrophy rate of 0.5% was measured globally in addition to brain shrinking related to normal aging [START_REF] Tabatabaei-Jafari | Cerebral atrophy in mild cognitive impairment: A systematic review with meta-analysis[END_REF]. Both the gray-and white-matter loss seem to participate in the cerebral atrophy observed with mild cognitive impairment pathology, Alzheimer's disease or in cerebral small-vessel diseases.

The development of a small-vessel disease during aging obviously accelerates the cerebral atrophy process [START_REF] Foster | Pyramidal neurons of the prefrontal cortex in post-stroke, vascular and other ageing-related dementias[END_REF]. Lacunes occurring in the deepest parts of the brain can promote the occurrence of cerebral atrophy. An incident small deep infarct was previously shown to cause regional cortical thinning presumably related to secondary degeneration of subcortical white-matter fibers [START_REF] Duering | Incident subcortical infarcts induce focal thinning in connected cortical regions[END_REF]. In line, hippocampal atrophy can also be detected with accumulation of ischemic subcortical lesions [START_REF] O'sullivan | Hippocampal volume is an independent predictor of cognitive performance in CADASIL[END_REF] (figure 2). This has been particularly reported in CADASIL, a pure model of ischemic small vessel disease caused by NOTCH3 protein mutation in the wall of arterioles and capillaries. The study of CADASIL also shows that, in contrast, white-matter signal abnormalities are not necessarily related to cerebral atrophy [START_REF] Jouvent | Brain atrophy is related to lacunar lesions and tissue microstructural changes in CADASIL[END_REF]. Some data even suggest that the deepest white-matter lesions predominating in periventricular areas might be associated with brain shrinking while white-matter signal abnormalities detected more remotely are associated with brain inflation [START_REF] Lambert | Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease[END_REF][START_REF] De Guio | White matter edema at the early stage of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy[END_REF][START_REF] Kloppenborg | Cerebral small-vessel disease and progression of brain atrophy: the SMART-MR study[END_REF].

An important aspect of atrophy measures is that they appear strongly related to the severity of cognitive decline and disability. Brain atrophy and cortex thinning appear not only key markers of aging and degenerative disorders but also of cerebral small-vessel diseases. Cerebral atrophy outperforms all other lesions in predicting cognitive outcome and disability in a genetic model of small-vessel disease. This is also observed in elderly individuals with memory complaints or minor stroke [START_REF] Jokinen | Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study[END_REF]. In summary, the atrophy process is a key marker of cerebral small-vessel disease and increases with accumulating cerebral tissue lesions leading to axonal loss, neuronal and astrocytes degeneration in addition to aging effects [START_REF] Jouvent | Cortical changes in cerebral small vessel diseases: a 3D MRI study of cortical morphology in CADASIL[END_REF]. In line, neuronal apoptosis can develop in the cortex with accumulation of subcortical lesions in the white matter or basal ganglia [START_REF] Viswanathan | Cortical neuronal apoptosis in CADASIL[END_REF]. Thus, measurement of atrophy may capture all these multifocal and/or diffuse pathological processes observed in elderly people related to cognitive and motor decline developing with aging. Recently, accumulation of very small ischemic lesions called microinfarcts was detected with high-resolution MRI in vivo or at post-mortem in patients with amyloid angiopathy [START_REF] Van Veluw | Microbleed and microinfarct detection in amyloid angiopathy: a high-resolution MRIhistopathology study[END_REF] or with ischemic small-vessel disease as CADASIL [START_REF] Jouvent | Intracortical infarcts in small vessel disease: a combined 7-T postmortem MRI and neuropathological case study in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy[END_REF]. They are not detected with clinical MRI but may also participate in the cortex shrinking and atrophy developing with aging.

Conclusion

Normal aging is associated with cerebral tissue loss and this process seems to accelerate after 60-70 years in healthy individuals. Cerebral and cortex atrophy develop earlier and more largely in Alzheimer's disease or mild cognitive impairment patients in relation to various degenerative processes. Cerebral atrophy is thus a key biomarker to investigate the course of degenerative disorders and potential effects of preventative drugs. In presence of a small-vessel disease, accumulation of white-matter lesions or lacunes can accelerate the development of cerebral tissue loss during aging. The most severe tissue lesions, lacunes (holes) and axonal lesions (directly related to lacunes or white-matter lesions) can lead to remote cerebral tissue degeneration that can involve both white-matter fibers and cortex. Tissue loss is thus increased with the severity of the underlying small-vessel disease.

In future, analysis of different small-vessel disease markers might help to select the population at highest risk of ischemic and hemorrhagic events but as well as individuals at highest risk of cognitive decline and increasing disability. These biomarkers might be used not only to stratify but also to control the efficiency of preventative strategies or treatments. In the future, prevention of cognitive decline and disability in elderly subjects may target the accumulation of microvascular lesions such as white-matter hyperintensities, lacunes, microinfarcts, microbleeds or the spread of dilated perivascular spaces that are now visible and measurable on MRI several decades before clinical manifestations related to cerebral aging.

Disclosure of interest

No conflict of Interest. Various types and degrees of imaging markers often associated with aging and related to cerebral smallvessel diseases; from the left; subtle (top) and extensive (bottom) white-matter hyperintensities, noncavitated focal ischemic lesion (top) and multiple lacunes (bottom), isolated microbleed (top) and multiple microbleeds mainly cortical and lobar, typical perivascular space as observed on 3DT1 images (top) and a typical état criblé (bottom). MRI data illustrating the development of cortical atrophy in presence of subcortical lesions accumulating in subcortical areas with major modifications of the shape of cerebral cortex sulci.

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