Sci. Aging Knowl. Environ., 9 June 2004
Vol. 2004, Issue 23, p. pe26
[DOI: 10.1126/sageke.2004.23.pe26]

PERSPECTIVES

Neurodegeneration in Normal Brain Aging and Disease

Dietmar Rudolf Thal, Kelly Del Tredici, and Heiko Braak

Dietmar R. Thal is in the Department of Neuropathology at the University of Bonn Medical Center, Sigmund Freud Strasse 25, D-53105 Bonn, Germany. Kelly Del Tredici and Heiko Braak are at the Institute for Clinical Neuroanatomy at Johann Wolfgang Goethe University, D-60590 Frankfurt am Main, Germany. E-mail: Dietmar.Thal{at}uni-bonn.de (D.R.T.)

http://sageke.sciencemag.org/cgi/content/full/2004/23/pe26

Key Words: Alzheimer's disease • Parkinson's disease • cerebrovascular disease • preclinical stages

Introduction

Normal "healthy" aging is defined as aging in the absence of disease. Many aged people who do not manifest clinical symptoms of a given age-related disorder do exhibit disease-related alterations that represent preclinical stages of such diseases. Examples of disease-related pathologies frequently found at autopsy in clinically normal-appearing elderly people are those associated with Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and cerebrovascular disease (CVD) (1-10). Because such nonsymptomatic patients are clinically indistinguishable from control cases, they often are included as control cases in studies aimed at differentiating pathological findings, as well as identifying associations with genetic polymorphisms, in diseased and nondiseased individuals (see "When Does Normal Aging Become Abnormal?").

To shed light on the preclinical disease stages in neurodegenerative and cerebrovascular disorders and their relevance to normal aging, this Perspective summarizes current hypotheses pertaining to the distinction between normal aging and disease at the clinical and neuropathological levels. It discusses the impact of presymptomatic stages of AD and PD and of pathological vascular changes in the brain on therapy and diagnostics.

The pathological processes that underlie these disorders require long periods of time before the full extent of the damage accruing in the central nervous system is reached (9-12). After a description of the pathogenesis of AD, PD, and CVD, the concluding section (i) summarizes the arguments for and against the relevance of preclinical stages for all three pathologies, (ii) discusses the criteria for distinguishing preclinical disease from healthy aging, and (iii) considers the potential impact of preclinical disease stages on diagnostic approaches and therapeutic strategies.

Characteristics of AD

AD is characterized, from a neuropathological standpoint, by the extracellular deposition of the amyloid {beta} protein (A{beta}) and by the intraneuronal generation of neurofibrillary tangles, neuropil threads, and abnormal material in dystrophic nerve cell processes of neuritic plaques (13, 14) (see "Detangling Alzheimer's Disease"). Neurofibrillary tangles are abnormal structures that contain paired helical filaments and straight filaments, both consisting of abnormally phosphorylated and aggregated tau protein (15-17) (see "Sticking It to Tau"), microtubules, and neurofilaments, a type of intermediate filament found in nerve cells. Neuropil threads are also composed of straight and paired helical filaments of abnormally phosphorylated tau and are found in dendrites. Extracellular A{beta} deposits chiefly consist of aggregated A{beta} and are located in the gray matter of the brain and, to a lesser extent, in adjoining portions of the white matter (18). Vascular A{beta} deposition, known as cerebral amyloid angiopathy (CAA), also occurs frequently (19, 20). In combination with CAA , neuronal and synaptic loss take place in AD (21-23).

Although the brains of some elderly individuals are completely free of AD-related pathology, the abnormal changes described above are found in a large number of nondemented elderly people as well (2-4, 9-11, 21-23). The difference between demented AD patients and nondemented elderly people with AD-related pathology is reflected by the distribution pattern of neurofibrillary tangles and A{beta} deposits (3, 10, 11, 24, 25). In nondemented elderly people, neurofibrillary tangles and A{beta} deposits are restricted to distinct predilection sites (2, 7, 9-11), whereas in AD patients who manifest clinical symptoms of dementia, these lesions are much more widespread and occur in many areas of the brain (10, 11) (Fig. 1). Currently, the clinical diagnosis of AD requires features of at least mild cognitive impairment (26), but even these mildly demented patients already exhibit widespread AD-related pathology, including neuronal loss and adaptive synaptic response (an increase in the amounts of synaptic proteins in response to neuronal damage) (10, 22, 24, 27-30).



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Fig. 1. Preclinical and clinical stages of AD-related A{beta} plaques. In nondemented elderly people, A{beta} deposits are restricted to the neocortex, allocortex, basal ganglia, and diencephalic nuclei (phases 1 to 3). Phase 1 is characterized by neocortical A{beta} deposits, and phase 2 shows additional A{beta} deposits in the allocortical brain regions (the allocortex is a part of the brain involved in memory processing). Phase 3 exhibits, in addition to neo- and allocortical A{beta} deposits, A{beta} plaques in the diencephalon and basal ganglia, whereas in AD cases with clinically apparent dementia, A{beta} deposits occur in all areas that are already affected in nondemented patients plus in the brain stem and cerebellum (phases 4 and 5). Phase 4 is characterized by A{beta} deposits within the neo- and allocortex, diencephalon, basal ganglia, midbrain, lower brain stem. Phase 5 shows additional A{beta} deposits within the pons (upper brain stem) and the cerebellum (10). Newly involved brain areas are marked in red. [Reproduced with slight modifications from (10) with permission.]

 
Brain regions become involved in AD in a hierarchical manner. A{beta} deposition begins in the neocortex (the major portion of the cerebral cortex, where thought processes occur) and then makes inroads into additional brain areas. The neurofibrillary lesions, on the other hand, first develop within the transentorhinal region (a brain region involved in memory processing) before advancing into other areas of the brain. Regions that become involved in late stages of AD-related pathology (Fig. 1) exhibit A{beta} and/or neurofibrillary tangle pathology predominantly in demented patients (10). The cerebellum, for example, shows A{beta} deposits almost exclusively in AD cases in which nearly the entire brain exhibits A{beta} plaques as well. Similarly, nondemented elderly people exhibit neurofibrillary tangles restricted to the entorhinal and limbic areas [neurofibrillary tangle (NFT or Braak) stages I to IV]. NFT stages I and II are characterized by entorhinal neurofibrillary tangles, and NFT stages III and IV are characterized by additional neurofibrillary tangles within the hippocampus and the inferior temporal neocortex adjacent to the entorhinal region. In demented AD patients (clinical stages), neurofibrillary changes are present throughout the entire neocortex [NFT (Braak) stages V and VI] (11).

AD-related changes occur in 81.5% of all individuals over the age of 55 (1). With increasing age, the frequency of higher neurofibrillary stages and higher A{beta} stages increases as well. For example, 11.9% of all autopsy cases over the age of 75 showed neurofibrillary stages V or VI (1). This increase in the frequency of AD-related brain changes is illustrated in Fig. 2 and indicates that late stages of AD-related intraneuronal pathology might evolve from earlier ones after a long period of time has elapsed (1, 31).



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Fig. 2. AD-related NFT and A{beta} lesions increase in the population with advancing age, as seen by the prevalence of NFT stages (11) and the mean A{beta} phases and NFT stages (10, 11). The prevalence of an increasing severity of NFT changes with greater age indicates that, given the increasing life expectancy in technologically advanced societies, the number of AD patients will increase. The rise in the progression of AD-related changes with age also corroborates the hypothesis that early stages, as seen in younger age groups, represent the preclinical stages of patients who enter clinical AD in advanced age (1). [Reproduced from (64) with permission from Springer-Verlag]

 
The pathogenesis of AD is linked to the generation and deposition of A{beta}. A{beta} is derived from the amyloid precursor protein (APP, a transmembrane protein of unknown function) by {beta}- and {gamma}-secretase cleavage (Fig. 3). During the generation of A{beta}, APP first is cleaved by {beta}-secretase [also known as beta-site APP cleaving enzyme (BACE)-1] (32, 33). {gamma}-secretase then cuts the BACE-1-cleaved APP stub within its intramembranous domain. The {gamma}-secretase complex consists of at least four proteins: presenilin 1 or 2 (PS1 and PS2; also known as PSEN1 and PSEN2); nicastrin; Aph-1; and Pen-2 (see Wolfe Perspective). Each of these four subunits is required for the function of this protein complex. Under normal conditions, APP is chiefly degraded by {alpha}-secretase, which results in the generation of harmless peptides, and only small amounts of A{beta} are produced by {beta}- and {gamma}-secretases (34). Cells transfected with mutant presenilins, however, produce elevated levels of A{beta}, and AD patients carrying a presenilin mutation exhibit a larger burden of A{beta} deposits as compared to AD patients without such a mutation (35). AD-associated mutations in the APP, PS1, and PS2 genes indicate the importance of these proteins and their roles in APP cleavage for the pathogenesis of AD (35-37). The process of A{beta} cleavage and A{beta} deposition is responsible for the existence of A{beta} deposits not just in the brains of AD patients but also in those of cognitively intact individuals (36).



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Fig. 3. A{beta} is derived from APP (65). Under physiological conditions, {alpha}-secretase cleavage is the major APP-degrading pathway and does not lead to the production of A{beta}. A{beta} is a transmembranous fragment of APP that results from {beta}- and {gamma}-secretase cleavage (34). This pathway does not seem to play a major role in physiological APP degradation but gains momentum under pathological conditions and results in the deposition of A{beta} in AD. This {beta}- and {gamma}-secretase cleavage mechanism is responsible for A{beta} deposition in nondemented as well as demented AD patients.

 
Characteristics of PD and DLB

PD and DLB are histopathologically indistinguishable entities, both of which are characterized by the presence of Lewy bodies (LBs) and Lewy neurites (LNs) in a few well-defined types of nerve cells (38, 39) (see Andersen Review, Trojanowski Perspective, and Lee Perspective). The lifetime prevalence of PD has been reported at 0.2% (40), and its incidence increases in individuals older than 70 years of age (40).

LBs and LNs comprise aggregates of ubiquitinated {alpha}-synuclein, neurofilaments, Parkin, and other proteins (38, 41, 42). They are not innocuous age-related alterations but are pathognomonic for PD or DLB. The severity of these pathological changes increases gradually during the course of the disorders (12), and lesions have already developed, to a moderate degree, in the nervous systems of individuals whose clinical evaluations fail to note disease-associated symptoms (12). The lesions in incidental (that is, preclinical) cases remain confined to olfactory structures and a few lower-brain stem nuclei, whereas in patients with PD or DLB the lesions are found in mid- and forebrain sites as well (12, 43). Because no substantial differences exist between the topographic lesional distribution patterns of PD and DLB (44), only the clinical symptoms might distinguish these two disorders (44).

In PD, large numbers of neurons that synthesize the neurotransmitter dopamine are characteristically lost from the substantia nigra (a region of the midbrain), but this change is only one of the hallmarks of the disease (39). Nigral damage is always accompanied by extensive extranigral involvement, as shown in Fig. 4. Brains with severe damage usually exhibit lesions in the neocortex (12, 38).



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Fig. 4. Stages in the evolution of Parkinson-related LB pathology (12). The first LBs occur in the dorsal motor nucleus of the vagal nerve and olfactory bulb (stage 1). From these induction sites, LB pathology makes inroads, first into additional brain stem nuclei, such as the locus coeruleus and substantia nigra, then into the amygdala (stages 2 to 4), and finally into the cerebral cortex (stages 5 to 6). Clinical symptoms of PD occur only when LB pathology already affects large areas of the brain, including the substantia nigra (stages 4 to 6). [Reproduced with slight modifications from (12) with permission from Elsevier]

 
The pathology does not evolve simultaneously at all of the susceptible sites. Instead, it begins at predisposed locations and progresses in a predictable manner. The disease process begins in the anterior olfactory nucleus and the visceromotor nucleus of the vagal nerve in the brain stem, as depicted in Fig. 4. From there, it advances steadily upward into other regions (12). Therapy with levodopa (a dopamine precursor) or transplantation of fetal dopaminergic cells helps to replenish the dopaminergic deficit (45, 46) but does not restore intact cell function to other affected neurons at other predilection sites, nor do these therapies stop disease progression.

Characteristics of CVD

The term CVD is used to designate lesions in the brain caused by vascular disorders. The three major lesions are cerebral infarction, hemorrhage, and vascular dementia (8, 47). All three can result from different vascular disorders (Fig. 5) (47). A short description of the major brain lesions follows, together with that of the four most important vascular pathologies involved in CVD.



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Fig. 5. Vessel diseases responsible for cerebral infarction, intracerebral hemorrhage, and vascular dementia.

 
Cerebral infarction results from an acute cessation of blood perfusion to a localized area of the brain. This cessation is caused by arterial or venous occlusion, with the result that the brain tissue of an affected vessel territory becomes necrotic. After the acute event, the necrotic tissue is removed by macrophages, and finally a pseudocystic cavity (a space filled with extracellular fluid, with a wall consisting of processes of reactive astrocytes) accompanied by astrogliosis (during which the number of astrocytes increases in response to injury) marks the residual stage of carnification (scarring) (47). The size and location of the infarction depend on the extent of the vessel territory affected by the perfusion deficit. The zone bordering on the infarction, the penumbra, shows edema (abnormal accumulation of fluid) and is marginally perfused by other vessel territories (47). Larger functional deficits are observed during the acute phase as compared with the periods after successful acute phase treatment, and restored function of neurons in the penumbra might account for this recovery (47). Fig. 5 summarizes the most important vascular disorders that can cause cerebral infarction. The clinical manifestation of a symptomatic acute cerebral infarction is the stroke. Small infarcts can be clinically silent or present as transitory ischemic attacks (stroke-like episodes from which, clinically speaking, patients may recover completely within 1 day) (47).

Hemorrhage occurs as the result of a rupture in a vascular wall (47). Nontraumatic hemorrhages are associated with vascular diseases that lead to fragile vessel walls and are supported by hypertension (47). Fig. 5 lists vessel disorders associated with hemorrhage. Stroke is the clinical correlate for acute symptomatic hemorrhages. Small hemorrhages remain clinically silent (47).

Vascular dementia can develop as a result of multiple small infarcts and subcortical Binswanger-like white-matter lesions (subcortical lesions with a loss of myelinated axons around arteries that have thickened walls as a result of fibrosis and hyalinosis, a degenerative process that can occur in the collagen of various tissue types) (47). The radiological correlate of these white-matter changes is leukoaraiosis [multiple subcortical perivascular lesions detected by computed tomography (in which a number of x-ray images are assimilated into a cross-sectional image) or magnetic resonance imaging] (47, 48). The most prevalent vascular disorders that induce dementia are small-vessel diseases. These include arteriosclerosis/lipohyalinosis [AS/LH; this term summarizes degenerative small-vessel changes in the leptomeninges (a portion of the membranes surrounding the brain and spinal cord) and cortical and subcortical areas caused by arteriosclerosis, arteriolosclerosis, and associated perivascular white-matter lesions that contain lipid-containing macrophages as a result of perivascular myelin loss] (49) and CAA (20, 47, 50, 51). AS/LH and CAA often occur in the brains of healthy elderly individuals (20, 47, 49-52). Both lesions, however, are more widespread in people with advanced stages of AD-related pathology (9). Because cerebral infarctions, especially watershed microinfarcts (cerebral infarcts that occur within the border zone between two arterial territories as a result of hypoperfusion associated with atherosclerotic and AS/LH vessel pathology), are more frequently encountered in patients with AD than in non-AD cases (53, 54), vascular dementia is often associated with AD-related lesions, neurofibrillary changes, and A{beta} deposition.

Atherosclerosis, AS/LH, CAA, and embolic events (all of which obstruct blood flow) are the most prevalent vascular disorders that are responsible for cerebral infarction, hemorrhage, and vascular dementia.

Atherosclerosis of the large vessels in the circle of Willis (a group of arteries that encircle the base of the brain) is a prerequisite for the formation of thrombi (aggregations of platelets and fibrin) at the site of atherosclerotic plaques. Such thrombi are capable of losing contact with the arterial wall and, in so doing, lead to thrombembolic events that cause cerebral infarction. Atherosclerotic changes in these vessels, however, prevail in most individuals over the age of 60 (82.8% in our sample), and the majority of these brains did not display cerebral infarctions at autopsy.

Small-vessel AS/LH is often seen in patients with and without hypertension (47, 49) and causes hypertension-related hemorrhages as well as cerebral infarction and vascular dementia (47, 49). Arising first in the deep white matter and basal ganglia, AS/LH subsequently expands into the rest of the brain according to a hierarchical pattern (Fig. 6) (9).



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Fig. 6. Stages of AS/LH in the human brain (9). The first vessels affected by AS/LH are those of the basal ganglia and deep white matter (stage A). In addition to these sites, abnormal changes also appear in the vasculature of the peripheral white matter, thalamus, cerebellum, and amygdala; and the leptomeninges develop AS/LH (stage B). Finally, vessels of the hypothalamus, midbrain, and lower brain stem become involved (stage C). The expansion of this vascular pathology is accompanied by the progression of NFT and A{beta} pathology as well as by the development of cognitive decline (9). [Reproduced with slight modifications from (9) with permission]

 
CAA leads to alterations of the vascular wall. It causes intracerebral hemorrhage and cerebral infarction (20, 50, 55-58) and contributes to the development of vascular dementia.

In addition to these changes in vessel walls, cardioembolic and arterioembolic events also cause cerebral infarction (47).

Vascular lesions as well as pathological changes in the vessel wall are frequent phenomena in nonsymptomatic individuals (47, 49, 54). In our sample of 172 nonselected autopsy cases from elderly people aged 60 or older, 47.7% displayed nonsymptomatic CVD. An additional 40.7% displayed CVD associated with neurological and/or cognitive deficits alone or combined with other changes. Only 11.6% of the cases were entirely free of CVD.

Conclusions

Preclinical stages of the neurodegenerative and cerebrovascular disorders described above are prevalent in the majority of elderly people; that is, in more than 80% of individuals over the age of 60. As a result, the question has arisen as to whether these abnormal changes represent normal aging. In the opinion of the authors, at least four arguments can be advanced against this point of view: (i) Although the brains of many aged individuals contain these pathological changes, individuals exist whose brains are devoid of disease even at the age of 90 years and beyond. (ii) Even preclinical brain changes in persons with preclinical AD (for example, neurofibrillary tangles in the enthorhinal region, a cortical region involved in memory processing) display neuronal loss and adaptive synaptic response (27, 30, 59). (iii) Identical biological mechanisms are responsible for preclinical as well as clinical pathology: (a) APP cleavage is involved in the production and deposition of A{beta} in nondemented elderly people and AD patients alike (34, 60, 61); (b) abnormal aggregation and ubiqitination of {alpha}-synuclein are observable in individuals with PD/DLB as well as in LBs/LNs of nonsymptomatic individuals (12); (c) atherosclerosis, AS/LH, and CAA are prevalent in elderly individuals with and without cerebral infarction, hemorrhage, and/or vascular dementia (10, 47, 49). (iv) The distribution of the pathological alterations in preclinical AD, preclinical PD, and preclinical CAA-AS/LH-associated vascular lesions represents early stages of disease processes that are limited to distinct brain areas and structures as opposed to end stages of these disorders, in which the characteristic lesions are nearly ubiquitous in the brain. This has been documented by staging systems for AD-related neurofibrillary tangles (11), A{beta} deposition (10), PD-associated LBs and LNs (12), and vascular changes in CAA and AS/LH (9). As such, we would argue that pathological changes associated with neurodegenerative and cerebrovascular diseases in nonsymptomatic elderly brains are indeed preclinical stages of AD, PD, and/or CVD rather than the result of normal aging. On the other hand, aging does appear to be the major risk factor for all three disorders.

In our view, current data about pathologies of the elderly brain point to three distinctive categories (Fig. 7): (i) healthy aging, (ii) aging with nonsymptomatic disease, and (iii) aging with symptomatic disease. Healthy aging can be defined as aging in the absence of pathological alterations irrespective of origin. This type of aging can be seen even in very old people, although the number of individuals whose brains display healthy aging does decrease with advancing age. Aging with nonsymptomatic disease is defined by the presence of disease-related pathological changes in nonsymptomatic individuals. For example, in a few individuals, AD-related neurofibrillary tangles and A{beta} plaques are already detectable at the age of 30 (1, 62) and lead to symptomatic AD two or three decades later (31). Elderly nonsymptomatic people, however, remain capable of living a normal life (1) (Fig. 2 and Fig. 7), although AD-, PD-, and/or CVD-associated lesions already exist in their brains and are progressive. As such, all of these individuals are at higher risk than "normals" to cross the threshold from nonsymptomatic disease to disease-related symptoms. In dementing disorders, such as AD, PD, and vascular dementia, this threshold is crossed with the involvement of a distinct number of strategic, selectively vulnerable brain regions in the disease process (9-12). Especially in AD, the age of disease onset and pace of progression vary considerably among individuals (Fig. 7). Genetic factors and gender influence the age of onset on the part of the pathology and the progression into higher stages in late-onset AD (63). The potential role of individual neuronal reserves in AD and PD, on the other hand, is still unknown.



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Fig. 7. Schematic representation of the onset and course of neurodegenerative and cerebrovasular disorders in relation to healthy aging, nonsymptomatic disease, and disease. The possible courses of AD (A) and PD (B) represent the continuous progression of pathological changes into additional brain regions. The age at onset and pace of disease progression might vary, possibly depending on the individual genetic background and individual neuronal reserve capacity (fast disease progression for AD and PD is indicated by line 1, slow progression by line 2). CVD is often characterized by abrupt worsening of neurological and cognitive status (C). The larger the area involved, the more severe the clinical symptoms. Because large infarctions and bleeding are attended by a perifocal edema, which disappears after the acute event (47), clinical recovery after the initial insult is possible (line 3). The remaining deficits are caused by the lesion and may disappear clinically if there is sufficient healthy brain tissue available to functionally replace damaged areas. Multiple small infarcts, on the other hand, might lead to a gradual worsening of brain function (8) (line 4). In the event that the vascular changes precede other types of brain damage, such as AD (D), this gradual progression will be clinically evident (marked in green); whereas the reverse sequence might exhibit a continuous, slowly progressive worsening typical of AD (marked in yellow). Each of these scenarios is outlined in (D). The explanation for clinically silent AD with prominent vascular dementia is that vascular dementia destroys strategic neurons and leads to dementia before AD can destroy them. Likewise, "silent" vascular dementia means that AD has already damaged the brain to such an extent that vascular lesions affect only damaged, nonfunctional brain areas and thus do not result in significant further clinical worsening. The multiple events presented in the schematic representations are intended to show that the disease process can commence at any time, regardless of the pace of disease progression.

 
According to this hypothesis, a large number of people who today are dying in preclinical or so-called "incidental" stages of neurodegenerative and/or cerebrovascular disorders will in the near future survive longer and go on to develop symptomatic disease stages, with all of the accompanying detrimental economic consequences for public health care systems, particularly as life expectancy in highly industrialized and technologically advanced populations increases. Because we anticipate a prolongation of life expectancy within the coming decades, it is important to find (i) the means for preclinical diagnosis of people who are considered at risk to develop AD, PD, or CVD and (ii) therapies capable of preventing these diseases, forcing them into remission, or stopping their progression. At the present time, when clinical symptoms of AD, PD, and CVD begin, large expanses of the brain are already severely--in all probability irreversibly--damaged. Thus, it is the preclinical disease stages that offer the best opportunity for initiating therapeutic strategies with the intention of halting disease progression before significant brain damage takes place.


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Citation: D. R. Thal, K. Del Tredici, H. Braak, Neurodegeneration in Normal Brain Aging and Disease. Sci. Aging Knowl. Environ. 2004 (23), pe26 (2004).




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