Neurodegenerative Changes in the Ageing Brain An Overview on Epidemiology, Pathogenesis, and Neuropathology of Dementias

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1 Neurodegenerative Changes in the Ageing Brain An Overview on Epidemiology, Pathogenesis, and Neuropathology of Dementias Johannes Attems Pathologic Institute, Otto Wagner Hospital, Vienna Paper prepared for the conference: Impact of Ageing: A Common Challenge for Europe and Asia University of Vienna, June 7-10,

2 1. Introduction and historical annotation Ageing of the Brain is associated with a slowly progressing decline in cognitive abilities including memory performance, cognitive speed, and flexibility. The clinical manifestation of dementia depends on the severity of these age associated symptoms. Dementia can thus be defined as an impairment of previously attained occupational or social functioning due to an acquired and persistent impairment of memory associated with an impairment of intellectual function in one or more of the following domains language, visiospatial skills, emotion, personality, or cognition in the presence of normal consciousness 1. Dementia is predominantly caused by neurodegenerative processes that evolve over many years. Different diseases preferentially affect different brain regions and so distinctive clinical patterns of dementia can be recognized. With progression of the disease, more of the cortical areas tend to be affected and a global deterioration in intellectual function ensues. As to date, the aetiology of age associated dementing diseases remains elusive. Throughout history various forms of dementia have always been an integral part of the human condition; the efforts for systematic description of the clinical and pathological characteristics of dementing diseases only date back to the late 1890s. This was at least partly due to the paralleling advances of light microscopy, neuroanatomy and other areas of biology 2, 3. In 1892 Blocq and Marinesco noticed miliar foci (i.e., senile plaques) in the neocortex of demented individuals and described a relationship between these neuropathological findings and senile dementia. This was also reported by Redlich (1898) and Fisher was one of the first to suggest that severity of dementia and memory loss might be associated with senile plaques (1907). The clinical entity that today is known as Alzheimer`s disease and represents by far the most common neurodegenerative disorder, clearly existed long before 1906, when Alois Alzheimer reported the case of Auguste D., a 51-year-old woman with dementia at the meeting of the South-West Germany Psychiatrists in Tübingen on November 3 and 4 of that year. His presentation was published in Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin in Consistent with his interest to help psychiatry through the microscope Alois Alzheimer described the clinical as well as the neuropathological characteristics of that case. As a matter of fact, even today the investigation and classification of neurodegenerative diseases is based on the combination of clinical observations with systematic neuropathological analysis of brain lesions and in most 2

3 neurodegenerative diseases no definite diagnosis can be given without neuropathological examination of the post mortem brain. The term Alzheimer`s disease did not receive broad endorsement until the eight edition of Emil Kraeplin`s Psychiatrie: Ein Lehrbuch für Studierende und Aerzte (i.e., Textbook of Pyschiatry) in In 1997 the original histological specimens of the case described by Alois Alzheimer in 1906 were rediscovered at the University of Munich by Manuel Graeber and colleagues. They investigated these specimens using state of the art methodologies and found out that these specimens indeed fulfilled all current neuropathological criteria for the diagnosis of Alzheimer`s disease. The present paper provides epidemiological data on age related neurodegenerative diseases and a brief overview on current concepts of the underlying pathomechansms. I will describe the characteristic major neuropathological changes which are frequently observed in post mortem brains of aged individuals and the morphological substrates of frequent diseases such as Alzheimer s disease, vascular dementia, and Parkinson s disease. 2. Epidemiology As a result of increased life expectancy and changing demographics (e.g., the ageing of baby boomers) neurodegenerative diseases are becoming more common. The risk of becoming demented is 0.4% at age 65 years while it is 50% at age 95 years, and we know now that both the incidence and the prevalence of Alzheimer`s disease rise between the ages of 65 and 95 years in an approximately exponential fashion, doubling with every 5 years of age (figure 1). As in developed countries the proportion of individuals over 60 years of age is expected to rise for roughly 2/3 in the long run, information about the age-specific incidence of Alzheimer`s disease and dementia is critical for evaluation of the public health impact. Comparison of population studies among different countries has shown age-specific prevalence and incidence rates to be similar within a factor of 2 in countries as diverse as China, Japan, Great Britain, France, Italy, and the United States and Canada, yet major ethnic differences exist 5. In Austria in 2000 nearly 1.5 millions were aged between 60 and 79 and 0.2 millions were over 79 years of age. In the years 2010, 2030, and 2050 the latter are expected to rise to 0.4, 0.6, and 1 million, respectively. Age is the single most important risk factor for dementias of all kinds and therefore it is very clear that both incidence and prevalence of dementias will rise dramatically. The 3

4 number of persons with dementia in developed contries will increase from 13.5 million in the year 2000 to 36.7 million in the year 2050 and by 2050, incident cases of dementia in the USA would approach the number of incident cases of cancer 5. These figures reflect increasing costs of care for demented patients; in the year 1993 in Austria the costs of care for demented seniors was 1.5 billion Euros, 85% of which were paid by relatives. In the USA in 2005 these costs were estimated to be billion dollars and would exceed 380 billion dollars (in constant 1998 dollars) by , 6. Figure 1: Prevalence of dementia in different age groups, modified from 7. The most common cause for dementia is Alzheimer s disease as it accounts for 60-65% of all dementias and this figure increases with increasing age at the onset of dementia. Ott et al. could show that 75% of demented individuals aged over 85 years suffered from Alzheimer`s disease 8. The second most common cause is dementia with Lewy bodies (10-15%), followed by vascular dementia (8-10%), and dementia secondary to other diseases (5-10%). Mixed type dementia, which represents a mixture between Alzheimer`s disease and vascular dementia accounts for 4% and all other various forms of dementia (e.g., frontotemporal dementia) for 5-10% of dementias, respectively (figure 2). Few studies have evaluated the immediate cause of death in elderly demented and also non-demented patients. The majority of these studies were based on death certificate information alone, which has been shown to be highly inaccurate in the geriatric population Autopsy studies on this topic, on the other hand, often lacked non-demented elderly controls, and thus had limitations in defining differences between cause of death in demented and non-demented subjects 12, 15, 20. 4

5 70% 60% 50% 40% 30% 20% 10% 0% Alzheimer`s disease Dementia with Lewy Bodies Vascular dementia Secondary Dementia Mixed type dementia Other dementias Figure 2: Frequency of different types of dementia. Dementia has been shown by some authors to decrease life expectancy and most authors claimed bronchopneumonia to be the leading cause of death in demented patients 8, 10, 12, 15, 16, 21. Death certificates often state dementia/alzheimer`s disease as the cause of death in a given patient, the question, however, if dementia/alzheimer`s disease is a frequent cause of death is still controversial 14, 16, In an autopsy study of over 300 cases of demented and non-demented elderly inpatiens we have shown that the leading cause of death in Alzheimer`s disease patients is bronchopneumonia (45.5%) followed by cardiovascular disease (31.3%). By contrast the leading cause of death in non-demented and demented patients with another cause of dementia than Alzheimer`s disease is cardiovascular disease (46.2%) followed by bronchopneumonia (28.0%) 28. Despite these differences regarding causes of death in demented and non-demented patients, Alzheimer`s disease is not a cause of death per se but rather a severe underlying disease. The pathological lesions in the brain are not lethal themselves but presumably lead to 5

6 reduced nutrient intake, when the patient relies on oral food administration alone. Without additional food administration, patients suffering from Alzheimer`s disease frequently show signs of marantic atrophy. Severely demented patients are bedridden, which favors the occurrence of so called hypostatic pneumonia. 3. Pathomechanisms of age associated neurodegenerative diseases A large body of evidence now suggests, that the aggregation of misfolded proteins represents a single common pathogenic mechanism underlying many diverse neurodegenerative disorders (table 1). Misfolding of proteins results in the deposition of insoluble filamentous aggregates of normally soluble proteins in the central nervous system (CNS) 29. In Alzheimer`s disease amyloid-beta protein (Aβ) and hyperphosphorylated tau protein (tau) constitute the majority of insoluble aggregates, which have been shown to be composed of 10-ηm-wide fibrils with crossed β-pleated sheet structure. The formation of Aβ results from cleavage of the amyloid-precursor protein (APP) by both β and γ secretases, while cleavage by α secretase inhibits Aβ formation. Physiologically, APP is an integral cell membrane protein and to date it is unclear whether the accumulation of Aβ is a result of increased β and γ secretases or of decreased α secretase activity, respectively. In addition, increased cell death with increased membrane breakdown could lead to accumulation of Aβ, simply as a consequence of over-accumulation of APP with subsequent cleavage of α, β, and γ secretases, which ultimately leads to increased amount of insoluble Aβ. Matters are further complicated by the fact that Aβ per se is neurotoxic and could thus lead to neuronal cell death with subsequent accumulation of Aβ (s.a.). The accumulation of insoluble Aβ fibrils could therefore be a consequence of disturbed secretase activity, neuronal cell death or a combination of both 30, 31. Physiologically, tau is a microtubule-associated protein that binds to and stabilizes microtubules, the latter being a fundamental part of the neuronal cytoskeleton. In inherited diseases mutations in the tau gene, and by analogy tau dysfunction in sporadic disease may be pathogenic through mechanisms involving both loss of function (decreased microtubule stabilization) and toxic gain of function (increased fibril formation). Tau hyperphosphorylation and aggregation leads to the formation of paired helical filaments followed by decreased microtubule-bound tau with subsequent microtubule depolymerization. This in turn results in impaired axonal 6

7 transport and finally in stasis/aggregation of axonal traffic. Ultimately, synaptic dysfunction and axonal degeneration lead to neuronal cell death 29. The pathological hallmarks of Alzheimer`s disease are Aβ deposits in plaques (e.g., senile plaques) and vessels (i.e., cerebral amyloid angiopathy, CAA) together with tau aggregation in the form of neurofibrillary tangles (NFT), neuropil threads (NT), and neuritic plaques 6, 32. Table 1 Neurodegenerative diseases with depositions of aggregated proteins Disease Lesion Location Aggregated protein Alzheimer`s disease Amyloid plaque Extracellular Neurofibrillary tangle Intracytoplasmatic (neurons) Tau Dementia with Lewy bodies Lewy bodies Intracytoplasmatic (neurons) a synuclein Amyotrophic lateral sclerosis Hyaline inclusions Intracytoplasmatic (neurons) Superoxide dismutase-1 Corticobasal degeneration/ Tau positive inclusions Intracytoplasmatic (neurons) Tau progressive supranuclear palsy Huntington`s disease Neuronal inclusions Intranuclar (neurons) Huntingtin Multiple system atrophy Glial cytoplasmatic Intracytoplasmatic a synuclein inclusions (oligodendroglia) Pick`s disease Pick bodies Intracytoplasmatic (neurons) Tau Parkinson`s disease Lewy bodies Intracellular a synuclein modified from Neuropathology 4.1. Alzheimer s disease On gross examination (i.e., macroscopy) the brain shows shrinkage of cerebral gyri and widening of sulci, most prominently in the medial and temporal regions, particularly in the hippocampus but also in the frontal and parietal regions, while the occipital cortex and the motor cortex are relatively spared. The cortical mantle (i.e., grey matter) may appear to be thinned, whereas the white matter is of normal colour and texture. The ventricular system may be considerably dilatated, especially that of the temporal horn of the lateral ventricles. Microscopically, AD is characterized by distinct morphological abnormalities: - Deposition of Aβ plaques (e.g., senile plaques, neuritic plaques, figure 3) - Intraneuronal depositions of hyperphosphorylated tau termed NFT (s.a., figure 4). - Extraneuronal depositions of hyperphosphorylated tau termed NT (figure 4). - Deposition of Aβ plaques which contain tau in dystrophic neurites (neuritic plaques, figure 3b). - Loss of synapses and neurons. 7

8 a b Figure 3: Senile plaques (a) and neuritic plques (b), Bielschovsky silver staining. In addition depositions of Aβ are present in the walls of arterial vessels in up to 90% of AD cases (cerebral amyloid angiopathy 32 ). None of these abnormalities are specific for AD. However, the assessment of their topographical distribution (i.e., location in the brain) together with the semiquantitative assessment of their extent leads to a valid neuropathological diagnosis of AD. Difficulties in making a pathologic diagnosis of AD occur because the histologic changes are not entirely pathognomonic and might show considerable overlap with those in cognitively normal elderly. On the other hand, these cognitively normal elderly could, at least partly represent early subclinical cases of AD (see 4.5.). Several different pathologic diagnostic criteria have been proposed and are currently widely used: - The Consortium to Establish a Registry for Alzheimer`s Disease (CERAD) guidelines for the diagnosis of AD are based on the semi-quantitative assessment of neuritic plaque density on a 4 point scale: none, sparse, moderate, and frequent. The patient`s age is taken into account in determining the diagnostic category for each case; to a limited extend the deposition of Aβ and tau is believed to be part of the so called normal aging process, therefore the amount of neuritic plaques which confirms the diagnosis of AD rises with the patient`s age The stages by Braak & Braak are based on the semiquantitative and topographical assessment of NFT and NT. It is assumed that in Alzheimer`s disease NFT and NT primarily occur in the entorhinal cortex (entorhinal stage, Braak stage I and II) and then spread to the adjacent subiculum and transentorhinal cortex, respectively (limbic stage, Braak stage III and IV). Finally NFT and NT are seen in the Ammons horn and in 8

9 isocortical/neocortical regions such as the frontal cortex and in very severe cases also in the occipital cortex (neocortical stage, Braak stage V and VI). Only the latter are considered to be indicative for definite Alzheimer`s disease The NIA-Reagan-Institute-Criteria (NIA-RI-Crit.) somewhat combine CERAD guidelines with Braak stages and yield a likelihood that clinical dementia has been caused by Alzheimer`s disease lesions: High probability that dementia was caused by Alzheimer`s disease, if the brain has both neuritic plaques and NFT in the neocortex (CERAD, frequent; Braak & Braak stage V/VI). Intermediate probability that dementia was caused by Alzheimer`s disease, if the brain has a moderate density of neocortical neuritic plaques and NFT in the limbic regions (CERAD, moderate; Braak & Braak stage III/IV). Low probability that dementia was caused by Alzheimer`s disease, if the brain has neuritic plaques and NFT in a more limited distribution and/or severity (CERAD, sparse; Braak & Braak stage I/II) 35. Figure 4: Severe amounts of neurofibrillary tangles (arrows) and neuropil threads (diffuse dots and lines in the background), AT8 immunohistochemistry Dementia with Lewy bodies The macroscopic appearance is similar to that in Alzheimer`s disease, the most prominent difference from Alzheimer`s disease is pallor of the substantia nigra and locus ceruleus. Microscopically dementia with Lewy bodies is defined by the presence of Lewy bodies in several brain regions (for details on Lewy bodies see section 4.4.). As in idiopathic Parkinson`s disease, there is almost invariably a significant loss of neurons from the substantia nigra and locus ceruleus. For 9

10 pathologic assessment of dementia with Lewy bodies the Newcastle criteria are used Vascular dementia Vascular dementia can be defined as an acquired intellectual impairment resulting from damage to the brain by cerebrovascular disease. However, several difficulties arise in applying this definition. Cortical or subcortical damage due to cerebrovascular disease usually results in circumscribed dysfunction in a cognitive domain related to the site of damage, but not in a general intellectual impairment as seen in dementia. Therefore some authors restrict the definition of vascular dementia to global cognitive decline resulting from the cumulative effect of multiple episodes of cerebral ischemia. In addition multiple small vascular lesions might clinically present as global cognitive decline. Neuropathologically vascular dementia presents as either small vessel disease, large vessel disease or gobal cerebral hypoperfusion 36, 37. In small vessel disease hyaline arteriosclerosis and artriolosclerosis is seen in small vessels and this is strongly associated with hypertension and diabetes mellitus. Due to small vessel disease additional pathologies may be present such as ischemic white matter degeneration and cribriform atrophy of white matter. Large vessel disease results in regional cerebral infarcts, which rarely contribute to cognitive decline. Likewise, severe cognitive dysfunction is rarely caused by multiple bilateral small infarcts in critical sites such as the hippocampal region. Conditions leading to cerebral hypoperfusion can cause ischemic injury to the hippocampus and hippocampal sclerosis with clinical dementia is seen in some elderly patients 38. Vascular dementia is still considered by some authors to be the leading cause of dementia in elderly patients, as they believe that Alzheimer s disease lesions are caused by cerebrovascular dysfunction Parkinson`s disease The manifestation of Parkinson`s disease is largely attributable to reduced dopaminergic input into the striatum, due to degeneration of neurons in the pars compacta of the substantia nigra. The pathological hallmark of Parkinson`s disease is the presence of neuronal inclusions called Lewy bodies. Lewy bodies contain several proteins; α synuclein is 10

11 seen in all Lewy bodies. In addition neurofilament proteins, ubiquitin, αb crystalline, tubulin, amyloid-precursor protein, and synaptic proteins might be present. The characteristic macroscopic feature of Parkinson`s disease is pallor of the substantia nigra and locus ceruleus, which is microscopically reflected by loss of pigmented neurons. In addition, Lewy bodies and pale bodies are present in the substantia nigra in remaining neurons and accumulation of neuromelanin in macrophages and astrocytic gliosis might be seen. Lewy bodies must be found to make a diagnosis of Parkinson`s disease Age associated changes In brains of cognitively normal elderly individuals many of the changes described above are found. They are usually of limited severity (i.e., number) and do not affect regions which are affected in clinically overt dementing diseases (e.g., neurofibrillary tangles in the neocortex in cases of Alzheimer`s disease). Indeed, nearly every brain of an individual aged over 80 years shows at least some neocortical senile plaques and neurofibrillary tangles in the entorhinal cortex. The severity and the topographical extension increases with increasing age. Therefore it is unclear if these age associated changes represent an early preclinical stage of the disease or if they are part of the normal ageing process. Autopsy studies suggested a loss of 10% of neurons over the entire lifespan, which is much less than the neuronal loss observed in Alzheimer`s disease and other dementias 42. Longitudinal studies suggested that the limited presence of senile plaques and neurofibrillary tangles in brains of cognitively normal individuals are the beginning of a continuum of change that eventually leads to Alzheimer`s disease 43, 44. In a study of 39 longitudinally followed cognitively normal elderly individuals (age range 74-95, median 85 years) 5 showed Braak stages V-VI and 15 at least some neuritic plaques 45. This finding of severe Alzheimer type pathology in cognitively normal individuals further complicates the question as to whether the presence of Alzheimer type pathology in the aged brain reflects an early preclinical stage of the disease or an age associated phenomenon. 5. Future perspectives Despite the remarkable progress toward understanding Alzheimer`s disease and other demetias, there are still many questions which need to be addressed in the near future. In particular, the pathogenesis of Alzheimer`s disease needs to be 11

12 further clarified, as to date we do not know the exact causes for sporadic age associated Alzheimer`s disease and other dementias. In order to further our knowledge worldwide networks of investigators from different specialities working closely and collaboratively are definitely needed. Time is running out and the pandemic of Alzheimer`s disease will completely overwhelm the health care systems because of the substantial increase of demented seniors. The projected costs in human suffering and public economic burden will be incalculable and unthinkable 46,

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