Alzheimer's Disease (AD)
ALZHEIMER’S DISEASE, PARKINSON’S DISEASE AND RELATED BRAIN DISORDERS: BRIEF OVERVIEW FOR PATIENTS AND CAREGIVERS
John Q. Trojanowski, M.D., Ph.D.
The life span is thought to be biologically fixed for each species, and the length of the human life span is uncertain, but may be ~120 years. Since life expectancy has risen significantly in this century, the elderly are an increasing segment of our population, and their health care needs will continue to grow for decades.
Although normal aging is characterized by modest reductions in the mass and volume of the human brain, which may be due to the atrophy and/or death of brain cells, these changes are far more profound in the brains of patients who succumb to a neurodegenerative disorder. Most of these diseases are sporadic (i.e., not due to genetic mutations) and of unknown cause, but hundreds of different mutations in many genes have been shown to cause familial (inherited) variants of several neurodegenerative disorders in numerous kindreds. Many of the dozen or more genes that harbor these mutations were discovered in the quest to determine the genetic basis of neurodegenerative diseases just in the last ten years. Neurodegenerative diseases evolve gradually, after a long period of normal brain function, due to progressive degeneration (i.e., nerve cell dysfunction and death) of specific brain regions. Since symptomatic expression of disease occurs when nerve cell loss exceeds a "threshold" for the continuing function (e.g., memory, movement) performed by the affected brain region, the actual onset of brain degeneration may precede clinical expression by many years. For example, clinical manifestations of parkinsonism become apparent following a loss of ~80% of nigral dopaminergic neurons (i.e., nerve cells involved in motor behavior), and this may occur over several years. However, all individuals with a genetic mutation that causes a hereditary neurodegenerative disorder who live long enough will develop disease, i.e., there are no "escapees."
In this brief overview of Alzheimer’s disease (AD), Parkinson’s disease (PD) and related mid- and late-life degenerative brain disorders, it is impossible summarize the many dramatic research advances into the causes of AD, PD and related diseases, but such advances provide fresh opportunities for the discovery of more effective therapies for these diseases. Thus, rather than trying to survey all of these advances, the goal here is to enable the reader to understand:
1) The concept of age-related sporadic and hereditary neurodegenerative diseases.
2) The concept of "selective vulnerability" or the predilection of subpopulations of brain cells to degenerate.
3) The parallels between the filamentous brain lesions characteristic of AD, PD and several other sporadic and hereditary neurodegenerative disorders.
4) Key neuropathology of AD, PD and a few other neurodegenerative diseases.
5) Insights into mechanisms of brain degeneration that have emerged from clinical and basic research on these diseases.
Intellectual and higher integrative cognitive faculties become progressively impaired and interfere with activities of daily living in dementing diseases. The precise prevalence of dementia in the elderly population is unknown, but may be ~15% of people 65 years old with ~5% severely and ~10% mildly to moderately demented. The prevalence of severe dementia increases from ~1% at 65 years to ~45% at 85 years. There are many causes of dementia, but AD accounts for ~50% of demented patients >65 years of age.
AD, the most common cause of dementia in the elderly, is a heterogeneous group of neurodegenerative disorders. The incidence rate for dementia in general is 187 new cases/100,000 population/year, and for AD it is 123 new cases/100,000 population/year. Due to the increasing number of individuals living beyond the 7th decade, AD has become the 4th leading cause of death in the United States. Males and females are affected about equally. AD has probably afflicted the elderly for centuries, but it was rare when first reported by Alois Alzheimer in 1907, only because life expectancy was ~50 years then, and few individuals lived to age 60 or longer when the risk of AD increases with advancing age beyond the 7th decade of life.
Sporadic AD accounts for ~90% patients with this disorder, and ~10% of patients have FAD. About 50% of familial AD (FAD) kindreds have been shown to have disease causing mutations in genes on chromosome 14 (Presenilin 1 or PS1), 1 (Presenilin 2 or PS2), and 21 β precursor protein or Aβ , while chromosome 19 harbors a risk factor gene (apolipoprotein E) for AD. It is not clear how these mutations or trisomy 21 in Downs’s syndrome (DS) lead to AD. The major symptom of AD is progressive forgetfulness leading to dementia, but other cognitive functions (language, orientation in time and place, etc.) also deteriorate, and disease may extend over 5-15 years. The end-stage AD brain shows diffuse cerebral atrophy with enlarged ventricles, narrowed cortical gyri and widened sulci. These changes are attributed to neuronal loss. While the loss of neurons in AD generally exceeds that seen during normal aging, there may be overlap between the AD brain and the brains of age matched normal subjects. However, individual neuronal groups in neurodegenerative disorders and normal aging vary in their susceptibility for degeneration. Specifically, the hippocampal formation is consistently and heavily involved in the pathology of AD, and considerably less affected in normal aging. This predilection has clinical correlates as well. Since the hippocampus is implicated in the formation of memory, the pathology occurs in a region where it can contribute to the intellectual deficits that are the hallmark of AD.
β-rich amyloid or senile plaques (SPs) in the extra-cellular space, and tau-rich intraneuronal neurofibrillary tangles (NFTs) are the two hallmark brain lesions of AD. They accumulate most prominently in neocortical and limbic brain regions for reasons that are not well understood, and a diagnosis of definite AD in a demented patient requires detection of abundant SPs and NFTs in the postmortem brain or a brain biopsy. The mechanisms leading to the formation of SPs and NFTs are not fully understood, but it is thought that these lesions form as a result of the conversion of normal Aβ peptides into amyloid fibrils and normal tau into paired helical filaments (PHFs) followed by their aggregation into SPs and NFTs, respectively. Over production (perhaps only in FAD) or impaired clearance of normal Aβ may exceed a critical "threshold" that "seeds" abnormal amyloid fibril formation followed by deposition in SPs. Significantly, the discovery of FAD mutations in the Aβ PP gene in 1991 led to the first transgenic mouse model of AD-like amyloidosis in 1995.
On the other hand, hyperphosphorylation of tau, presumably due to abnormal kinase and/or phosphatase activities, has been implicated in PHF formation followed by aggregation of PHFs into NFTs. NFTs could kill neurons by blocking intracellular transport, or transport may fail because tau in PHFs cannot bind to and stabilize microtubules, which are required for transport. Moreover, the discovery in 1998 of pathogenic tau gene mutations in kindreds with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), a rare disorder characterized by prominent intracellular neuronal and glial inclusions formed by PHF-like tau filaments, provided proof that tau abnormalities cause neurodegenerative diseases. Further proof of this has come from recent successful efforts to generate a transgenic mouse model of filamentous tau inclusions similar to the tau-rich tangles found in FTDP-17, AD and related tau diseases (tauopathies), and this should hasten the discovery of new therapies for these diseases.
Parkinsonism, as described by James Parkinson in the early 19th Century, includes an "involuntary tremulus motion, with lessened muscular power in parts not in action and even when supported with a propensity to bend the trunk forward, and to pass from a walking to a running pace." These neurologic signs are due to malfunction of the major efferent projection of the substantia nigra, i.e., the nigrostriatal tract. The cell bodies of neurons in this dopaminergic system are in the pars compacta of the substantia nigra and their axons ascend to the striatum. Clinical manifestation of parkinsonism are thought to first become apparent following a loss of 80% of nigral dopaminergic neurons. Examples of primary parkinsonian syndromes include Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and striatonigral degeneration (SND), which is included with olivopontocerebellear degeneration (OPCD) and Shy Drager syndrome (SDS) in a syndrome known as multiple system atrophy (MSA). Secondary parkinsonisms can occur following infarction, infection, trauma, or be drug or toxin induced. Because it is the prototypical primary parkinsonian syndrome, PD is discussed below.
Idiopathic PD (paralysis agitans) is a relatively common disease characterized by parkinsonism and intraneuronal filamentous inclusions known as Lewy bodies (LBs), which commonly form in the dopaminergic neurons that degenerate in PD. However, parkinsonism is not unique to PD, and LBs in cortical neurons are hallmarks of a disorder known as dementia with LBs (DLB) that is clinically similar to AD. Each year about 1/4000 of the total population 50 years and over are newly affected, and 2-3% of the population (1/40) develop parkinsonism at some time during life. The age of onset in most series is 50-60 years of age. The principal symptoms are tremor, rigidity, akinesia, and postural difficulties. Patients with PD generally respond well, at least initially, to antiparkinsonian medication (e.g., Levodopa), which enable remaining substantia nigra neurons to generate more dopamine and improve motor functions. However, PD patients eventually fail to respond to these medications, and basic research as well as clinical trials are in progress to determine if grafting fetal substantia nigra into the putamen or pallidotomy has therapeutic benefit for these patients. Although PD is relentlessly progressive, the course and prognosis of PD are not uniform. The neuropathology of PD is a massive loss of neuromelanin containing neurons, gliosis and hallmark LBs. These filamentous inclusions are found typically in neurons of the substantia nigra (mainly the pars compacta), locus ceruleus, dorsal nucleus of the vagus, and the substantia innominata. Other movement disorders characterized by parkinsonism may be difficult to distinguish from classic PD on clinical grounds, but these so-called "Parkinson Plus" disorders can be separated from PD because of their unique neuropathological features. In addition, it is well known that PD and AD frequently co-occur in the same patient. For example, a progressive dementia and the neuropathologic changes of AD (i.e., numerous SPs and NFTs) occur more commonly in patients who first present with PD than in age-matched controls. Moreover, ~8-45% of classic AD patients develop parkinsonism and the neuropathology of PD, including brainstem LBs. Indeed, LBs occur in >56% of FAD brains and in >50% of brains of elderly DS patients all of whom show classic AD pathology by age 40. Further, DLB may share clinical and pathological features of both PD and AD. Regardless of the clinical feature of the disorder or the predominant location of the pathology, LBs contain aggregated filaments that accumulate in neurons. The demonstration of mutations in the α-synuclein gene on chromosome 4 in several familial PD kindreds, the presence of α-synuclein in all LBs, and the detection of a fragment of α-synuclein in AD amyloid plaques serve to link α-synuclein to the formation of LBs and to neuron loss in PD and DLB, as well as a fragment of α-synuclein to amyloid plaque formation in AD. Thus, AD and the disorders discussed here are examples of a large group of neurodegenerative diseases with a common mechanistic theme, i.e., the conversion of a normal brain protein into insoluble filamentous aggregates appears to play a critical role in the progressive degeneration of brain cells that cause the relentless loss of specific brain functions.
CONCLUDING REMARKS: "FATAL ATTRACTIONS" OF PROTEINS AS A COMMON UNDERLYING MECHANISM OF MANY DIFFERENT NEURODEGENERATIVE DISEASES
While there is no single cause or pathologic mechanism for the disorders reviewed here, abnormal protein-protein interactions resulting in the formation of intracellular and extracellular aggregates of proteinacious fibrils are a common theme of many different sporadic and hereditary neurodegenerative diseases. This is exemplified by the intranuclear filamentous inclusions in neurons formed by abnormal expansions of polyglutamine tracts in hereditary tri-nucleotide repeat disorders, the similar inclusions in a rare and seemingly sporadic disorder known as neuronal intranuclear inclusion disease (NIID), the cytoplasmic tau filament inclusions in neurons and glia of "tauopathies," the NFTs and extracellular amyloid plaques in sporadic and familial AD, the prion protein filament deposits in sporadic and genetic spongiform encephalopathies, the α-synuclein-rich filamentous LBs in familial and sporadic PD, DLB, and other LB disorders, as well as similar filamentous α-synuclein inclusions in glial cells of MSA. Thus, increasing evidence suggests that abnormal protein-protein interactions and/or the lesions that result from aggregation of these proteins could play a mechanistic role in the dysfunction and death of neurons in many different neurodegenerative diseases. Accordingly, insights into mechanisms of the pathologic processes that lead to these lesions, and the identification of strategies to prevent their formation or eliminate them after they have formed, may yield new opportunities to discover more effective therapies for these diseases.
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