The New England Journal
of Medicine -- May 17, 2001 -- Vol. 344, No. 20
Stanley B. Prusiner
Twenty-five years ago, little was known
about the causes of neurodegenerative diseases. Now, however, it is clear that
they result from abnormalities in the processing of proteins. In each of these
diseases, defective processing causes the accumulation of one or more specific
neuronal proteins.
Of all the laboratory research on
neurodegenerative diseases, the studies that led to the discovery of prions
have yielded the most unexpected findings. The idea that a protein can act as
an infectious pathogen and cause degeneration of the central nervous system was
accepted only after a long and arduous battle. (1)
The concept of prions not only has provided an explanation of how a disease can
be both infectious and genetic, but has also revealed hitherto unknown kinds of
neurologic diseases. This review presents a unifying concept of degenerative brain
diseases, based on what we have learned about prions. (2)
Alzheimer's disease is the most common
neurodegenerative disorder (Table
1). In the United States, approximately 4 million people have Alzheimer's
disease, and approximately 1 million have Parkinson's disease. (3,4,5)
Much less common are amyotrophic lateral sclerosis, frontotemporal dementia,
prion diseases, Huntington's disease, and spinocerebellar ataxias.
With the increase in life expectancy,
there has been concern about the incidence of Alzheimer's and Parkinson's diseases.
Among persons who are 60 years old, the prevalence of Alzheimer's disease is
approximately 1 in 10,000, but among those who are 85 years old, it is greater
than 1 in 3. (6)
These data suggest that by 2025, there will be more than 10 million cases of
Alzheimer's disease in the United States, and by 2050, the number will approach
20 million. (4)
The annual cost associated with Alzheimer's disease in the United States is
estimated at $200 billion. Age is also the most important risk factor for
Parkinson's disease. Nearly 50 percent of persons who are 85 years old also
have at least one symptom or sign of parkinsonism. (7)
Virtually all neurodegenerative disorders
involve abnormal processing of neuronal proteins. The aberrant mechanism can
entail a misfolding of proteins, altered post-translational modification of
newly synthesized proteins, abnormal proteolytic cleavage, anomalous gene
splicing, improper expression, or diminished clearance of degraded protein.
Misprocessed proteins often accumulate because the cellular mechanisms for
removing them are ineffective. The particular protein that is improperly
processed determines the malfunction of distinct sets of neurons and thus the
clinical manifestations of the disease.
Prions are infectious proteins. In
mammals, prions reproduce by recruiting normal cellular prion protein (PrPC)
and stimulating its conversion to the disease-causing (scrapie) isoform (PrPSc).
A major feature that distinguishes prions from viruses is that PrPSc
is encoded by a chromosomal gene. (8)
Limited proteolysis of PrPSc produces a smaller, protease-resistant
molecule of approximately 142 amino acids, designated PrP 27-30, which
polymerizes into amyloid. (9)
The polypeptide chains of PrPC
and PrPSc are identical in composition but differ in their
three-dimensional, folded structures (conformations). PrPC is rich
in (alpha)-helixes (spiral-like formations of amino acids) and has little
(beta)-sheet (flattened strands of amino acids), whereas PrPSc is
less rich in (alpha)-helixes and has much more (beta)-sheet. (10)
There is evidence that PrPC has three (alpha)-helixes and two short
(beta)-strands; in contrast, a plausible model suggests that PrPSc
may have only two (alpha)-helixes and more (beta)-strands (Figure
1). (11,12)
This structural transition from (alpha)-helixes to (beta)-sheet in PrP is the
fundamental event underlying prion diseases.
Four new concepts have emerged from
studies of prions. First, prions are the only known example of infectious
pathogens that are devoid of nucleic acid. All other infectious agents possess
genomes composed of either RNA or DNA that direct the synthesis of their
progeny. Second, prion diseases may be manifested as infectious, genetic, or
sporadic disorders. No other group of illnesses with a single cause has such a
wide spectrum of clinical manifestations. Third, prion diseases result from the
accumulation of PrPSc, which has a substantially different
conformation from that of its precursor, PrPC. Fourth, PrPSc
can have a variety of conformations, each of which seems to be associated with
a specific disease. How a particular conformation of PrPSc is
imparted to PrPC during replication in order to produce a nascent
PrPSc with the same conformation is unknown. The factors that
determine the site in the central nervous system where a particular PrPSc
is deposited are also not known.
Prion diseases have a broad spectrum of
clinical manifestations, including dementia, ataxia, insomnia, paraplegia,
paresthesias, and deviant behavior. (13)
Neuropathological findings range from an absence of atrophy to widespread
atrophy, from minimal to widespread neuronal loss, from sparse to widespread
vacuolation or spongiform changes, from mild to severe reactive astrocytic
gliosis, and from an absence of PrP amyloid plaques to an abundance of plaques.
(14)
None of these findings except the presence of PrP amyloid plaques is
unequivocally diagnostic of a prion disease.
The sporadic form of Creutzfeldt-Jakob
disease, which is typically manifested as dementia and myoclonus, accounts for
approximately 85 percent of all cases of prion disease in humans, whereas
infectious and inherited prion diseases account for the rest. Familial
Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and fatal
familial insomnia are all dominantly inherited prion diseases caused by
mutations in the prion protein gene (PRNP) (Table
2). (15,16,17,18,19)
Experiments that showed transmission of these diseases by filtrates of brain
from familial cases (20,21)
were wrongly attributed to a virus. There is no Creutzfeldt-Jakob disease
virus, and familial prion diseases are caused by mutations in PRNP. (22)
Epidemiologic Features
Prions cause Creutzfeldt-Jakob disease in
humans throughout the world. The incidence of sporadic Creutzfeldt-Jakob
disease is approximately 1 case per 1 million population, (23)
but among persons between the ages of 60 and 74 years, the incidence is nearly
5 per 1 million. (24)
Cases in patients as young as 17 years and as old as 83 have been recorded. (23,25)
Creutzfeldt-Jakob disease is relentlessly progressive and usually causes death
within a year after its onset. Each geographic cluster of cases of prion
disease was initially thought to be a manifestation of viral communicability, (26)
but each was later shown to be due to a PRNP gene mutation except for new
variant Creutzfeldt-Jakob disease.
Neuropathological
Features
There are often no recognizable gross
abnormalities in the brains of patients with Creutzfeldt-Jakob disease.
Patients who survive for several years have variable degrees of cerebral
atrophy. The microscopical features of Creutzfeldt-Jakob disease are spongiform
degeneration and astrogliosis (Figure
2A and Figure
2B). (27)
Amyloid plaques occur in approximately 10
percent of cases of Creutzfeldt-Jakob disease. These plaques are positive for
antibodies against PrPSc on immunohistochemical staining. (28,29)
The amyloid plaques in patients with Gerstmann-Straussler-Scheinker disease
consist of a dense core of amyloid surrounded by smaller globules of amyloid (Figure
2). A characteristic feature of new variant Creutzfeldt-Jakob disease is
the presence of "florid plaques" composed of a core of PrPSc
amyloid surrounded by vacuoles (Figure
2E and Figure
2F).
Strains of Prions
The existence of prion strains raises the
question of how heritable biologic information can be encrypted in a molecule
other than nucleic acid. (30,31,32)
Strains of prions have been defined by the rapidity with which they cause
central nervous system disease and by the distribution of neuronal vacuolation.
(30)
Patterns of PrPSc deposition have also been used to characterize
these strains. (33,34)
There is mounting evidence that the diversity of prions is enciphered in the
conformation of the PrPSc protein. (35,36,37,38,39)
Studies involving the transmission of fatal familial insomnia and familial
Creutzfeldt-Jakob disease to mice expressing a chimeric human-mouse PrP
transgene have shown that the tertiary and quaternary structure of PrPSc
contains strain-specific information. (37)
Studies of patients with fatal sporadic insomnia have extended these findings,
(40)
making it clear that PrPSc acts as a template for the conversion of
PrPC into nascent PrPSc.
Sporadic, Genetic, and
Infectious Forms of Prion Disease
Sporadic prion diseases might be initiated
by a somatic mutation and in this respect might develop in a manner similar to
prion diseases caused by germ-line mutations. In this situation, the mutant PrPSc
must be capable of recruiting wild-type PrPC, a process that may
occur with some mutations but is unlikely with others. (41)
Alternatively, the activation barrier separating wild-type PrPC from
PrPSc may be crossed on rare occasions in the context of a large
population of people. (42)
Twenty mutations in the human PRNP gene have been found to segregate with
inherited prion diseases. (43)
Missense mutations and expansions in the octapeptide-repeat region of the gene
cause familial prion diseases. (15,16,17,18,19)
Although infectious prion diseases
constitute less than 1 percent of all cases of prion disease, the circumstances
surrounding the transmission of these infectious illnesses are often dramatic (Table
2). Ritualistic cannibalism has resulted in the transmission of kuru among
the Fore people of New Guinea, industrial cannibalism has been responsible for
bovine spongiform encephalopathy (BSE), or "mad cow disease," in
Europe, and an increasing number of patients have contracted new variant
Creutzfeldt-Jakob disease from prion-tainted beef products. (13)
The restricted geographic and temporal
distribution of cases of new variant Creutzfeldt-Jakob disease raises the
possibility that BSE prions have been transmitted to humans. Although over 100
cases of new variant Creutzfeldt-Jakob disease have been recorded, (44,45)
no dietary habits distinguish patients with this disease from apparently
healthy persons. Moreover, it is unclear why teenagers and young adults seem to
be particularly susceptible to the disease. These cases may mark the start of
an epidemic of prion disease in Great Britain like those of BSE and kuru, or
the number of cases of new variant Creutzfeldt-Jakob disease may remain small,
as with iatrogenic Creutzfeldt-Jakob disease caused by cadaveric human growth
hormone. (46)
The most compelling evidence that new
variant Creutzfeldt-Jakob disease is caused by BSE prions comes from studies of
mice expressing the bovine PrP transgene. (47)
The incubation times, neuropathological features, and patterns of PrPSc
deposition in these transgenic mice are the same whether the inoculate
originated from the brains of cattle with BSE or from humans with new variant
Creutzfeldt-Jakob disease. (47)
The origin of BSE is still obscure, although epidemiologic studies indicate
that BSE probably arose from a single point source in the southwest of England
in the 1970s. (48)
It probably originated from a rare case of prion disease in either sheep (Scott
M, Prusiner SB: unpublished data) or cattle. (48)
Once established, the disease was spread in cattle by ingestion of
prion-contaminated meat and bone meal.
The accidental transmission of
Creutzfeldt-Jakob disease to humans appears to have occurred with corneal
transplantation (49)
and use of contaminated electroencephalographic electrodes. (50)
The same improperly decontaminated electrodes that had caused Creutzfeldt-Jakob
disease in two young patients with intractable epilepsy were found to cause
Creutzfeldt-Jakob disease in a chimpanzee 18 months after their implantation in
the animal. (51)
More than 70 cases of Creutzfeldt-Jakob disease associated with the
implantation of dura mater grafts have been recorded. (52)
One case occurred after the repair of a perforated eardrum with a pericardial
graft. (53)
Prion-contaminated human growth hormone preparations derived from human
pituitary tissue have caused fatal cerebellar disorders with dementia in more
than 120 patients ranging in age from 10 to 41 years. (13,54,55)
Four cases of Creutzfeldt-Jakob disease have occurred in women who received
human pituitary gonadotropin. (56)
Polymorphisms influence the susceptibility
to sporadic, inherited, and infectious forms of prion disease. Dominant
negative alleles in approximately 12 percent of the Japanese population (57)
encode for lysine at position 219 and interfere with the conversion of
wild-type PrPC into PrPSc. (58,59)
Dominant negative inhibition of prion replication has also been found in sheep,
with a substitution of the basic residue arginine at position 171. (60,61)
Like cases of the prion diseases, most
cases of Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, and frontotemporal dementia are sporadic; 10 percent or less are
inherited. Although age is the most important risk factor in all these sporadic
forms of disease, the factors that initiate neurodegeneration remain unknown.
In the prion diseases, the initial formation of PrPSc leads to an
exponential increase in the protein, which can be readily transmitted to
another host. In the other neurodegenerative diseases, the events that lead to
the production of aberrantly processed proteins, as well as the driving forces
that sustain their accumulation, are unknown. It is important to stress that in
contrast to the prion diseases, Alzheimer's disease, Parkinson's disease,
amyotrophic lateral sclerosis, and frontotemporal dementia are not infectious
and have not been transmitted to laboratory animals.
Alzheimer's Disease
A(beta)-amyloid plaques and
neurofibrillary tangles are found in both sporadic and inherited forms of
Alzheimer's disease (Table
3). Like familial prion diseases, familial Alzheimer's disease has an
autosomal dominant pattern of inheritance. Familial Alzheimer's disease can be
caused by a mutation in the gene for amyloid precursor protein (APP),
presenilin 1, or presenilin 2 (Table
4). (62)
Cleavage of amyloid precursor protein at residue 671 by (beta)-secretase and at
either residue 711 or residue 713 by (gamma)-secretase produces A(beta)(1-40)
and A(beta)(1-42), respectively. A(beta)(1-42) forms amyloid fibrils readily
and is thought to cause central nervous system dysfunction before it is
deposited in plaques. (63,64,65)
Presenilin 1 and presenilin 2 may form complexes with at least one other
protein, nicastrin, a transmembrane neuronal glycoprotein, and these complexes
may contribute to the production of A(beta)(1-42). (66)
The age of onset of both sporadic and
familial forms of Alzheimer's disease is modulated by allelic variants of
apolipoprotein E. (67)
Three alternative allelic products of apolipoprotein E, denoted (epsilon)2,
(epsilon)3, and (epsilon)4, differ at amino acid residues 112 and 158. In many
persons with two (epsilon)4 alleles, Alzheimer's disease develops at least a
decade before it does in those with two copies of (epsilon)2, and (epsilon)3 is
associated with an onset of disease at an intermediate age. (68)
Frontotemporal Dementia
and Pick's Disease
Mutations in the tau gene, which codes for
tau, a protein associated with microtubules, cause inherited forms of frontotemporal
dementia and Pick's disease. (69,70,71)
As with Alzheimer's disease, about 90 percent of cases of frontotemporal
dementia are sporadic, and the rest are familial. Straight filaments composed
of hyperphosphorylated mutant tau have been found in the brains of patients
with familial frontotemporal dementia (Table
3). (72)
In some cases, neurofibrillary tangles composed of paired helical filaments
have been found; the formation of these filaments seems to depend on the
specific mutation and on the specific isoform of the protein (Table
4). (73)
In sporadic cases of frontotemporal dementia, aggregates of tau are uncommon.
Approximately 15 percent of patients with frontotemporal dementia have Pick
bodies, (74)
which are intracellular collections of partially degraded (ubiquinated) tau
fibrils in the brain. (75)
As with frontotemporal dementia, most cases of Pick's disease are sporadic.
Other disorders caused by the misprocessing of tau include progressive
supranuclear palsy, progressive subcortical gliosis, and corticobasal
degeneration. (73,75,76,77)
Parkinson's Disease
Most cases of Parkinson's disease are
sporadic, (78,79)
but both sporadic and familial forms of the disease are characterized by
protein deposits in the central nervous system. Mutations in the gene for
(alpha)-synuclein have been found in patients with familial Parkinson's
disease. (80)
In both sporadic and familial cases, antibodies to (alpha)-synuclein, a
presynaptic intracellular protein, stain Lewy bodies in neurons of the
substantia nigra. (81)
Whereas the inheritance of Parkinson's disease due to mutations in the
(alpha)-synuclein gene is autosomal dominant, a childhood form of the disease
due to mutations in the gene for ubiquitin-protein ligase (parkin) is a
recessive disorder (Table
4). (82)
Parkin seems to promote the degradation of certain neuronal proteins, and
selective nitration of (alpha)-synuclein has been observed in Lewy bodies. (83)
Parkinson's disease in older persons is
associated with a high incidence of dementia. (84)
At autopsy, the brains of such patients often have the neuropathological
hallmarks of both Alzheimer's disease and Parkinson's disease.
Immunohistochemical studies showing the presence of (alpha)-synuclein in
cortical Lewy bodies have helped resolve the conundrum of how a patient could
have insufficient numbers of plaques and neurofibrillary tangles for the
diagnosis of Alzheimer's disease but still have dementia. The presence of these
(alpha)-synuclein deposits, alone or in combination with changes that are
characteristic of Alzheimer's disease, may be the second most common form of
neurodegeneration, accounting for 20 to 30 percent of cases of dementia among
persons over the age of 60 years. (85,86)
A small number of younger persons with Parkinson's disease also have dementia
due to diffuse Lewy body disease. (87)
Amyotrophic Lateral
Sclerosis
Although most cases of amyotrophic lateral
sclerosis are sporadic, familial cases have been identified. (88,89,90)
In approximately 20 percent of familial cases of amyotrophic lateral sclerosis,
there are mutations in the gene for cytoplasmic superoxide dismutase type 1
(SOD1) (Table
4). (91)
Moreover, deposits of SOD1 in the central nervous system have been found in
both sporadic and familial cases of amyotrophic lateral sclerosis. (92)
Although in some cases abnormal collections of neurofilaments have been seen in
degenerating motor neurons, no familial cases have been shown to be due to
mutations in neurofilament genes. (92)
Huntington's Disease and
Spinocerebellar Ataxias
Unlike Alzheimer's disease, frontotemporal
dementia, Parkinson's disease, amyotrophic lateral sclerosis, and the prion
diseases, which in most cases are sporadic, all cases of Huntington's disease
and of spinocerebellar ataxia are caused by expanded polyglutamine repeats (Table
4). (93,94,95)
But these diseases are similar to the inherited forms of Alzheimer's disease,
frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis,
and the prion diseases in that they are usually manifested as neurologic
deficits in adulthood, even though the expression of the mutant gene products
in the central nervous system begins early in life. Childhood forms of
Huntington's disease and spinocerebellar ataxia are known to be due to large
expansions of the causative triplet repeats. (94,96,97)
Transgenic Mouse Models
Although virtually every facet of the
human and animal prion diseases has been reproduced in transgenic mice,
attempts to develop transgenic models for the other neurodegenerative diseases
have proved more difficult. Despite the lack of perfect transgenic models for
Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,
frontotemporal dementias, Huntington's disease, and the spinocerebellar
ataxias, many aspects of these human disorders have been reproduced. Mice
expressing transgenes carrying mutations found in the inherited forms of these
neurodegenerative diseases develop disorders with many of the neuropathological
features that characterize the corresponding human illnesses (Table
3 and Table
4).
There is an urgent need for a rapid,
antemortem test for prions in humans and livestock. A highly sensitive
quantitative immunoassay has been developed on the basis of antigens that are
exposed in PrPC but buried in PrPSc. Unlike earlier
immunoassays for PrPSc, this conformation-dependent immunoassay does
not require limited proteolysis to hydrolyze PrPC before the
protease-resistant core of PrPSc (PrP 27-30) is measured. (38)
This assay has been used to identify a new form of PrPSc, which is
protease-sensitive (sPrPSc).
A diagnostic test would be valuable for
distinguishing between early Alzheimer's disease and depression in older
persons, since both disorders are so common. In Alzheimer's disease,
frontotemporal dementia, Parkinson's disease, and the prion diseases, computed
tomography or magnetic resonance imaging may show normal findings or cortical
atrophy. In patients with Alzheimer's disease, widespread atrophy with enlarged
ventricles is often seen, especially late in the disease, but this finding is
not diagnostic. Many elderly persons with normal cognition have similar
radiographic findings. (98,99)
Although many patients with Creutzfeldt-Jakob disease have elevated levels of
protein 14-3-3 in cerebrospinal fluid, this finding is not specific for the
diagnosis. (100,101)
Attempts to measure A(beta)(1-40) in blood and urine as diagnostic tests have
been unrewarding, (102)
but the use of fluorescence correlation spectroscopy to measure A(beta)(1-40)
in cerebrospinal fluid may provide a reliable diagnostic test for Alzheimer's
disease. (103)
Whereas electroencephalographic studies
are not useful for the diagnosis of Alzheimer's disease, frontotemporal
dementia, or Parkinson's disease, they are often useful for the diagnosis of
Creutzfeldt-Jakob disease. Repetitive, high-voltage, triphasic and polyphasic
sharp discharges are seen in most advanced cases of Creutzfeldt-Jakob disease,
but their presence is often transient. (25,101,104,105)
As the disease progresses, normal background rhythms become fragmentary and
slower.
Hashimoto's thyroiditis should always be
considered in the differential diagnosis of Creutzfeldt-Jakob disease, (106)
since the former disorder is a treatable autoimmune disease whereas
Creutzfeldt-Jakob disease is not. The clinical and neuropathological findings
in these two disorders can be quite similar, raising the possibility that
protein misprocessing underlies both degenerative and autoimmune diseases.
With the exception of levodopa, which
ameliorates the symptoms of Parkinson's disease but does not halt the
underlying degeneration, there are no effective therapies for neurodegenerative
diseases. The history of successful attempts to prevent or reverse protein
misprocessing is extremely limited. (107)
Developing new drugs directed to specific regions of the central nervous system
will be challenging.
Preventing Abnormal
Processing of Proteins and Enhancing Their Clearance
Structure-based drug design based on
dominant negative inhibition of prion formation has resulted in the development
of several compounds. (108)
However, the task of exchanging polypeptide scaffolds for small heterocyclic
structures without the loss of biologic activity remains difficult. Whether
this approach to preventing the aberrant processing of proteins will lead to
the development of new treatments for Alzheimer's and Parkinson's diseases, as
well as other neurodegenerative disorders, remains to be established.
Several compounds can eliminate prions
from cultured cells. A class of compounds known as "dendrimers" seems
particularly effective in this regard. (109)
Some drugs delay the onset of disease in animals that have been inoculated with
prions if the drugs are given around the time of the inoculation. (110)
A novel approach to treating Alzheimer's disease has been developed in
transgenic mice that overexpress a mutant APP gene. Immunization of these mice
with the A(beta) peptide or injection of antibodies to A(beta) reduces plaque
formation. (111)
Whether this approach will prove fruitful in patients is unknown.
Replacement Therapy
Because the neurodegeneration in Parkinson's
disease is confined largely to the substantia nigra, especially early in the
disease process, replacement therapy with levodopa has proved useful; in many
patients, however, the disease eventually becomes refractory to levodopa. (112)
Similar approaches to the treatment of Alzheimer's disease have been
disappointing, primarily because the disease process is so widespread.
Similarly, the widespread neuropathological changes in amyotrophic lateral
sclerosis, frontotemporal dementia, and prion diseases make it unlikely that
replacement therapy will be successful.
It is tempting to speculate that abnormal
processing of neuronal proteins also occurs in other diseases of the central
nervous system, such as schizophrenia, bipolar disorders, autism, and
narcolepsy. (113)
Most cases of these diseases are sporadic, but a substantial minority appear to
be familial. The absence of neuropathological changes in these conditions has
impeded phenotypic analysis. In a group of patients with inherited
frontotemporal dementia who have a mutation in the tau gene, alcoholism and
Parkinson's disease are prominent features. (114)
Whether multiple sclerosis is also the
result of defective processing of brain proteins is unknown. (115)
The immune system features prominently in the pathogenesis of multiple
sclerosis, and it is often argued that this disease is a T-cell-mediated,
autoimmune disorder. Antibody-mediated demyelination has been found in some
cases of multiple sclerosis, (116)
and in others, degeneration of oligodendrocytes has been observed, with little
or no evidence of immune-mediated damage. (117)
Perhaps ulcerative colitis, Crohn's disease, rheumatoid arthritis, type 1
diabetes mellitus, and systemic lupus erythematosus ought to be considered
disorders of protein processing in which misfolded proteins evoke an autoimmune
response.
The systemic amyloidoses share important
features with the neurodegenerative diseases. In primary amyloidosis,
immunoglobulin light chains form amyloid deposits that can cause
cardiomyopathy, renal failure, and polyneuropathy. (118)
In response to chronic inflammatory diseases, the serum amyloid A protein is
cleaved and forms the amyloid A protein, which is deposited as fibrils in the
kidney, liver, and spleen. The most common form of systemic hereditary
amyloidosis is caused by the deposition of mutant transthyretin. Also
noteworthy are amylin deposits in the (beta)-islet cells of patients with type
2 diabetes mellitus. These deposits contain amyloid fibrils that are composed
of the amylin protein.
As life expectancy continues to increase,
the burden of degenerative diseases is growing. Developing effective means of
preventing these disorders and of treating them when they do occur is a
paramount challenge. The problems caused by Alzheimer's disease and Parkinson's
disease are already so great that if the prevalence of these maladies continues
to increase in accordance with the changing demographic characteristics of the
world population, they will bankrupt both developed and developing countries
over the next 50 years. It is remarkable to think that by the year 2025, more
than 65 percent of persons over the age of 65 years will be living in countries
that are now designated as developing countries. (119)
Unless effective methods of prevention and treatment are developed, this
enormous population of people will be subjected to the same risks of
Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders
as are older persons currently living in the most affluent countries.
Over the past two decades, remarkable
progress has been made in elucidating the causes of neurodegenerative diseases,
and the time has come to intensify the search for drug targets and for
compounds that interrupt the disease processes. Drugs that block the mishandling
of a particular protein may be most effective for certain disorders; for
others, drugs that enhance the clearance of an aberrant protein or fragment may
prove most useful. Regardless of the therapeutic approach, accurate, early
detection of neurodegeneration will be extremely important so that drugs can be
given before substantial damage to the central nervous system has occurred.
However, the enormity of these tasks -- developing useful diagnostic tests and
discovering effective therapies -- should not be underestimated.
Supported by grants from the National
Institutes of Health (NS14069, AG02132, and AG10770), the American Health
Assistance Foundation, and the Leila and Harold Mathers Foundation.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.