Beta amyloids. Why don't we all get Alzheimer's disease: a new hypothesis about the trigger of the disease Substances that dissolve amyloid plaques
Human antibodies against a pathogenic protein that causes Alzheimer's disease destroy dangerous protein deposits in the brains of patients.
Alzheimer's disease, like other neurodegenerative diseases, begins due to the fact that too many protein molecules appear in the nerve cells of the brain in an incorrect spatial conformation, which, due to their irregularity, stick together and form insoluble complexes that harm the neuron and, ultimately, leading him to death. Not every protein turns out to be pathogenic; in the case of Alzheimer's disease, this is beta-amyloid and tau protein, and one of the characteristic signs of the disease is the so-called amyloid plaques, accumulations of beta-amyloid peptides that appear in the patient's brain. It is not yet entirely clear how exactly such proteins harm neurons, but there is no doubt that they do harm.
Brain tissue with Alzheimer's plaques. (UCSF/Corbis photo)
Alzheimer's plaques in the mouse brain. (Photo by Enrique T/Flickr.com)
It is obvious that drugs against neurodegenerative diseases must, on the one hand, suppress the appearance of pathogenic proteins and their interaction with each other, and on the other, destroy already formed deposits, that is, those same notorious plaques. Many here rely on immunotherapy: antibodies that specifically bind to beta-amyloid molecules could prevent them from sticking together and provoke the destruction of already formed amyloid deposits. However, for the time being, there were no special breakthroughs here: immunotherapeutic methods gave, at best, only a very moderate effect. But with antibodies obtained by employees of the biotechnology company Biogen, Inc. , things are completely different.
As you know, antibodies are synthesized by B lymphocytes. Jeff Sevigny ( Jeff Sevigny) and his colleagues found among human B lymphocytes those that produce immunoglobulins against beta-amyloid peptide - a drug of such antibodies was called aducanumab. Experiments with transgenic mice, in which deposits of human amyloid formed in the brain, showed that antibodies injected into the blood penetrate into the brain of animals, bind to filamentous amyloid accumulations, transforming them into a soluble state, and activate microglial cells, which represent the brain branch of the immune system. systems. (Ordinary immune cells roaming our bodies cannot penetrate the brain.) Activated microglia begin to literally absorb amyloid, which has been made soluble by the drug aducanumab.
But these are animals, and transgenic ones at that, but what about people? To participate in the clinical trial, 165 patients aged 50 to 90 years were invited who either had a mild form of Alzheimer's syndrome or were in the so-called prodromal period, when some symptoms already indicate the disease, but it has not yet manifested itself clinically. Some of the experiment participants received a placebo, while the other four groups used an antibody drug in different concentrations. Immunoglobulins were administered once a month, and there were fourteen such injections. Along the way, forty patients dropped out of the study for various reasons, leaving between 21 and 32 people in each of the five groups. The condition of the brain was assessed using positron emission tomography and a special radioactively labeled substance that settled in amyloid deposits and thereby made them visible to the tomograph.
In general, as the authors of the work write in Nature, Alzheimer's plaques in people were noticeably reduced, and this reduction was even called “unprecedented” - compared to other attempts of this kind. The disappearance of amyloid deposits occurred more rapidly the higher the dose of the experimental drug. Some cognitive tests showed that those patients who received the antibody drug did not decline as quickly in their mental abilities as those who received a placebo, and that again it depended on the dose of the drug. At the same time, it is worth noting that other tests did not reveal any cognitive differences. On the other hand, some experts, in particular Ronald Petersen ( Ronald Petersen) from the Mayo Clinic say it's not worth putting too much emphasis on cognitive assessments just yet—more subjects and more research time are needed for them to become reliable.
Now the next stage of clinical trials is underway, in which more people are participating. The researchers hope that they will be able to not only confirm the initial results, but also understand what to do about a side effect that was especially noticeable in some patients receiving the highest dose of the drug - scans showed that they had small swelling and microscopic swelling in some parts of the brain. hemorrhages leading to headaches. One explanation is that amyloid deposits sometimes form close to blood vessels, and when these deposits begin to be pulled away by antibodies, the vessels react somewhat painfully to their work. But, we repeat, we would like to hope that in further clinical experiments the side effects will be overcome.
Amyloidosis (amyloid dystrophy, Latin amyloidosis, Greek amylon starch + eidos species + ōsis) is a group of diseases that are distinguished by a wide variety of clinical manifestations and are characterized by extracellular (in the extracellular matrix) deposition (systemic or local) of insoluble pathological fibrillar proteins (protein- polysaccharide complex - amyloid) in organs and tissues that are formed as a result of complex metabolic changes (protein dystrophies). The main target organs are the heart, kidneys, nervous system [central and peripheral], and liver, however, in systemic forms, almost all tissues can be affected (rare localizations include adrenal amyloidosis). They were called amyloids because, in reaction with iodine, they resembled starch. Amyloid persists in the body for a long time and even after death does not rot for a long time (I.V. Davydovsky, 1967). Amyloidosis can occur independently or “secondarily” as a result of another disease.
Currently, amyloidosis is considered as a group of diseases that are characterized by the deposition in tissues and organs of amyloid fibrillar protein (AFA) - a special protein structure with a diameter of 5 - 10 nm and a length of up to 800 nm, consisting of 2 or more parallel multidirectional (antiparallel) filaments that form cross-β-sheet conformation(see picture on the left). It is this that determines the specific optical property of amyloid - the ability to undergo birefringence (detected by Congo red staining [= method for determining amyloid in tissues]). According to modern data, the prevalence of amyloidosis in the population ranges from 0.1 to 6.6%.
The protein name amyloid was proposed by Rudolf Virchow, who borrowed it from botany, where the word meant cellulose or starch. In its structure, amyloid is a complex glycoprotein in which fibrillar and globular proteins are found in a structure with polysaccharides (galactose, glucose, glucosamine, galactosamines, mannose and fructose). Amyloid contains proteins similar in their characteristics to α1-, β- and γ-globulins, albumin, fibrinogen, and it contains neuraminic acid. The bonds between proteins and polysaccharides are very strong, which maintains its stability. The structure of amyloid also contains a P component, which makes up up to 15% of the total amyloid and is identical to the serum protein SAP (serum amyloid P). SAP is a protein produced by liver cells, classified as acute phase (SAP is a constant component of amyloid deposits in all forms of amyloidosis).
Amyloidosis is polyetiological. Of primary importance is the amyloidogenicity of the major amyloid precursor protein (BPA), which is specific for each form of amyloidosis. Amyloidogenicity is determined by changes in the primary structure of APA, fixed in the genetic code or acquired during life due to mutations. To realize the amyloidogenic potential of BPA, exposure to a number of factors is necessary, such as inflammation, age, and physicochemical conditions in situ.
TABLE: Classification of amyloidosis (in all names of types of amyloidosis, the first letter is the capital letter “A”, meaning the word “amyloid”, followed by the designation of the specific APA - A [amyloid A protein; formed from the serum precursor protein SAA - acute phase protein, in normally synthesized by hepatocytes, neutrophils and fibroblasts in trace amounts], L [immunoglobulin light chains], TTR [transthyretin], 2M [β2-micro-globulin], B [B-protein], IAPP [islet amyloid polypeptide], etc. .).
Please note! The structural and chemical-physical characteristics of amyloid are determined by the main BPA, the content of which in the fibril reaches 80% and is a specific feature for each type of amyloidosis. Each protein (AP) has significantly different mechanisms of synthesis, utilization, and biological functions, which determines differences in clinical manifestations and approaches to the treatment of amyloidosis. For this reason, different forms of amyloidosis are considered different diseases (see table).
Despite the progress achieved in the study of various types of amyloid, the final stage of amyloidogenesis—the formation of amyloid fibrils in the intercellular matrix of BPA—remains largely unclear. Apparently, this is a multifactorial process that has its own special features in different forms of amyloidosis. Let us consider the process of amyloidogenesis using the example of AA amyloidosis. It is believed that in the formation of AA from SAA, the process of incomplete cleavage of SAA by proteases associated with the surface membrane of monocyte-macrophages and the polymerization of soluble AA protein into fibrils, which is believed to also occur with the participation of membrane enzymes, are important. The intensity of AA amyloid formation in tissues depends on the concentration of SAA in the blood. The amount of SAA synthesized by cells of different types (hepatocytes, neutrophils, fibroblasts) increases many times during inflammatory processes and tumors (increased SAA levels in the blood play a major role in the pathogenesis of AA amyloidosis). However, for the development of amyloidosis, only a high concentration of SAA is not enough; the presence of amyloidogenicity in the BPA (i.e., SAA) is also necessary. The development of amyloidosis in humans is associated with SAA1 deposition. Currently, 5 isotypes of SAA1 are known, of which the greatest amyloidogenicity is attributed to isotypes 1.1 and 1.5. The final stage of amyloidogenesis - the formation of amyloid fibrils from BPA - occurs during incomplete cleavage of monocyte-macrophages by proteases. Stabilization of the amyloid fibril and a sharp decrease in the solubility of this macromolecular complex are largely due to interaction with interstitial polysaccharides.
Despite the differences in the types of amyloid protein, there is a common pathogenesis of various clinical forms of amyloidosis. The main reason for the development of the disease is the presence of a certain, often increased amount of amyloidogenic APA. The appearance or enhancement of amyloidogenicity may be due to the circulation of protein variants with increased overall hydrophobicity of the molecule, an imbalance in the ratio of surface molecular charges, which leads to instability of the protein molecule and promotes its aggregation into an amyloid fibril. At the last stage of amyloidogenesis, amyloid protein interacts with blood plasma proteins and tissue glycosaminoglycans. In addition to structural features, the physicochemical properties of the intercellular matrix, where the amyloid fibril is assembled, are also important. Many forms of amyloidosis can also be combined based on their occurrence in old and senile age (AL, ATTR, AIAPP, AApoA1, AFib, ALys, AANF, A-beta), which indicates the presence of mechanisms of age-related evolution of the structure of certain proteins towards increasing amyloidogenicity and allows consider amyloidosis as one of the models of aging of the body.
Neurological aspects of amyloidosis :
ATTR amyloidosis. ATTR amyloidosis includes familial amyloid polyneuropathy, which is inherited in an autosomal dominant manner, and systemic senile amyloidosis. The precursor protein in this form of amyloidosis is transthyretin, a component of the prealbumin molecule, synthesized by the liver and performing the functions of the thyroxine transport protein. It has been established that hereditary ATTR amyloidosis is the result of a mutation in the gene encoding transthyretin, which leads to the replacement of amino acids in the TTR molecule. There are several types of hereditary amyloid neuropathy: Portuguese, Swedish, Japanese and several others. In the most common familial variant (Portuguese), in the 30th position from the N-terminus of the transthyretin molecule, methionine is replaced with valine, which increases the amyloidogenicity of the precursor protein and facilitates its polymerization into amyloid fibrils. Several variant transthyretins are known, which accounts for the variety of clinical forms of hereditary neuropathy. Clinically, this disease is characterized by progressive peripheral and autonomic neuropathy, which is combined with damage to the heart, kidneys and other organs of varying degrees. Systemic senile amyloidosis develops after age 70 as a result of age-related conformational changes in normal transthyretin, apparently increasing its amyloidogenicity. The target organs of senile amyloidosis are the heart, cerebral vessels and aorta.
read also the post: Transthyretin amyloid polyneuropathy(to the site)
read also the article “Damage to the peripheral nervous system in systemic amyloidosis” Safiulina E.I., Zinovieva O.E., Rameev V.V., Kozlovskaya-Lysenko L.V.; Federal State Autonomous Educational Institution of Higher Education “First Moscow State Medical University named after. THEM. Sechenov" Ministry of Health of the Russian Federation, Moscow (magazine "Neurology, neuropsychiatry, psychosomatics" No. 3, 2018) [read]
Alzheimer's disease(AD) is a genetically determined progressive neurodegenerative disease, which is based on the death of neurons in the cerebral hemispheres; clinical manifestations of the disease are a decrease in memory and other cognitive functions (intelligence, praxis, gnosis, speech). At the moment, 4 main genes have been identified that are responsible for the development of this disease: the gene encoding the amyloid precursor protein (APP, chromosome 21), genes encoding enzymes [alpha-, beta-, gamma-secretases] that metabolize APP: presenilin-1 (chromosome 14), presenilin-2 (chromosome 1). A special role is played by hetero- or homozygous carriage of the fourth isoform of apolipoprotein E (APOE 4).
Normally, the amyloid precursor protein (APP) is cleaved by alpha-secretase into soluble (equal in size) polypeptides that are not pathogenic, and (APP) is excreted from the body; in the case of pathology of the genes responsible for the metabolism of APP, the latter is cleaved by beta and gamma secretases into fragments of different lengths. In this case, the formation of insoluble long fragments of amyloid protein (alpha-beta-42) occurs, which are subsequently deposited in the substance (parenchyma) of the brain and the walls of cerebral vessels (stage of diffuse cerebral amyloidosis), which leads to the death of nerve cells. Next, in the brain parenchyma, aggregation of insoluble fragments occurs into a pathological protein - amyloid beta ("nest" deposits of this protein in the brain parenchyma are called senile plaques). Deposition of amyloid protein in cerebral vessels leads to the development of cerebral amyloid angiopathy, which is one of the causes of chronic cerebral ischemia.
read the article: Cerebral amyloid angiopathy(to the site)
Beta-amyloid and insoluble fractions of diffuse amyloid protein have neurotoxic properties. The experiment showed that against the background of cerebral amyloidosis, tissue inflammatory mediators are activated, the release of stimulating mediators (glutamate, aspartate, etc.) increases, and the formation of free radicals increases. The result of this entire complex cascade of events is damage to neuronal membranes, which is indicated by the formation of neurofibrillary tangles (NFTs) within the cells. NSF are fragments of a biochemically altered inner membrane of a neuron and contain hyperphosphorylated tau protein. Normally, tau protein is one of the main proteins in the inner membrane of neurons. The presence of intracellular NSFs indicates irreversible damage to the cell and its rapid death, after which NSFs exit into the intercellular space (“NPS-ghosts”). The neurons surrounding the senile plaques are the first and most affected.
It takes 10-15 years from the onset of amyloid protein deposition in the brain to the development of the first symptoms of the disease - mild forgetfulness. To a large extent, the rate of progression of asthma is determined by the severity of concomitant somatic pathology, vascular risk factors, as well as the intellectual development of the patient. In patients with a high level of education and sufficient intellectual activity, the disease progresses more slowly than in patients with secondary or primary education and insufficient intellectual activity. In this regard, the theory of cognitive reserve was developed, according to which, during intellectual activity, the human brain forms new interneuronal synapses and increasingly larger populations of neurons are involved in the cognitive process. This makes it easier to compensate for the cognitive defect even with progressive neurodegeneration.
Diagnosis of amyloidosis. Amyloidosis suspected on the basis of clinical and laboratory data must be confirmed morphologically by the detection of amyloid in tissue biopsies. If AL-type amyloidosis is suspected, a bone marrow puncture is recommended. Most often, to diagnose different types of amyloidosis, a biopsy of the mucous membrane of the rectum, kidney, and liver is performed. A biopsy of the mucous and submucosal layers of the rectum can detect amyloid in 70% of patients, and a kidney biopsy - in almost 100% of cases. In patients with carpal tunnel syndrome, tissue removed during carpal tunnel decompression surgery should be tested for amyloid. To detect amyloid, biopsy material must be stained with Congo red, followed by polarized light microscopy to detect birefringence.
Modern morphological diagnosis of amyloidosis includes not only detection, but also typing of amyloid, since the type of amyloid determines therapeutic tactics. For typing, a test with potassium permanganate is often used. When Congo red-stained preparations are treated with a 5% solution of potassium permanganate, the AA-type amyloid loses its color and loses its birefringence properties, while the AL-type amyloid retains them. The use of alkaline guanidine makes it possible to more accurately differentiate between AA and AL amyloidosis. The most effective method for amyloid typing is immunohistochemical research using antisera to the main types of amyloid protein (specific antibodies against AA protein, immunoglobulin light chains, transthyretin and beta-2-microglobulin).
Please note! Amyloidosis is a multisystem disease; damage to only one organ is rarely observed. If the history suggests a combination of symptoms such as general weakness, emaciation, easy bruising, early onset of dyspnea, peripheral edema, sensory changes (carpal tunnel syndrome), or orthostatic hypotension, amyloidosis should be suspected. Hereditary amyloidosis is characterized by a burdened family history of “neuromuscular” lesions of unknown etiology or dementia, Aβ2M amyloidosis is characterized by the use of hemodialysis, and AA amyloidosis is characterized by the presence of a chronic inflammatory process. Also, amyloidosis must be excluded in patients with kidney diseases of unknown origin, especially with nephrotic syndrome, incl. in patients with restrictive cardiomyopathy. Amyloidosis is more likely in the presence of both of these syndromes. In AA amyloidosis, the dominant target organ, in addition to the kidneys, is the liver, therefore, in the differential diagnosis of the causes of severe hepatomegaly in combination with kidney damage, amyloidosis should be excluded.
Further reading:
article “Difficulties in diagnosing and treating AL amyloidosis: review of the literature and own observations” by V.V. Ryzhko, A.A. Klodzinsky, E.Yu. Varlamova, O.M. Sorkina, M.S. Sataeva, I.I. Kalinina, M.Zh. Aleksanyan; Hematological Research Center of the Russian Academy of Medical Sciences, Moscow (journal “Clinical Oncohematology” No. 1, 2009) [
The results of a study by scientists from the Northwestern University Feinberg School of Medicine, USA, showed that beta-amyloid, a pathological protein, the accumulation of which is the main sign of the development of Alzheimer's disease, begins to be deposited inside human neurons from the age of 20 . The results of the study were published in the journal Brain.
According to lead researcher Changiz Geula, a postdoctoral fellow at Northwestern Feinberg University's Cognitive Neurology and Alzheimer's Disease Center, there is unprecedented evidence that amyloid is beginning to accumulate in the brain. in the human brain from a young age. According to Geul, this is of great importance, since it is known that if amyloid is in the human body for a long time, it negatively affects his health.
American scientists studied cholinergic neurons in the basal forebrain, trying to explain the cause of their early damage and why these cells are among the first to die during natural aging and Alzheimer's disease. These sensory neurons are essential for maintaining memory and attention.
Geula and his colleagues examined neurons obtained from the brains of three different groups of patients - 13 cognitively healthy people aged 20-66 years, 16 elderly people aged 70-99 years without dementia, 21 patients with Alzheimer's disease aged 60-95 years .
The results of the study showed that amyloid molecules begin to be deposited inside these neurons at a young age, and this process continues throughout a person's life. Similar amyloid deposition was not observed in nerve cells in other areas of the brain. In the cells studied, amyloid molecules formed tiny toxic plaques, amyloid oligomers, which can be detected even in young people as young as 20 years old. The size of amyloid plaques increased in older people and patients with Alzheimer's disease.
According to Geul, the findings provide insight into the early death of basal forebrain neurons, which may be due to small amyloid plaques. In his opinion, the accumulation of amyloid in these neurons during human life likely makes these cells susceptible to the pathological processes of aging and to the loss of neurons in Alzheimer's disease.
With a high degree of probability, growing plaques can damage and even cause the death of neurons - they can provoke an excessive flow of calcium into the cell, which can lead to its death. The plaques can become so large that the cell's degradation machinery can't dissolve them and they clog up the neuron, Geul says.
Additionally, plaques can cause damage by secreting amyloid outside the cell, leading to the formation of large amyloid plaques found in Alzheimer's disease.
Original article:
Alaina Baker-Nigh, Shahrooz Vahedi, Elena Goetz Davis, Sandra Weintraub, Eileen H. Bigio, William L. Klein, Changiz Geula. Neuronal amyloid-β accumulation within cholinergic basal forebrain in aging and Alzheimer’s disease. Brain, March 2015 DOI:
Amyloidosis- a group of diseases (forms), the common feature of which is the deposition of a special protein of b-fibrillar structure in organs and tissues.
Amyloid in tissues appears either around collagen fibers (pericollagenous amyloidosis) or on basement membranes or around reticular fibers (perireticular amyloidosis).
Epidemiology. The frequency in the population is at least 1:50,000. Some clinical forms of amyloidosis are noted in certain areas of the world: for example, familial Mediterranean fever or familial amyloid polyneuropathy (the latter is common in Japan, Portugal, Sweden, Italy).
Amyloidosis is more often detected in the second half of life.
Classification Committee of Nomenclature of the International Union of Immunological Societies (WHO Bulletin, 1993).
- AL-amyloidosis (A - amyloidosis, amyloidosis, L - light chains, light chains) - primary, associated with multiple myeloma (amyloidosis is registered in 10-20% of cases of multiple myeloma).
- AA amyloidosis (acquired amyloidosis, acquired amyloidosis) - secondary amyloidosis against the background of chronic inflammatory diseases, as well as familial Mediterranean fever (periodic disease).
- ATTR amyloidosis (A - amyloidosis, amyloidosis, TTR - transthyretin, transthyretin) - hereditary familial amyloidosis (familial amyloid polyneuropathy) and senile systemic amyloidosis.
- Аb2М-amyloidosis (A-amyloidosis, amyloidosis, b2М - b2-microglobulin) - amyloidosis in patients undergoing planned hemodialysis.
Localized amyloidosis often develops in older people (AIAPP amyloidosis - in non-insulin-dependent diabetes mellitus, AV amyloidosis - in Alzheimer's disease, AANF amyloidosis - senile atrial amyloidosis).
Pathogenesis and pathomorphology. Modern ideas about amyloidogenesis suggest the production of a special amyloid precursor protein under the influence of the so-called amyloid-releasing factor produced by macrophages due to a genetic defect under the influence of a stimulating agent. The formation of AA from SAA occurs through incomplete cleavage by proteases associated with the surface membrane of monocyte-macrophages.
Polymerization of soluble AA protein into fibrils also occurs on the surface of macrophages by the mechanism of cross-linking of polypeptides with the participation of membrane enzymes.
An experiment with casein amyloidosis in mice demonstrated the important role of the so-called amyloid-accelerating factor, which is formed during inflammation in the spleen and liver, in the induction of AA deposits. ATTR amyloidosis includes familial amyloid polyneuropathy (less commonly cardiopathy and nephropathy) with an autosomal dominant type of inheritance and systemic senile amyloidosis. The serum precursor protein of amyloidosis in this group is a component of the prealbumin molecule - transthyretin (TTR) - a transport protein for thyroxine and retinol, primarily synthesized in the liver. Hereditary familial amyloidosis is the result of a mutation in the gene responsible for the synthesis of the transthyretin molecule. Mutant transthyretin has a point substitution in the molecule. It is assumed that familial hereditary amyloidosis may be based on mutant forms of other proteins. The basis of amyloid deposits is fibrils.
Purified amyloid derived from fibrils is a protein. In renal amyloidosis, the glomeruli are primarily affected, although amyloid is also found in the interstitial, peritubular and vascular zones. In the early stages, amyloid is deposited in the form of small foci in the mesangium and along the basement membrane.
As the disease progresses, the glomeruli are intensively filled with amyloid masses and their capillary bed is reduced.
Clinical picture.
Very often, amyloidosis is asymptomatic for a long time.
The nature of clinical manifestations depends on the biochemical type of amyloid, the localization of amyloid deposits, the degree of their prevalence in organs, the duration of the disease, and the presence of complications. As a rule, a complex of symptoms associated with damage to several organs is observed. Signs of kidney involvement (renal amyloidosis itself) are typical for AA and AL amyloidosis; they are not observed in familial amyloid polyneuropathy and Alzheimer's disease.
Clinical manifestations of renal amyloidosis vary from mild proteinuria to full-blown NS: massive proteinuria, hypoproteinemia, hyperlylidemia (hypercholesterolemia, lipid balance disorders, increased levels of E-LP and triglycerides), edematous syndrome.
Edema may not occur with adrenal amyloid infiltration and hyponatremia.
Hypertension develops in 20-25% of cases, mainly with long-term AA amyloidosis.
Concomitant tubular dysfunctions include canal acidosis and renal diabetes.
Against the background of renal amyloidosis, renal vein thrombosis may develop.
Cardiac amyloidosis can develop with AL amyloidosis, rarely with AA amyloidosis; it usually presents as restrictive cardiomyopathy. The most common clinical manifestations: cardiomegaly, heart failure, various arrhythmias.
Effusive pericarditis is rare.
Localized atrial amyloidosis is often seen in people over 80 years of age.
Damage to the gastrointestinal tract is explained either by the direct involvement of organs in the amyloid process, or by indirect changes due to amyloid infiltration of regional nerve fibers.
Amyloidosis of the esophagus occurs more often simultaneously with lesions of other parts of the digestive system. Dysphagia when swallowing dense and dry food, especially when eating while lying down, and belching are typical. On X-ray examination, the esophagus is hypotonic, peristalsis is weakened; when examining the patient in a horizontal position, the barium suspension lingers in the esophagus for a long time.
Complications: amyloid ulcers of the esophagus and esophageal bleeding.
Amyloidosis of the stomach is usually combined with amyloidosis of the intestines and other organs. Clinical picture: feeling of heaviness in the epigastric region after eating, dyspeptic disorders; X-ray examination shows smoothness of the folds of the mucous membrane, weakening of peristalsis and evacuation of contents from the stomach.
Complications: amyloid gastric ulcers, gastric bleeding, perforation of ulcers.
Differential diagnosis carried out with chronic gastritis, gastric ulcer, less often - a tumor.
Biopsy data (detection of amyloidosis) are decisive. Intestinal amyloidosis is a common site of this disease. It manifests itself as a feeling of discomfort, heaviness, less often moderate dull or cramping pain in the abdomen, bowel disorders: constipation or persistent diarrhea.
A scatological examination reveals severe steatorrhea, amilorrhea, and creatorrhoea. In the blood there is anemia, leukocytosis, increased ESR, hypoproteinemia (due to hypoalbuminemia), hyperglobulinemia, hyponatremia, hypoprothrombinemia, hypocalcemia.
Special research methods detect violations of parietal digestion and absorption in the intestine.
X-ray examination is characterized by the expansion (“bulging”) of intestinal loops, thickening of the folds and smoothing of the relief of the intestinal mucosa, slowing down or accelerating the passage of barium suspension through the intestines.
A biopsy of the mucous membrane of the small and large intestines confirms the diagnosis and allows for differential diagnosis with enteritis and colitis, especially with ulcerative colitis. Isolated tumor-like intestinal amyloidosis occurs under the guise of a tumor (pain, intestinal obstruction) and is usually detected already on the operating table.
Complication: severe hypoproteinemia due to impaired absorption processes in the intestine, polyhypovitaminosis, intestinal stenosis, amyloid ulcers, intestinal bleeding, perforation.
Liver amyloidosis is relatively common.
The liver is characterized by enlargement and thickening; upon palpation, its edge is smooth and painless. Portal hypertension syndrome and ascites are common. Less common are pain in the right hypochondrium, dyspepsia, splenomegaly, jaundice, and hemorrhagic syndrome.
Laboratory research determine changes in protein-sedimentary samples, hyperglobulinemia, hypercholesterolemia, in some cases - hyperbilirubinemia, increased activity of alkaline phosphatase, serum aminotransferases; positive test with bromsulfalein.
A puncture biopsy of the liver is of decisive importance in diagnosis. Complications: liver failure (in 7% of cases).
Pancreatic amyloidosis is rarely diagnosed (occurs under the guise of chronic pancreatitis); Characterized by dull pain in the left hypochondrium, dyspepsia, pancreatogenic diarrhea, steatorrhea.
Examination of duodenal contents reveals exocrine pancreatic insufficiency.
In severe cases, secondary diabetes mellitus develops.
Skin lesions look like translucent waxy papules or plaques on the face, neck, and in areas of natural folds.
Periorbital ecchymoses (“raccoon eyes”) have been described.
Itching is not typical. Hemorrhages into plaques are possible.
In some cases, dense swelling on the fingers, reminiscent of scleroderma, is observed.
Mental disorders in the form of dementia are noted in localized forms of amyloidosis (Alzheimer's disease).
Hemorrhagic syndrome can develop with AL amyloidosis due to deficiency of coagulation factor X, which has an affinity for amyloid fibrils.
Diagnostics.
Laboratory research.
Urinalysis. Proteinuria ranges from microalbuminemia to massive proteinuria accompanying NS. Hematuria occurs rarely, leukocyturia is not massive and is not associated with concomitant infection (“scanty changes in urinary sediment”). The cylinders are hyaline, waxy, less often granular; they do not have metachromasia when stained, but give a sharply positive CHIC reaction.
Due to massive proteinuria, hypoproteinemia occurs (due to hypoalbuminemia).
Leukocytosis is possible, and an increase in ESR is typical.
Anemia accompanies chronic renal failure or is associated with a chronic inflammatory process. Kidney biopsy in the early stages of amyloidosis reveals amorphous hyaline masses in the mesangium, as well as thickening of the basement membrane.
Subsequently, diffuse extracellular eosinophilic material is found, stained with Congo red with a specific green birefringence when examined under a polarized microscope. In an immunofluorescence study, there is a weak glow of Ig, since amyloid fibrils (in AL amyloidosis) contain variable regions of light chains. EM reveals characteristic non-branching amyloid fibrils with a diameter of 7.5-10 nm. Deposits of amyloid masses are found not only in the glomeruli, but also in the interstitium.
Ultrasound. The size of the kidneys is increased or normal.
Functional tests with Congo red or methylene blue (the rapid disappearance of dyes from the blood serum when administered intravenously due to their fixation by amyloid, as well as a significant decrease in their excretion by the kidneys) are of historical importance due to their low information content. It is necessary to assume the development of amyloidosis when proteinuria is detected in patients at risk (with RA, multiple myeloma, EBD, tuberculosis and leprosy).
In hereditary familial syndromes manifested by peripheral neuropathy, nephropathy, cardiomegaly, amyloidosis should be excluded. Treatment. Objectives: limiting the synthesis of amyloid precursor (colchicine); inhibition of amyloid synthesis and prevention of its deposition in tissues; lysis of tissue amyloid structures.
Treatment underlying disease (chronic inflammation, RA) is necessary.
With active treatment of RA with cytostatics (cyclophosphamide, chlorambucil, azathioprine, methotrexate), amyloidosis occurs less frequently, and with amyloidosis that has already developed, a decrease in the severity of its clinical manifestations is observed - stabilization of renal function and a decrease in proteinuria. Chemotherapy (for example, combination therapy with melphalan and prednisolone) is used to treat primary amyloidosis and multiple myeloma.
However, its lack of effectiveness and high toxicity necessitate the search for new treatment methods.
Among the latest developments in this direction are anthracycline and iododokeorubicin, which bind to AL amyloid and promote its resorption.
Colchicine. In familial Mediterranean fever, the use of colchicine in the early stages delays the development of nephropathy, but it has a worse effect on already formed renal amyloidosis.
The effect of colchicine in secondary renal AA amyloidosis is being studied.
In the early stages of AA amyloidosis, an attempt at treatment with aminoquinoline derivatives (chloroquine 0.25-0.5 g/day for a long time) is permissible, but its effectiveness has not been proven in controlled studies.
For the treatment of amyloidosis, it is suggested to use dimethyl sulfoxide orally.
The initial dose is a 1% solution of dimethyl sulfoxide, 10 ml 3 times a day. If well tolerated, the dose is gradually increased to 100-200 ml of a 3-5% solution per day.
Treatment regimens for primary amyloidosis.
- Cyclic oral administration of melphalan (0.15-0.25 mg/kg body weight per day) and prednisolone (1.5-2.0 mg/kg per day) for four to seven days every four to six weeks for a year, until the course dose of 600 mg is reached.
- Oral use of melphalan at a dose of 4 mg/day for three weeks, then, after a two-week break - 2-4 mg/day four days a week continuously, until a course dose of 600 mg is reached, in combination with prednisone.
- Intravenous administration of high doses of melfolan (100-200 mg/m2 of body surface for two days) followed by transplantation of autologous stem cells.
- Intravenous administration of dexamethasone at a dose of 40 mg for four days every three weeks - eight cycles.
- Intravenous administration of dexamethasone at a dose of 40 mg on days 1-4, 9-12 and 17-20 of a 35-day cycle, three to six cycles, followed by the use of os-interferon at a dose of 3-6 million units three times per week.
- Vincristine-doxoribucin-dexamethasone (VAD) regimen.
The development of chronic renal failure is an indication for routine dialysis.
Peritoneal dialysis is preferable, as it creates conditions for the removal of b2-microglobulin.
The survival rate of patients with renal amyloidosis on hemodialysis is lower than that of patients with other causes of chronic renal failure (one-year survival rate 60%).
Kidney transplantation is performed for AA amyloidosis (subject to successful treatment of the underlying disease) and AL amyloidosis.
However, survival rates are lower than for other renal pathologies, which is associated with serious extrarenal organ damage, mainly cardiovascular.
Recurrence of amyloidosis in the graft occurs frequently but has little impact on the overall prognosis.
By liver transplantation, the site of synthesis of the amyloid precursor, transthyretin, is eliminated.
Splenectomy is performed to relieve hemorrhagic syndrome (removal of the spleen, which binds the largest amount of factor X).
“Miracles” in recent years have been associated with the use of stem cells. Let's dream together. Employees of the Pittsburgh Institute of Malignant Tumors proposed the following technique.
First, Neupogen is administered intravenously for 4 days, stimulating the release of hematopoietic stem cells into the peripheral bloodstream. Then, using special equipment, a fraction of hematopoietic stem cells is isolated from the blood.
After that, the isolated cells are frozen in a cryochamber so that they can be stored for a long time.
After the “cure” is prepared, the patient is given a course of high-dose chemotherapy for one or two days to destroy proteins found in the blood plasma.
After chemotherapy courses, the patient is injected intravenously with his own stem cells, which have been frozen.
Forecast.
The cause of death was heart or kidney failure.
After the development of chronic renal failure, patients usually live less than a year, after the development of heart failure - about 4 months.
Secondary amyloidosis has a better prognosis than AL amyloidosis.
With any type, the disease is more severe in older people.
After age 65, the risk of developing Alzheimer's disease doubles every 5 years. Now, a new study has found that the brain's ability to clear toxic protein fragments associated with disease is significantly reduced in older adults.
After age 65, the risk of developing Alzheimer's disease doubles every 5 years.
In the journal Annals of Neurology, researchers from Washington University in St. Louis, Missouri, described how they found that the brains of older adults take much longer to clear beta-amyloid 42, the main ingredient in the protein plaques that accumulate in the brain when Alzheimer's disease.
Randall J. Bateman, senior author and professor of neuroscience, said: “We found that people in their 30s typically take about 4 hours to clear half of amyloid beta 42 from the brain. In this new study, we show that at age 80, this process takes more than 10 hours."
If it is not cleared, there is a greater chance that beta-amyloid 42—a protein fragment that is a natural byproduct of brain activity—will clot into plaques that impair brain functions such as communication between cells.
Scientists have long suspected that these plaques are a major factor in Alzheimer's disease, a form of dementia.
Dementia is a progressive disease in which memory, thinking and behavior decline until the person can no longer speak or care for themselves. Although this disease primarily affects older people, it is not a normal part of aging.
According to the World Health Organization, approximately 48 million people worldwide suffer from dementia, and this figure is growing by almost 8 million every year. Alzheimer's disease accounts for about two-thirds of these cases.
Lower clearance values of beta-amyloid 42 in people with symptoms of Alzheimer's disease
In their study, Professor Bateman and his colleagues tested 100 volunteers aged between 60 and 87 years. Half of these participants showed clinical signs of Alzheimer's disease, such as memory problems, and 62 participants had plaque formation in the brain.
The researchers determined the presence of these signs and symptoms during detailed mental and physical examinations that the participants underwent. In addition to brain scans to screen for plaque, the scientists tested the participants' cerebrospinal fluid using technology they developed themselves.
Using this technology - called SILK (stable isotope-linked kinetics - stable isotope-linked kinetics) - the researchers were able to observe what happens to beta-amyloid 42 and other proteins.
In participants who had evidence of plaque, the researchers found that beta-amyloid 42 was more likely to leak out of the brain fluid and accumulate in the plaque.
Additionally, lower rates of amyloid beta 42 clearance—such as what the researchers saw in older participants—were associated with symptoms of Alzheimer's disease, including memory loss, personality changes, and dementia.
Professor Bateman says scientists believe the brain has four ways of disposing of beta-amyloid: moving it to the spinal cord, moving across the blood-brain barrier, dissolving or absorbing it with other proteins, and depositing it in plaques. He concludes:
“With additional studies such as this, we hope to determine which of the first three pathways of amyloid beta disposal slows down with brain aging. This could help us in our attempts to develop new treatments."
