The WCC Note

Your Weekly Guide to Harmonizing Clinical Trial Imaging

Knee Osteoarthritis: MRI in the Landscape of Current and Potential Treatment – Vol. 3, Number 10 - December 3rd, 2009 by worldcare

Like trying to mend broken glass in the hope that it will shine clearly again, repairing the destruction of knee osteoarthritis (OA) looms as an arduous and complex task – if it can ever be accomplished.

Where is current science, then, on the path to one day preventing, arresting, or reversing this debilitating crippler of joints?  This issue of The WCC Note continues our series on knee OA by examining current literature on treatment and prospective cures, and how MRI is poised to aid monitoring the disease.

As outlined in previous issues of this newsletter, the enormity of knee OA as a population problem – the scope of its occurrence, pathogenesis, and heterogeneity – confounds a simplistic approach to therapy.  Rather than a single disease-modifying drug, surgery, or physical therapy procedure, the idea that multiple influences lead to a common endpoint of joint destruction means that this multi-dimensional disease will, in most cases, always require a multi-faceted treatment approach.

While this can seem like a frustrating and daunting process, it helps to step back and tease apart the fundamental questions at hand, imposing structure on the analysis of this most labyrinthine of common disorders.

TREATMENT

What Treatment Approaches to Knee OA Are Currently Practiced?

  1. At 2008 overview of knee osteoarthritis management in Rheumatic Disease Clinics of North America called for conservative treatment, outlining recommendations from the Task Force of Standing Committee for International Clinical Studies including Therapeutic Trials (ESCISIT).  In summary, the guidelines were:
    a.  Combination nonpharmacologic and phamacologic treatment
    b.  Treatment tailored according to risk factors, such as obesity and activity, age, level of pain, signs of inflammation,and location and extent of structural damage
    c.  Education, exercise, use of appliances, and weight reduction
    d.  Paracetamol (acetaminophen) as the first analgesic used and the preferred long-term choice if efficacy is established
    e.  Topical NSAIDs and capsaicin are efficacious and safe
    f.  NSAIDs can be considered in patients for whom paracetamol is not helpful.  Nonselective NSAIDs or COX-2 inhibitors play a role for a subset of patients
    g.  Opioid analgesics, with or without paracetamol, can be useful in patients for whom NSAIDs are contraindicated or do not work
    h.  Symptomatic, slow-acting drugs such as avocad-soybean unsaponifiables may be of benefit
    i.  Intra-articular injection of long-acting corticosteroids may be useful in settings of pain flare
    j.  Joint replacement becomes a consideration for patients with refractory pain and disability
  2. In the September 2009 Journal of the American Academy of Orthopedic Surgery, authors from The New England Baptist Hospital in Boston reported practice guidelines for knee OA that were developed explicitly aside from knee replacement (arthroplasty).  The authors recommend that patients participate in educational programs regarding self-management, weight loss, exercise, and quadriceps strengthening.  The guidelines recommend taping for short-term pain relief, analgesics, and intra-articular corticosteroids.  The report advises against free-floating interpositional devices and lateral heel wedges for medial compartment knee OA.  The authors note that the group did not come to a recommendation in regards to the use of braces with valgus- or varus-directing forces.

OA & MENISCAL TEARS

Are Meniscal Tears Caused By, or a Result of, OA, And What Does Current Literature Advise About the Role of Surgery for Them?
It is well known that normal menisci are rare in osteoarthritic knees.  While meniscal lesions in healthy knees may result in osteoarthritis due to loss of meniscal function, osteoarthritis may itself lead to mensical tears, which subsequently accelerate the disease.  Proteolytic degradation and shear stress may lead to decreased meniscal tensile strength.  Meniscal tears may then result from teh compromised meniscus being unable to withstand loads and force transmitted during normal joint loading.

Meniscal resection is reported as the procedure most frequently performed by orthopaedic surgeons in the United States.  A recent review called for well-designed, randomized, controlled clinical trials to study the true effects of meniscal resection repair or transplant, or nonsurgical treatments, as compared with placebo or sham treatment.

Noting that a meniscal tear is an almost ubiquitous MRI finding in a person with knee arthritis and is not necessarily responsible for symptoms, Hunter and Low wrote in Rheumatic Disease Clinics of North America that the removal of menisci should not be preformed unless there is clinical locking or extension blockade, since strong evidence supports that even partial meniscectomy increases the risk for worsening osteoarthritis.

Allogenic, xenogenic, or artificial material meniscal replacements have been attempted in younger subjects post-total meniscectomy, but transplant survival is variable and long-term results prove lacking.

Individuals with initial asymptomatic meniscal lesions have a clinical course that shows an increased frequency of symptoms compared to those without meniscal lesions, though the pain and impairment remain of low severity.

MRI T2 measurements of cartilage in patients with osteoarthritis show them to be increased in patients with meniscal tears.  Friedrick, et al., note that this supports the theory of meniscal and hyaline cartilage damage occurring in the setting of osteoarthritis.

SURGERY FOR KNEE OA

What Surgical Approaches Exist, And What Does Recent Literature Report About Them?

  1. Lavage and Debridement: Arthroscopic lavage and debridement are not recommended for routine treatment, as they do not alter disease progression.  In a study involving 92 patients assigned to surgery (and six not undergoing surgery), as well as 86 controlled subjects who received only physical and medical therapy, arthroscopic surgery with surgical lavage and debridement failed to add additional benefit to patients with moderate to severe osteoarthritis over optimized physical and medical therapy.
  2. Microfracture: A technique for therapy of focal chondral defects, the microfracture surgical procedure involves subchondral drilling to crate 4mm-deep pits, into which multipotential stem cells migrate from the subjacent marrow to form fibrocartilaginous tissue repair.
  3. Cell-Based Cartilage Repair:
    a.  Autologous Chondrocyte Implantation (ACI):  In this procedure, chondrocytes are harvested from nonweight-bearing cartilage, cultured in vitro and subsequently reimplanted.  Elegant reviews of the technique geared towards imaging were published in Radiographics in 2007 and 2008.  MRI can depict the state of cartilage healing, as well as the subchondral bone and bone marrow.
    Noting that young individuals with early osteoarthritis who want to remain physically active have limited treatment options, ACI may offer benefit, according to Minas, et al., in a 2009 study.
    ACI can be performed using a polymer-based graft to repair cartilage defects.  While the ACI typically requires a rim of intact cartilage at the periphery of the defect, such a recent report states that a newer technique can allow cartilage repair even when such a rim is not present.  In general, the technique uses chondrocytes harvested from healthy cartilage in nonwweight-bearing regions of the knee and transplants them into areas of defect.  A report from 2009 states that chondrocytes cultivated in a three-dimensional matrix of bioresorbable material avoided the use of covering materials such as periosteum or collagen sheets.  The fibrin polymer matrix provided a scaffold to stabilize the graft.  The authors reported that improvements were still present four years after graft implementation for patients who had undergone the procedure.
    A 2009 study of symptomatic cartilage defects of the knee reported that chondrocyte implantation had better clinical outcomes at 36 months than the microfracture technique.
    b.  Autologous Osteochoncral Autograft Transplantation:  This technique harvests osteochondral plugs from the lateral femoral condyle or trochlear nonweight-bearing areas and transplants them into an area of articular defect.
    c.  Osteochondral Allograft Implantation:  Osteochondral allograft transplantation involves the harvesting of cadaveric bone cartilage.
  4. Osteotomy: Osteotomy can be considered for unicompartmental knee OA, with the intent to shift the weight load away from the damaged compartment.
  5. Arthroplasty (Joint Replacement):
    a.  Joint replacement surgery includes: unicompartmental athroplasty and patellofemoral replacement in selected patients with isolated meial or patellofemoral OA, and total knee arthroplasty for patients with severe OA.

GLUCOSAMINE AND CHONDROITIN

Do Glucosamine and Chondroitin Work?
Glucosamine and chondroitin sulfate, alone or in combination, failed to reduce pain effectively in a study of 1,583 patients with symptomatic knee osteoarthritis.  The analysis suggested that the combination of both medicines may be of benefit to a subgroup of individuals who have moderate to severe knee pain.  Glucosamine, but not ibuprofen, has been shown to alter cartilage turnover in patients with osteoarthritis undergoing physical training.

MRI AS BIOMARKER

How Can MRI Be Used to Grade the Impact of Therapies – Pharmaceutical, Operative, Physical Therapy, and Behavioral Interventions?

  1. MRI can provide semi-quantitative assessment in osteoarthritis because it can detail articular cartilage integrity; subchondral bone-marrow pathology; edema or cysts; subchondral bone attrition; marginally, centrally, and posteriorly positioned osteophytes; meniscal and ligament integrity; synovitis and effusion; and loose bodies.  Three commonly sued whole-joint MRI imaging assessments are:
    a.  Whole-organ MR imaging score (WORMS)
    b.  Knee osteoarthritis scoring system (KOSS)
    c.  Boston leads osteoarthritis knee score (BLOKS)
  2. Cartilage can be reproducibly and accurately measured by MRI.  Cartilage morphology and trabecular bone may be quantitatively measured in the research arena to provide baseline and follow-up monitoring of treatment in OA.  In a clinical trial, cartilage thickness can provide the same level of sensitivity as cartilage volume to estimate cartilage loss.
  3. MRI shows potential value as a biomarker, since studies have indicated that the presence of either bone-marrow lesions or meniscal disease is predictive of those OA patients at greater risk for disease progression.
  4. Very early changes in cartilage biochemistry, prior to joint damage or pain, may be able to be measured by experimental MRI methods of T1-rho and T2.
  5. Specialized research MRI protocols of T2 mapping, T1-rho, sodium MR, and delayed gadolinium-enhanced MRI imaging to assess the macromolecular status of cartilage may be useful in assessing disease-modifying strategies for OA.
  6. Molecular and functional techniques for imaging early osteoarthritis include charged-based methods such as delayed gadolinium-enhanced MRI of cartilage, which is based on teh negatively charged T1-shortening agent gadopentetate dimeglumine.  Hyaline cartilage has negatively charged molecules, similar in charge to gadolinium, and thereby repulses gadolinium when the cartilage is normal and intact.  Conversely, damaged cartilage lacks the negatively charged hydrophilic molecules, allowing the gadolinium into the cartilage proper.
  7. Sodium-23 MR spectroscopy also takes advantage of the negative-fixed charged density (FCD) of cartilage.  In this technique, sodium-23 atoms, which are positively charged, correlate directly with cartilage-fixed charged density.  Sodium-23, therefore, decreases in abnormal cartilage.
  8. In the research arena, cathepsin B-sensitive near-infared fluorescent probes have been used to image osteoarthritic knees in animals.  Since damaged cartilage may release proteases such as cathepsins, this method is used experimentally to image matrix-degrading enzymes.
  9. Since OA is widely thought to result from local mechanical factors in people with systemic susceptibility, the influence of biomechanics in osteoarthritis, and the imaging quantification of them, is both interesting and important.  Joint kinematics assessed with MRI imaging have been preformed with patients supine in the magnet, with some recent work attempted in open-configuration scanners with vertical gaps, which allow standing.

OA PROGRESSION

What Have We Learned About OA Progression from MRI?

  1. Patients with knee OA who display MRI evidence of meniscal damage or extrusion, as assessed by WORMS score, show association with cartilage loss over a 30-month period.
  2. In a 2009 study from the Multicenter Osteoarthritis Study Group (MOST), a longitudinal study of people with, or at high risk for, knee OA, those subjects who had minimal baseline cartilage damage but high body-mass index, meniscal damage, synovitis or effusion, or any baseline severe MRI lesion, had a strongly increased risk of fast cartilage loss.
  3. The finding of MRI-evident bone-marrow lesions (BMLS) shows association with change in knee cartilage over two years in asymptomatic subjects.  As the size of the BMLS increases, there is increased progression of cartilage defects.  The 2008 study included 271 healthy adults with no history of knee injury, knee pain, or clinical knee OA, who underwent knee MRI at baseline and two-year follow-up to study the relationship between presence of BMLS as baseline and cartilage change over two years.
  4. The role of alignment and biomechanics in osteoarthritis underwent review this year in Radiologic Clinics of North America.  Valgus and varus malalignment were reported as increasing risk for OA, with patellar malalignment asociated with patellofemoral OA progression.  MR imaging measurements of kinematics, and measurements of contact area, were both discussed.
  5. The incidence of degenerative cleavage trizonal body tears in patients with moderate to advanced osteoarthritis is over 50 percent in patients over age 50 (personal observation by Dr. Stephen J. Pomeranz).

MRI IN OA CLINICAL TRIALS

What Are Some Examples Where MRI Played a Biomarker Role in OA Clinical Pharmaceutical Trials?

  1. In patients with knee pain on efficacious doses of NSAIDs or acetaminophen, a decrease in effusion volume (quantified by gadolinium-enhanced T1 imaging) was observed and rapidly reversed when treatment was withdrawn.
  2. In a placebo-controlled, double-blind study of 377 knee OA patients, changes in MRI assessment of subchondral bone marrow abnormalities were observed within three months of treatment and were positively correlated with type II collagen degradation (determined by urinary CTX-II).

MRI imaging is a sensitive and early marker of OA that can correlate with drug efficacy. (Contributed by Rick Walovitch, Ph.D., WorldCare Clinical)

CONCLUSION

The complexity of knee osteoarthritis etiologies complicates the search for a single disease modifying therapeutic approach.  Current treatment emphasizes conservative management including mechanical joint preservation measures.  MRI depicts the whole joint nature of the disease and serves as a barometer of its time course.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher: Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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Osteoarthritis
Vol. 3, Number 9 - September 16th, 2009 by worldcare

Osteoarthritis: “The Malady of the Masses Re-Examined”
Like the common cold and taxes, osteoarthritis (OA) sweeps so ubiquitously over humanity, and looms so complex in its etiology and cure, that it can seem to drop off the analytical radar.  Not trendy or exotic, and taking a back seat to more mortal diseases, it nevertheless presents a scourge to a large percentage of the population.

This issue of The WCC Note discusses the prevalence and pathology of osteoarthritis, with specific emphasis on its most common focus of affliction – the knee.

OA: THE NUMBERS

How many people are afflicted with OA?

  1. OA afflicts 13.9% of all people 25 years old and older and 33.6% of all people 65 years old and older.
  2. In 2005, a conservative estimate of U.S. adults with OA numbered 26.9 million.
  3. In 2006, an estimated 11.7 million ambulatory care visits were made for OA and allied disorders.
  4. Knee OA accounts for 1 of 5 primary factors of disability in non-institutionalized adults.
  5. Lifetime risk estimates project that nearly half of adults in a longitudinal osteoarthritis project in rural North Carolina will develop symptomatic knee OA by age 85.
  6. The estimated annual U.S., expenditure for OA treatment and lost work is more than $33 billion.

OA RISK FACTORS

Who gets OA? What risk factors are associated with OA?
Both avoidable and nonmodifiable factors influence the development of OA, as outlined below.

  1. Modifiable risk factors:
    a.  Excess weight, especially with knee OA.  For some women, weight loss of as few as 11 pounds can decrease the risk of developing knee OA by 50%
    b.  Joint injury (including occupational and sports-related)
    c.  Occupation – excess mechanical stress or repetitive injury
    d.  Muscle weakness or structural malalignment
  2. Nonmodifiable risk factors:
    a.  Gender (female risk is higher)
    b.  Advancing age
    c.  Race (risk lower in some Asian populations)
    d.  Genetic predisposition

OA GENETICS

What is the genetic component of OA?

  1. A clear genetic component has been apparent since it was first reported by Kellgren in 1963, who found that nodal OA was twice as likely to occur in first-degree relatives than in control subjects.
  2. The genetic basis fails to follow typical Mendelian inheritance patterns, and multiple genetic alterations probably underlie the disease.
  3. The polygenic nature of OA, with its strong hereditary component, is supported by evidence from familial aggregation and classic twin studies.  Traits associated with OA, such as cartilage volume changes, also come under genetic control.
  4. The complex, multifactorial genetic basis has been partially revealed by genome-wide linkage scans.  Thus far, implicated genes include:
    a.  Interleukin I gene cluster at chromosome 2q11.2-q13
    b.  Matrilin 3 gene at 2p24.1
    c.  IL-4 receptor alpha-chain gene at 16p12.1
    d.  Secreted frizzled-related protein 3 gene at 2q32.1
    e.  Metalloproteinase gene ADAM12 at 10q26.2
    f.  Asporin gene at 9q22.31
    g.  Growth differentiation factor 5
    h.  DVWA gene on human chromosome 3p24.3, found in OA in Japanese and Chinese patients
  5. A recent review of the science of OA by Aramson and Attur describes the following:
    a.  Coexisting individual genes may give rise to an additive affect.
    b.  Some genes that encode extracellular matrix articular cartilage proteins have links to early OA.
    c.  Mutations in several genes expressed in cartilage and point mutations in type II collagen may cause inherited OA.
    d.  Genetically linked abnormal subchondral bone can cause OA in mice.

OA PATHOGENESIS

What is the pathogenesis of OA?
Abnormal biochemical processes occur in the cartilage, bone, and synovium, instigated by the risk factors delineated above.  Progressive cartilage damage occurs, with accompanying osteophyte formation, meniscal degeneration, bone-marrow and subchondrial lesions, synovial proliferation, and effusion.

The following list outlines the proposed mechanisms causing OA, segregated by risk factor – a subject elegantly reviewed by Abramson and Attur.

  1. Obesity
    a.  Increased mechanic force: Obese individuals commonly exhibit varus knee malalignment, increasing forces in the medial compartment.
    b.  Adipocytes play roles regulating cells in bone, cartilage, and joint tissue.
    c.  Adipocyte-derived factors may encourage catabolism for chondrocytes.
  2. Joint Injury
    a. Chondrocytes act as mechano-sensors and osmo-sensors, changing their metabolism depending upon local physical and chemical alterations.
    b.  Response to mechanical stress can change gene expression, resulting in increased formation of inflammatory cytokines and matrix-degrading enzymes.
    c.  A focal cartilage injury can result in matrix disruption and chondrocyte apoptosis, or both, which begins a vicious cycle.  Trauma can cause chondrocyte death by two mechanisms: via mechanical load or via disruption of extracellular matrix leading to chondrocyte physical isolation.  Detached chondrocytes undergo apoptosis (programmed cell death) and injured areas make degradative enzymes.  Load transfer to normal peripheral regions then undergo abnormal forces, resulting in their apoptosis.
    d.  An enzyme called Smurf2 (Smad Ubiquitination Regulatory Factors) controls whether a chondrocyte matures and calcifies and, in the setting of cartilage injury, may cause a chain reaction that deteriorates cartilage.
  3. Joint malalignment
    a.  This is debated as an etiological factor, but altered joint geometry may interfere with cartilage nutrition or change load distribution.  Knee malalignment may be a marker of disease, and the literature is conflicting about is role as an OA instigator.
  4. Gender
    a.  Estrogen receptors exist in joint chondrocytes.
    b.  It has been hypothesized that the markedly increased risk of knee OA in women after age 50 is due to estrogen insufficiency, though this is actually poorly understood and evidence for such a relation is reported as inconsistent.
  5. Age
    a.  This factor may alter mechanical stress on cartilage because of changes in muscles, gait, etc.
    b.  Aging probably decreases chondrocytes’ ability to maintain and repair tissue, as they sustain “decreased responsiveness to anabolic growth factors, and synthesize smaller and less uniform large aggregating proteoglycans and fewer functional link proteins.”
    c.  Aging predisposes chondrocytes to apoptosis.
    d.  Deviant chondrocyte behavior in age-related cartilage destruction has recently been found to be associated with altered signaling via LK1.
  6. Genetic predisposition
    a.  The newly identified DVWA genetic link to OA, found in certain populations, has been further revealed as the human gene encoding for collage VI alpha4 chain.
  7. Inflammation and angiogenesis
    a.  Challenging the notion that osteoarthritis is primarily a disease of the cartilage, newer findings relating to inflammation and angiogenesis postulate that these factors modulate chondrocyte function and contribute to abnormal tissue growth and perfusion, ossification, and endochondral bone development.
  8. Diet
    a.  Increased fatty acid consumption may increase the risk of developing bone-marrow lesions.

OA ANATOMY & PATHOLOGY

What is the gross anatomic and cellular pathology of OA?
The morphology of OA initially shows that:

  • Chondrocytes proliferate with increased water and decreased proteoglycans.
  • Then, vertical and horizontal fibrillation and matrix cracks occur.
  • Next, full-thickness cartilage areas are lost.
  • Friction smooths exposed bone (bone eburnation).
  • Sclerosis and rebuttressing of underlying bone happens
  • Small fractures of subjacent bone lead to dislodged pieces (loose bodies).
  • Synovial fluid is forced through the fractures into subchondral bone.
  • The fluid forms subchondral cysts with fibrous walls.
  • Bone outgrowths grow at articular margins (osteophytes).
  • Synovium becomes congested and fibrotic, and may have inflammatory cells.

Further details include:

  1. Cartilage:
    a.  Normal articular cartilage contains water (75% by weight), collagen (predominantly type II; 20% by weight), aggrecan (5% by weight), and other extracellular matrix molecules, all maintained by chondrocytes.  As reviwed by Biswal, et al., collagen provides tensile strength, while aggrecan (glycosaminoglycan molecules) affords compressive strength.
    b.  In OA, articular cartilage loss occurs due to proteolytic enzymes that destroy proteoglycans and collagen.  Increased cartilage degradation occurs with insufficient repair.
    c.  OA cartilage shows the presence of hypertrophic chondrocyte phenotype, leading to type II collagen degradation, endochronal ossification, and chondrocyte apoptosis.
    d.  Normal cartilage extracellular matrix has two main constituents: a type II, collagen-rich network providing tensile strength; and aggrecan, a cartilage-specific proteoglycan that is highly hydrated and helps cartilage resist compressive loads.  In OA, the degeneration of extracellular matrix outpaces its creation, leading to exposure of cartilage and, subsequently, bone.
    e.  In early OA, cartilage degenerates and contains increased water and decreased proteoglycans.  The collagen network weakens, due to decreased synthesis of type II collage and increased preexisiting collagen breakdown.  Apoptosis decreases functional chondrocytes.
  2. Inflammation
    a.  Inflammatory mediators like IL-1beta and tumor necrosis factor induce chondrocytes to make proteases, chemokines, nitric oxide, prostaglandins, and leukotrienes, which drive catabolism, impair cartilage substance generation, and encourage cell death.  Oxygen and nitrogen-derived free radicals promote chondrocyte cell death, probably by mitochondrial dysfunction.
  3. Abnormal bone
    a.  Osteophytes are theorized to develop from penetration of blood vessels into degenerating cartilage basal layers, or from the abnormal healing of stress fractures at the joint margins with subchondral bone.
    b.  Subchondral bone sclerosis may arise from excessive loads leading to microfractures in the trabeculae that go on to heal with callus and remodeling.
    c.  The histopathology of bone-marrow lesions in OA is unclear, by microfractures, cysts, and avascular necrosis may give rise to findings appreciable by MRI.
  4. Synovial proliferation and inflammation
    a.  Synovial hypertrophy and hyperplasia have been noted by arthroscopic studies in up to 50% of OA patients.
    b.  Cartilage breakdown products from mechanically or enzymatically destroyed cartilage can provoke release of collagenase and other enzymes from synovial cells and macrophages, lead to mononuclear cell infiltration and vascular hyperplasia in synovium, and induce synovial IL-1beta and tumor necrosis factor that continue the cascade of degredation.
  5. Meniscal tears
    a.  Degenerative meniscal tears may signal the first symptom of OA.  When an isolated meniscal tear has undergone limited meniscectomy treatment, there is a high risk of tibiofemoral OA at 16-year follow-up.
    b.  Meniscal damage without surgery is also a high-risk factor for subsequent OA.

CONCLUSION

Osteoarthritis currently seems inevitable and unavoidable for a large swath of the population.  Its etiology relates to a strong, but complex, non-Mendelian genetic basis, combined with mechanical and metabolic factors that cause molecular alterations – the end results of which affect the whole joint.

The next issue of The WCC Note will continue this three-part series with a discussion of the MRI appearance of OA.  The third and final article will review available treatments, clinical trials, and research developments.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher: Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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Alzheimer’s Disease, Part III: Further Imaging and Treatment – Vol. 3, Number 8 - July 10th, 2009 by admin

Our memories form the collective essence of ourselves.  They create the framework of our contemplative and imaginative abilities.  But what molecular arrangement stores these experiences, where are they held, and how are they retrieved?  What cascade of events marks some memories for long-term storage and not others?

Imagine looking into a lens that shows structures on an ever-smaller scale. Envision the anatomy of memory by viewing the brain’s parenchyma, then the cellular circuitry, the micro-environmental, the molecular, and finally the subatomic basis of memory, its electromagnetic energy.  What comprises these pieces?  And how does this anatomic memory network function?

It is this fundamental understanding that will help unlock clues to protecting memories from the destructive force of Alzheimer’s disease (AD).  While answers to many of these questions remain an undiscovered frontier, imaging has afforded insight into some of them.  This week’s WCC Note examines some of the applied and experimental literature about memory gone awry in the anatomy and physiology of Alzheimer’s.  This issue, the third in a three-part series, concludes with an overview of attempts at AD treatment and prevention.

PET & SPECT FINDINGS

What Are the PET and SPECT Findings in Alzheimer’s Disease?
To evaluate AD, PET scans can be performced with (18F)-2-fluoro-2-deoxy-D–glucose (FDG-PET) to image the brain’s glucose metabolic rate or, more recently, with specific agents to directly image amyloid plaques.

  1. FDG-PET
    a.  FDG-PET in AD demonstrates a pattern of abnormality, with decreased FDG in the parietotemporal cortex and posterior cingulate cortex.  The severity of decreased metabolism correlates with the degree of cognitive impairment.  Frontal-lobe abnormality frequently develops as the disease advances.
    b.  Different patterns of FDG-PET characterize other causes of dementia, helping to differentiate between AD and frontotemporal dementia (decreased uptake in frontal, anterior temporal, and medial temporal cortices), pseudodementia caused by depression (normal scan), and vascular dementia (patchy defects of the central white matter and cortex).  Dementia with Lewy bodies (DLB) can show a pattern similar to AD, but DLB has frequent association with Parkinson’s disease, which involves the occipital lobes that are spared in AD.
    c.  FDG-PET scans show changes year before clinical AD, according to a recent study.  The research imaged cognitively normal elderly people who subsequently displayed Alzheimer’s disease symptoms, and who underwent post-mortem exams.  The subjects’ FDG-PET scans had show progressive loss in cerebral metabolic rate for glucose in the hippocampus to the parietotemporal and posterior cingulated cortices.
  2. Amyloid plaques can be visualized directly by positron emission tomography (PET) using a radioactive ligand bound to them.  Those currently under scrutiny include carbon 11-labeled Pittsburgh Compound B (PIB-PET), developed at the University of Pittsburgh, and the 18f-(2-(1-(6-[(2-[18F]fluoroethyl)(methyl)amino]-2–naphthyl}ethylidene) (FDDNP-PET).  Studies of these agents concluded that:
    a.  PIB-PET and FDG-PET and both can diagnose early cognitive impairment with similar accuracy, but PIB-PET better distinguishes between amnestic and nonamnestic MCI, according to authors from The Mayo Clinic.  The authors theorize that PIB-PET may reflect early amyloid deposits before cerebral metabolism becomes distrupted.
    b.  A study that performed PIB-PET mapping of amyloid toxicity with volumetric MRI in AD subjects concluded that the medial temporal lobe may be more susceptible to amyloid toxicity than neocortical areas.
    c.  The severity of dementia significantly associates with PIB-PET uptake, according to a study from Munich, Germany.  The authors propose that PIB-PET could be a potential surrogate marker for demential severity.
    d.  Using FDDNP-PET as a molecular imaging probe for plaques and tangles, in association with MRI cortical surface models, researchers at UCLA found PET results correlated with cognitive performance.
    e.  A recent report evaluating these two tracers in AD, MCI, and controls found that PIB-PET showed higher binding in AD than controls or MCI.  The FDDNP-PET uptake was higher in AD than controls, but MCI proved indistinguishable.
  3. SPECT
    a.  Single-photo emission CT (SPECT) shows altered brain perfusion similar to the metabolic changes reflected at PET.  According to a review by Coleman, SPECT findings, in general, tend to display less sensitivity and accuracy compared to FDG-PET.
    b.  Regionally distinct patterns of hypoperfusion on SPECT or PET can help distinguish AD from vascular dementia, and dopaminergic loss in the basal ganglia can discriminate dementia with Lewy bodies (DLB) from AD.

FRONTIERS IN AD IMAGING

What Other Experimental Imaging Work Is Being Done on AD, Molecular and Otherwise?

  1. Time-lapse imaging of astrocytes in a mouse model of Alzheimer’s disease showed that amyloid plaques caused widespread effects on astrocytes beyond just the local region.  To do this, researchers at Massachusetts General Hospital used multiphoton calcium imaging, a technique that uses fluorescence and microscopy.
  2. MRI spectroscopy in AD showed significant correlation between myo-inositol/N-acetylaspartate (ml/NAA) ratio and cognitive decline, according to a recent report.  The study performed exams at 3T and evaluated different limbic regions in AD and MCI subjects.
  3. Imaging mapping studies report:
    a.  Tensor-based morphometry, a method that maps regions on images and statistically analyzes their differences, can demonstrate three-dimensional brain changes in AD over time.  Serial MRI brain scans can track the disease in 3-D, according to imagers at UCLA working with the Alzheimer’s Disease Neuroimaging Initiative.  The authors examined patients with AD and MCI, as well as healthy elderly controls, and reported temporal-lobe atrophy occurred significantly faster in MCI subjects who converted to AD.
    b.  A fully automated mapping system was used on the hippocampus in very mild AD.
    c. Diffusion tensor imaging and cortical thickness analyses may serve as markers to discriminate MCI from normal aging.
  4. Functional MRI studies include:
    a.  4T functional MRI performed on subjects with MCI showed different regions of brain decreased and increased activation, finding lower hippocampal activation during memory retrieval the most significant correlate for severity of memory loss.
    b.  4T functional MRI performed on healthy controls, and subjects with MCI and AD, reported that as subjects displayed increasing memory impairment, exams showed decreasing activation of the medial temporal lobe and increasing activation in the posteriomedial cortices – the precuneus and posterior cingulate gyrus in particular.
  5. Diffusion-Tensor Imaging (DTI):
    a.  DTI assesses the magnitude and direction of microscopic water movement in the brain.  Therefore, AD-related damage to myelin sheaths or axonal membranes can change brain/water dynamics.
    b.  A review article about DTI states that it can serve as an adjunct to support the clinical impression of AD.
  6. In vivo imaging of brain serotonin 4 receptors, which are involved in learning and memory, has been achieved with a novel marker using PET.

WHAT HAVE WE LEARNED?

How Has Imaging Advanced Our Global Understanding of Memory’s Anatomy?
A recent, elegant review of the anatomy of the hippocampal-parahippocampal network discusses neuronal circuitry and connections of memory, then elaborates on their functional implications.  These include memory function, ability to navigate, and synchronization of the neuron firing that is probably needed for memory consolidation.

Much of the information about these neuronal pathways was discovered using neuroanatomical tract racing and imaging live rats’ brains.  Cells underwent labeling with techniques such auto-fluorescent dyes so that they could be visualized with light, electron, or confocal microscopy.

WHAT CAUSES FOR HOPE?

What AD Treatment Approaches Are Possible, How Have They Fared, and What Else Is Being Tried?

  1. Four medications currently carry FDA approval for treating AD symptoms and are being prescribed, according to the National Institutes of Health.  These drugs all try to stimulate areas of damaged brain, but afford marginal help.  The agents include three cholinesterase inhibitors used for mild to moderate AD:
    a.  Razadyne (galantamine).  This agent both stimulates more brain acetylcholine release and prevents its breakdown.
    b.  Exelon (rivastigmine).
    c.  Aricept (donepezil), which can using be used in moderate to severe AD.
    The first approved agent, Cognex (tacrine), lacks current wide usage because of safety issues.  The theory behind these drugs rests in the requirement of acetylcholine for memory and thinking.  As AD advances and the brain makes acetylcholine, these medications may stop working.
    For moderate to sever AD, Namenda (memantine) can be given.  This is an N-methyl D-asparate (NMDA) antagonist and is thought to regulate glutamate, which when overproduced may cause brain-cell death.
  2. No drugs now available can “stop, slow, or prevent the disease.”
  3. Recent investigational drug failures included two targeting amyloid:
    a.  Tarenflurbil (Flurizan), which modulated secretase.
    b.  Tamiprosate (Alzhmed), which bound to amyloid.
  4. Other recent drug trials have involved:
    a.  Bapineuzumab, a humanized monoclonal antibody made for removing brain amyloid, which resulted in a mixed response
    b.  Semagacestat, a secretase inhibitor
    c.  BPT2, which interferes with amyloid interaction with zinc and copper
    d.  Methylthioninium chloride, which targets tau aggregation and whoed promising Phase II results
    e.  Dimebon (Medivation), which provided subjects with improved cognition and memory, and appeared safe and well-tolerated, according to a report last year in Lancet.
    f.  Gammagard, an intravenous immunoglobulin
    g.  Methylene blue
  5. Vaccines developed and tested so far have attempted to get a person’s immune system to perceive amyloid protein as foreign and attack it.  Last year, long-term follow-up of an amyloid 42 immunization trial reported that although autopsies showed decreased plaque, most of these subjects died with severe dementia.  It is possible that the vaccine was given too late in the disease process.
  6. Potential strategies to thwart AD include:
    a.  Blocking cyclophilin D, since amyloid interacts with it, which may lead to mitochondrial dysfunction and neuronal death.
    b.  Targeting serum amyloid P (SAP), which binds to amyloid deposits and prevents their proteolytic degradation and may also be directly neurotoxic.  A compound called CPHPC depletes SAP.
    c.  Targeting Orphan G protein receptor, a modulator of amyloid production in neurons.

CONCLUSION

PET imaging in Alzheimer’s disease patients hows decreased FDG uptake in the parietotemporal cortex and posterior cingulate cortex; helps distinguish between dementia types; can reflect AD prior to symptoms; and can image amyloid directly.  Molecular and other imaging techniques advance our understanding of memory anatomy and AD, which is crucial to treating and preventing this devastating disease for which no prevention or cure yet exists.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher: Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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Alzheimer’s Disease, Part II: Diagnosis and MRI Imaging – Vol. 3, Number 7 - June 8th, 2009 by worldcare

The first day a person walks or rides a bike becomes a celebrated moment in every family’s history.  But the final time a person fills out a crossword puzzle or charts a stock ledger usually goes unnoticed.  No photographs capture the last stroke of a pencil; such monumental losses slip by without fanfare.

The silent disposition of amyloid occurs the same way, insidiously laying down and killing brain cells without heralding its presence.  How, then, do we know Alzheimer’s disease is taking hold in a life?  This entry of The WCC Note examines recent literature on the diagnosis and biomarkers of Alzheimer’s disease.

DIAGNOSIS

How is Alzheimer’s Disease Diagnosed?
Currently, no single definitive test marks the disease.  A combination of mental status exams, blood markers, cerebral spinal fluid (CSF) markers, and brain imaging studies helps to secure the diagnosis.

IMAGING’S ROLE

How Does Imaging Play a Role at the Gross Anatomic Level?
What Is the Alzheimer’s Disease Neuroimaging Initiative (ADNI)?

  • In April 2009, results from the ADNI, published in Radiology, reported that semi-automated quantitative MRI can identify a brain atrophy pattern predictive of clinical mental decline.  The study examined 84 people with mild Alzheimer’s disease (AD), 175 with mild cognitive impairment (MCI), and 139 healthy controls.
  • Results showed that atrophy in the mesial and lateral temporal, isthmus cingulate, and orbitofrontal areas helps to distinguish control subjects from AD subjects, with 83% sensitivity and 93% specificity.  People with MCI whose MRIs showed the AD atrophy pattern displayed significantly greater one-year clinical decline, brain loss, and progression to probable AD than those whoe MRIs did not (29% of those with MCI and AD atrophy, compared to 8% with MCI without AD atrophy).
  • The superior temporal gyrus showed significant atrophy in a subgroup of MCI subjects with AD atrophy.  The authors hypothesize that this portends a greater risk of mental decline.
  • Brain MRIs showed differential rates of temporoparietal region atrophy in prodromal AD, according to a 2008 report in Neurology.  People who developed AD during the study showed greater atrophy in the hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, and inferior temporal gyrus compared to individuals with stable MCI.
  • Subjects with MCI underwent fractional anisotropy, apparent diffusion coefficient, and cortical thickness measurements, which were then compared to those of the controls.  Results revealed decreased fractional anisotropy and increased apparent diffusion coefficient in white matter of the frontal, temporal, and parietal lobes in people with MCI, according to data in the American Journal of Neuroradiology.
  • Hippocampal atrophy rates add value over whole-brain volume measurements is distinguishing AD, MCI, and controls, according to a study from the Netherlands.  The hippocampal atrophy rate proved especially valuable in discriminating MCI from controls.
  • In a study of the Mayo Clinic, gray-matter atrophy patterns correlated with neurofibrillary tangles at autopsy pathology.  The authors note that this validates MRI three-dimensional atrophy patterns as surrogate indicators of AD pathology.
  • The Alzheimer’s Disease Neuroimaging Initiative (ADNI) began in October 2004 as a five-year collaboration effort between the National Institute on Aging, the National Institute of Bioimaging and Bioengineering, private pharmaceutical companies, the U.S. Food and Drug Administration, and several nonprofit foundations.  With a $60 million budget, ADNI seeks to examine the mental status, brain structure, and brain function of 200 people with AD, 400 people with mild cognitive impairment, and 200 elderly controls.  Subject recruitment involves more than 50 sites in the United States and Canada.

IMAGING AND BIOMARKERS

Why Are Imaging and Biomarkers Important in AD?
Developing sensitive and specific tools to diagnose and quantify AD prior to memory loss is critical to disease prevention and monitoring therapy.  Evaluating interventions need to be done in people who have not yet sustained irreparable brain cell loss.  Recent disappointing outcomes in vaccine trials, for example, underscore the need for such subjects.

As noted in a recent editorial, markers will identify AD pathology in normal elders or those with mild symptoms; help predict future mental decline; mark progression; and stratify subjects into groups.

Large-scale, international, controlled multicenter trials performing Phase III development of imaging and CSF biomarkers include the U.S., European, Australian, and Japanese Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the German Dementia Network.

BLOOD-BASED MARKERS

Are There Any Blood-Based Alzheimer’s Disease Markers?
No currently accepted biomarkers of sporadic AD exist.  Since AD can alter peripheral tissue, examination for blood constituent footprints of the disease has involved the following:

  • Peripheral blood mononuclear cells are being studied for their molecular signatures of DNA, RNA, and protein.
  • While plasma studies of A are reported as inconsistent, decreased plasma A 42 relative to A 40 may increase AD risk.
  • Short-wavelength near-infared spectrophotometry of blood plasma differentiated AD from normal elderly controls with 80% sensitivity and 77% specificity.
  • A 42 was shown to be elevated in plasma of familial AD mutation carriers, and data suggest the levels may decrease with disease progression before overt AD occurs.

CSF MARKERS

What Are the CSF Biomarkers for Alzheimer’s Disease?

  • As reported recently in Nature, “concentrations of amyloid peptides, particularly one called amyloid-61-42, are low in the cerebrospinal fluid of patients with Alzheimer’s disease compared to healthy controls because the plaques are thought to suck them out of circulation, and concentrations of tau protein and phosphorylated tau are high.
  • CSF A 42, tau, and hyperphosphorylated tau protein (p-tau) can differentiate people with mild cognitive impairment (MCI) from those with AD.  They may show changes that predict future AD in currently asymptomatic people.
  • In the setting of very mild AD, lower CSF A 42, high tau or p-tau181, or high tau/A 42 ratios predict a more rapid onset of dementia.
  • A recent CSF study from the Netherlands included 177 patients with AD, examining CSF amyloid 1-42, tau and tau phosphorylated at threonine 181 (p-tau).  The authors reported different clusters of CSF biomarker levels and found them to correlate with cognition.  Patients with very high CSF tau and p-tau displayed worse memory, mental speed, and executive function.
  • In subjects who are familial AD mutation carriers, the ratio of A 43 to A 60 was reduced in the CSF of nondemented subjects.  Elevated t-tau and p-tau181 proved to be sensitive presymptomatic disease indicators.
  • CSF marker variability, however, proved high between and also within centers, according to a recent report.

CONCLUSION

While no single finding affords the diagnosis of Alzheimer’s disease, the brain MRI pattern of atrophy in the mesial and lateral temporal, isthmus cingulate, and the orbitofrontal areas provides 83% sensitivity and 93% specificity.  In Alzheimer’s CSF amyloid is decreased, while tau is increased.  Pursuit of suitable blood markers continues.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher: Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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Alzheimer’s Disease, Part I: Who Gets It and Why?
Vol. 3, Number 6 - May 13th, 2009 by worldcare

Charlton Heston, actor.  Rita Hayworth, actress.  John F. Riordan, mathematician and engineer who specialized in combinatorial mathematics.  Tom O’Horgan, director of the Broadway musical “Hair.”  William W. Kaufmann, “a close adviser to seven defense secretatires and a major proponent of a shift away from the early Cold War strategy of mass nuclear retaliation against the Soviet Union.”  Jack Cover, physicist who invented the Taser stun gun.  Sammy Baugh, great National Football League quarterback.  C. Lester Hotan, a pioneer in the electronics industry.  Arthur Hill, actor who won a Tony Award for “Who’s Afraid of Virginia Woolf?”  Donald Finkel, noted American poet.  Dr. William B. Schwartz, “a leading health economist whose studies of the effects of market forces on medicine led him to predict that unbridled costs could lead to a rationing of care.”  Charles Morgan, Jr., civil rights lawyer.  Rear Admiral Eugene B. Fluckey, “one of America’s most daring submarine commanders of World War II.”  Milton Jerrold Shapp, former Governor of Pennsylvania.

All these people died with Alzheimer’s disease (AD), according to their New York Times obituaries.  Alzheimer’s does not discriminate.  It ravages the very essence of our humanity – our memories.  From a former president to the neighbor next door, it plays a roulette game with our lives.

This issue of The WCC Note begins with a review of recent literature on Alzheimer’s, starting with what we know about its pathology and genetics.  Upcoming issues will address its diagnosis, biomarkers, treatment, and prevention, and the status of imaging’s very important role.

WHO GETS IT?

Who Gets Alzheimer’s?
The National Institute on Aging estimates between 2.4 to 4.5 million Americans and more than 20 to 37 million people worldwide currently live with AD.  Reports predict a United States prevalence of 8.64 million (range: 4.37-15.4 million)by the year 2047.

The percent of people with AD doubles about every five years of age, beginning with roughly 1% of those age 60 and reaching 40% or more of those 85 years old.  Research estimates 5% fo 10% of cases are familial, most being sporadic.

ALZHEIMER’S AND GENETICS

What Do We Know About Alzheimer’s Genetics?
While AD typically afflicts the elderly after age 60, a small subset of patients, roughly 5%, develops it at a younger age – from their thirties through their fifties, and in rare cases as early as their twenties.  The genetic basis of the disease remains under continued scrutiny, but research has established several known links, which differ between these two groups.

Early-onset AD genetics: A mutation in one of three inherited genes carries the risk of AD.  These mutations result in formation of abnormal proteins and are autosomal-dominant.
a.  Chromosome 21:  Causes abnormal amyloid precursor protein (APP).  The Aβ peptide which accumulates in AD is cleaved from APP, the gene for which resides on chromosome 21.  People with Trisomy 21 (Down’s syndrome) sustain the brain pathology of AD.
b.  Chromosome 14:  Causes abnormal presenilin 1.
c.  Chromosome 1:  Causes abnormal presenilin 2.

Late-onset AD genetics: The mutations found in early-onset AD do not carry association with late-onset AD.  No signature genetic link to late-onset AD has been identified, but genetic risk factors appear to be present.  Such genetic risk factors are variants in cellular DNA that increase disease likelihood, but do not directly cause the disease.  A genetic profile related to apolipoprotein E (APOE) increases likelihood of AD.  APOE encodes instructions for a cholesterol transport protein, and APOE exists in several alleles (or forms).  One of these alleles is APOE  є4.

Genetic Risk in late-onset AD include:
a.  APOE є4:  About 40% of AD patients carry the APOE є4 form of the gene APOE, though not everyone with APOE є4 allele.
b.  SORL1:  Discovered in 2007, it may be another genetic association and is involved with APP transport within cells.
c.  CALHM1:  This appears to be involved in calcium homeostasis.
d.  PCDH11X:  A single nucleotide polymorphism in this X-linked gene is the first sex-specific risk factor found.
e.  Other genetic risk factors may exist.  The ongoing genome-wide association study (GWAS) employs rapidly scanning markers in complete DNA sets to assess for genetic variations that may associate with AD.

BRAIN PATHOLOGY

What Is the Pathology of Alzheimer’s?
Macroscopically, the brain in AD demonstrates cortical atrophy, which is most severe in the frontal, temporal, and parietal lobes.  Microscopically, neuritic (senile) plaques, neurofibrillary tangles, and amyloid angiopathy occur – all of which can happen to a lesser degree with normal aging.  The pathologic plaques and tangles, and ensuring neuronal loss and glial reactions, start first in the entorhinal cortex, move on to the hippocampal formation and isocortex, and then to the neocortex.

  1. Amyloid:  For years, research has linked AD to accumulation of amyloid β peptides (Aβ).  These peptides first form short chains, called oligomers, that are thought to be toxic and make long, sticky fibrils that create brain plaques.  Subsequent neuronal cell dysfunction and death ensue, accompanied by deficient neurotransmitters.
    a.  Neuritic plaques often contain central amyloid (amyloid β in dominance), with microglial cells and reactive astrocytes peripherally.  Other plaque proteins included complement components, proinflammatory cytokines, alpha1-antichymotrypsin, and apolipoproteins.
    b.  Neurofibrillary tangles: Inside neurons, these consist of an insoluble protein called tau.  The Aβ peptides become cleaved from the amyloid precursor proteins (APP) by γ-secretase and β-secretase enzymes.  (The function of APP is unknown.)  The toxic Aβ peptides get taken up and released by plaques, stressing cells and creating so much phosphorylation of tau that it tangles.
    c.  Cerebral amyloid angiopathy almost always occurs in AD, but also can occur in people without the disease.
  2. Role of astrocytes:  Reports theorize that atrophy of astroglia and reactive hypertrophic astrogliosis both may occur in dementia.  Astrocytes comprise the most numerous brain cell type.  To review their function, they are glial cells believed to participate in metabolic buffering or detoxifying, nutrient supply, electrical insulation, barrier functions, repair, and scar formation.
  3. Other features:  These include granulovaculr degeneration, most commonly occuring in the hippocampus and olfactory bulb; and Hirano bodies, most commonly in hippocampal pyramidal cells.  Of note, the symptom of decreased sense of smell can be a harbinger complaint of AD.
  4. Does the pathology cause immediate symptoms?
    No.  A subliminal, asymptomatic state of AD brain damage with tangle and plaque formation occurs in people for up to 1o to 20 years.

AMYLOID AND ALZHEIMER’S

How Does Amyloid β Cause AD?
This is a complex and compelling questions; two recent studies attempt to tackle it.  One found that amyloid β may disrupt mitochondrial function.  Another study looked at the production of Aβ pyroglutamate (pE)-modified peptides.  These are peptides prone to aggregate that are created by the enzyme glutaminyl cyclase.  Both these peptides and this enzyme are upregulated in Alzheimer’s patients as compared to controls.

CAUSES

Why Does AD Happen?
Attempting to solve this labyrinthine problem, researchers speculate that, in the general population, predisposing genetic risks and environmental factors interact with physiological brain aging processes to cause AD.

Some of the proposed nongenetic risks include toxins, viruses, prions, a low level of education, and head trauma.  Controversy accompanies studies related to traumatic head injury, hypercholesterolemia and high- and low-density lipoprotein factors, elevated serum homocysteine, and vitamin E.

Regular light alcohol use, especially of wine, may decrease AD.  This may relate to grapeseed polyphenols, which have been shown to inhibit amyloid β-protein aggregation into high-molecular weight oligomers in vitro.  However, heavy drinking (more than two drinks per day) and smoking may increase risk, according to a report from the American Academy of Neurology meeting.

Diabetes Type 2 and AD may be linked, since insulin influences the metabolism of beta-amyloid precursor proteins (APP) in neurons, decreasing the intracellular accumulation of Aβ peptides.  This carries implications for oral hypoglycemic agents.

EARLY DIAGNOSIS

Would Early Diagnosis Make a Difference?
Trials to assess therapeutic intervention in AD have included patients with advanced disease, people whose brains may have already sustained irreversible damage.  Diagnosing the disease before irreparable brain damage would allow assessment of a therapy’s true ability to allay systems.

PRIONS AND ALZHEIMER’S

“Mad Cow” Disease is Linked to Prions; What Do They Have to Do with Alzheimer’s?
Recent literature reports non-infectious prion proteins may be a mediator in the development of AD.  The brain produces normal prion proteins, but these can result in disease if they contact an infectinos form called PrPSc.  The normal prion protein in cellular form (PrPc) anchors to the cell membrane and helps maintain brain white matter.  A misfolded, clumped, and very pathogenic form of infections prion protein, called PrPsc, causes Creutzfeldt-Jakob and “Mad Cow” diseases.

The function of normal brain prions is unknown, but recently a study found that they may be needed for mice to possess a normal sense of smell.

Amyloid-β oligomers interact with neuronal membrane prion protein, which may impair the signaling pathway needed for synaptic plasticity important in learning and memory.  Alternatively, internalization of the prion protein PrPc may let the amyloid-β oligomers into the cell, where they might disrupt cell functions.

CONCLUSION

A global, common, and tyrannical disease, Alzheimer’s displays a multifactorial risk profile of genetic and nongenetic causes and a link to amyloid – all factors that are undergoing continued investigation.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher: Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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