Reversible Alzheimer’s Disease: The role of normal-pressure hydrocephalus

Between 9 and 13 percent of residents in nursing homes and assisted living facilities are likely mis-diagnosed with Alzheimer’s disease and can be cured. Anthony Marmarou with the Virginia Commonwealth University Medical Center, Richmond, Virginia and his colleagues investigated how common it is to find buildup of fluid in the brain among clients in assisted-living and extended-care facilities. [1]  Known as idiopathic (unknown cause) normal-pressure hydrocephalus (iNPH), this condition mimics the behavior of Alzheimer’s disease. Normal-pressure hydrocephalus occurs when there is a restriction in the spaces that hold fluid deep inside the brain, resulting in pressure build-up. The pressure compresses the soft tissues of the brain restricting its function. The authors found that out of 147 patients between 9 to 14% had NPH depending on the diagnostic criteria used. Among these 17 patients, 11 received shunts and seven of these showed either transient or sustained improvement a year later. Although they were likely diagnosed with Alzheimer’s disease, a year later most were cured.

The symptoms of normal-pressure hydrocephalus are very similar to Alzheimer’s disease. When identified as a distinct disease it is known as the “wet, wild, and wobbly.”  Characterized by urinary incontinence (wet), dementia (wild), and gait dysfunction (wobbly). It is estimated that 1.6–5.4% of those with dementia are affected by iNPH.[2]  If the condition is left untreated—most of these cases are overlooked as Alzheimer’s disease—chronic iNPH patients share overlapping characteristics with Alzheimer’s disease in 75% of the time. It becomes increasingly difficult to differentiate the two the longer that iNPH is left untreated since the NPH syndrome will become Alzheimer’s disease.

Although there is no community-wide study looking at how common NPH is, there are some small sample studies that indicates that it is likely to be very common among older adults 65 years older. [3]  Among older adults in the community, the prevalence is around 1.3%, higher in assisted-living and extended-care residents with 11.6%. A small proportion of patients (2%) show permanent improvement after releasing the pressure in the brain using a shunt. The problem is that there are no easy indicators—including brain imaging—for distinguishing iNPH and Alzheimer’s disease. The images must still be interpreted with clinical features, blood measurements, CSF biomarker measurements, tap test, and CSF drainage results.

Because it is hard to diagnose, iNPH remains under recorded. Many studies report an association between hypertension, vascular disease and iNPH—with strokes and heart attacks being common precursors—so there is a need to look at any vascular disease as a precursor to Alzheimer’s. And the problem is that Alzheimer’s disease is so broad a category that most things that affect the brain and cause behavior changes are likely to be diagnosed Alzheimer’s disease even though it is likely not, such as amyloid deposition, CSF biomarker content, and presence of vasculature diseases. [4] A diagnosis of Alzheimer’s disease is a prescription for lost hope, whereas vascular disease is more likely to be amenable to therapy.

Vascular dementia—where the plaques and tangles are caused by a lack of blood flow in the brain (called cerebral perfusion)—is confused with Alzheimer’s disease most often because both share the same biomarkers and have the same expression. They look the same to the inexperienced clinician. Cerebrovascular disease among adults over 75 years of age is a common condition—36 percent overall, 25 percent for coronary, 58 percent hypertension, and 11 percent for stroke. [5]  It seems likely that because of these co-morbidities, vascular dementia contributes to, and is sometimes mis-diagnosed as Alzheimer’s disease. The silent issue is recognizing how frequently vascular disease promotes dementia.  Contemporary neuroscience still lacks a thorough understanding of exactly what contribution cerebrovascular disease makes to cognitive impairment. [6]

The answer is to move away from the practice of calling anything that disturbs cognition as Alzheimer’s disease.[7] Clinicians need a strategy, a roadmap to differentiate all these different type of diseases because they have different causes. Knowing the cause is the first step to formulating a cure. That is, if we are truly serious about finding a cure for Alzheimer’s disease.

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[1] Marmarou A, Young HF & Aygok GA (2007) Estimated incidence of normal-pressure hydrocephalus and shunt outcome in patients residing in assisted-living and extended-care facilities. Neurosurgical Focus, 22(4); 1-8.

[2] Gallia GL, Rigamonti D, Williams MA (2006) The diagnosis and treatment of idiopathic normal pressure hydrocephalus. Nat Clin Pract Neurol 2, 375-381.

[3] Martín-Láez, R., Caballero-Arzapalo, H., López-Menéndez, L. Á., Arango-Lasprilla, J. C., & Vázquez-Barquero, A. (2015). Epidemiology of Idiopathic Normal Pressure Hydrocephalus: A Systematic Review of the Literature.World neurosurgery, 84(6), 2002-2009.

[4] Di Ieva, A., Valli, M., & Cusimano, M. D. (2014). Distinguishing Alzheimer's disease from normal pressure hydrocephalus: a search for MRI biomarkers.Journal of Alzheimer's Disease, 38(2), 331-350.

[5] Schiller J.S., Lucas J.W. & Peregoy J.A. (2012.) Summary health statistics for U.S. adults:National Health Interview Survey, 2011. National Center for Health Statistics. Vital Health Stat, 10(256).

[6] Jellinger K.A. (2008). Morphologic diagnosis of 'vascular dementia' - a critical update. J Neurol Sci, 270: 1-12

[7] Garrett MD (2015) Politics of Anguish: How Alzheimer's disease became the malady of the 21st century. Createspace. USA

© USA Copyrighted 2016 Mario D. Garrett

Early Emotional Cascade and Alzheimer’s disease

Wrong on so many levels: The Amyloid Cascade hypothesis and Alzheimer's disease

Our body, including our brain, is constantly changing. Within each of the 37 trillion cells [1]  there is a constant dynamic activity. A relentlessly hive of activity maintaining, coordinating and enhancing functioning. All of this activity is based on four major molecules—macromolecules—essential for all known forms of life. These are fats, carbohydrates, nucleic acids and proteins. 

Fats and carbohydrates are the source of all energy for the body, while nucleic acids (meaning from the nucleus) and proteins (meaning primary or first) constitute the components of the body.

Nucleic acids hold our genetic material our DNA—Deoxyribonucleic Acid—whose sole purpose is to make and coordinate the production of proteins. DNA is stored in the nucleus while a replica of this DNA called RNA—Ribonucleic Acid—is a working copy of the many parts—called genes—of the DNA. The sole purpose of the DNA and RNA is to hold information that make up all the proteins that our body needs.

RNAs are thought to be earlier versions of DNA, our genetic templates. At some point the strand of information that contains the four nucleotides—chemical codes—must have combined with another RNA strand to form a DNA helix, a more stable and accurate structure. This structure is more stable because each nucleotide, piece of information, is matched on the other side of the double helix—like double entry book keeping, resulting in less chance of making mistakes. This robustness is a necessary feature if you aim to become immortal, as genes are.

Because the DNA is a stable structure, it must however be unwound and transcribed to form copies of RNAs which can then be translated to proteins. Proteins—which are made up of amino acids—function as enzymes, hormones and body tissues. The importance of proteins is expressed by the recent ambition to map all human proteins in the Human Proteome Project. Just because we mapped the genome does not mean very much if you do not know what those codes mean. Proteins are the deciphering tool.

As there are more proteins than genes, the aim to map all proteins is ambitious and much larger than mapping the genome. It is also very complex. The proteome has two additional levels of complexity. While the genome is defined by the sequence of four nucleotides, the proteome is determined by the same genome but then involving the permutations of 20 different amino acids. Each amino acid is defined by a set of three nucleotides on the RNA—a codon. A chain of amino acid is defined as a protein, having varying sequence and lengths. Each variation defines the physical structure, and the structure determines its function. This complexity resides within nearly each of our 37 trillion cells. Cells within specific organs produce specific proteins, although all cells have the capacity to synthesize all proteins.

In our body, most of our cells have a nucleus and a membrane around it—Eukaryotic Cell as apposed to Prokaryotic Cell. Within these eukaryotic cells is a complex factory of activity. Not only have eukaryotic cells evolved to include alien small organs— organelle such as mitochondria which have their own genetic material separate from the cell’s DNA—each cell has a copy of all of our genetic material, our body’s complete template.  How our genes virtually replace or maintain each and every cell as we live, is one of the most intriguing enigmas in science.

The DNA is like a musical record that is being played constantly. Instead of sound, the player—an enzyme, another protein, called ribozyme—makes negative copies of one strand of the DNA. Through a process known as transcription—it produces a negative copy called the RNA. As the DNA is transcribed, a strand of RNA is created within the nucleus of the cell. This RNA strand migrates out of the nucleus wall into the cytoplasm, the main part of the cell. This small negative replica is composed of a string of nucleotides which are “read” three nucleotides at a time—these keys are called codons. To produce protein, the DNA transcribes three types of RNA.

One part defines the type of protein to build, this is the messenger RNA—mRNA. The second RNA strand is a transfer RNA—tRNA—which attaches to a specific amino acid. Like a shopping trolley, it selects individual amino acids as the building blocks of protein. The final structure —rRNA—is the two-part machine called a ribosome, that builds the protein itself. Ribosomes combine the messenger and the transfer RNA according to the code, the codon. As it matches them together it then steals their amino acids. Ribosomes join one amino acid with the subsequent amino acid, creating chains of amino acids. This is the birth of a protein.

A protein starts life in the cell as a long chain of, on average, 300 of these amino acids. There are 20 different types of amino acids—nine are called essential that we need to get from our diet and cannot be manufactured. The sequence and number of amino acids determines how the protein chain will fold upon itself once completed. Some proteins provide structure, others transport molecules, while others help cells to divide and grow. The function of a protein is dependent on their folding structure. It is an origami dictated by the sequences of amino acids and the length of the chain.[2]

Back to Alzheimer’s disease

The Amyloid Cascade hypothesis was first articulated in 1992 [3] and became enshrined in the guidelines published by the National Institute on Aging and Alzheimer’s Association (Jack et al., 2011).  The amyloid cascade hypothesis posits that the deposition of the amyloid-β peptide in the brain is a crucial step that ultimately leads to Alzheimer's disease. Amyloid-β peptide is a small protein called a beta (β) that has misfolded and became an amyloid. [4] Amyloid refers to how small proteins interact together by combining and forming a solid insoluble mass—they become hydrophobic, shy of water, because of how they fold. This type of interaction has its own designation as a disease called amyloidosis. These misfolded proteins combine together to create plaques of a million or so amyloid beta molecules. According to the National Institute on Aging and Alzheimer’s Association, these amyloid beta molecules grow until they interfere with the normal functioning of the brain. This is the cause of Alzheimer’s disease. And they have tested and substantiated this theory with mice models. But there is a problem.

The problem

The Amyloid Cascade hypothesis has not been supported by the data on humans. To date most of the treatments tested in human clinical trials are amyloid-β-based drugs, including those that remove amyloid-β. Despite the success of these drugs in removing the plaques from the brains of Alzheimer’s disease patients, the effect on behavior and thinking was negative.  [5]    Patients who had the misfolded proteins removes chemically did worse in tests than before the intervention. [6]

It seems that the clinical expression, the behavior, is not solely determined by increases in misfolded protein. A longitudinal study reported that eight percent of participants who behaved and acted free from dementia—when they died and had their brain examined—were found to have the most severe neuropathology. [7]  Despite having abundant and severe disease—neurofibrillary tangles and senile plaques—they had normal functioning.

Approximately half of clinically demented oldest-old have insufficient neuropathology to account for their dementia. [8]  While approximately thirty to fifty percent of older adults without dementia meet the neuropathological criteria for Alzheimer’s disease. [9]

The reality

The story of errors in making proteins which end up in the brain, as the cause of neurological disease, is incomplete. The repetitive story about the biology is also intentionally simplistic. In reality, science is still too naïve to understand the molecular biology of cells and therefore the biology of Alzheimer’s disease. Although geneticists play with genes and create amazing results, we still do not understand the fundamental nature of biology. And we cannot understand the biology of Alzheimer’s disease before we can understand the molecular biology of cells.

Scientists make simplified determination despite knowing only a very small proportion of the biology of cell functioning. We might have traced most of the dance moves, but we still do not know the music. That symphony that all our cells are all dancing to remains mute. With a complex choreography of steps there remains new ones to identify. We are missing the poetry because of the words, and we are missing the music because of the steps.

Each DNA sequence that contains instructions to make proteins is known as a gene. There are two variants of the same type of gene called alleles. Consider these as the paired dancers, with one being “dominant” over the other. There might be many (more than two) alleles for the same gene. How alleles communicate each other’s protein is unknown, especially how they communicate with alleles from a different gene. Unless we know the music of the dance, all that we can see is that there is communication and we can predict the outcome using a mathematical model. [10] However, prediction does not mean that we understand the mechanism.  

Another perplexity is that the size of a gene may vary greatly, ranging from about 1,000 individual nucleotides (bases) to 1 million bases. Genes that make protein—defined by unique start and stop codons—only make up about 1 percent of the DNA sequence. The rest is—we think—involved in the regulation. Around 99 percent of all genetic material is devoted to coordination.

Coordination of protein production—-how and how much of a protein is made; distribution, equilibrium and maintenance, including protection from viruses, bacteria, aberrant cells and malformations. This is the dance music and it seems that DNA is more invested in the music than the dance.

Regulation is the music of this dance that we see in protein synthesis. The transcription—DNA to RNA—and translation—RNA to protein synthesis—involves constant feedback, ensuring an equilibrium within the whole body. So far we are still mapping steps in the dance. It is a mystery how DNA self-polices itself, but it does. It edits code and monitors outcomes. [11]  For example in gene splicing, the initial messenger RNA is edited by removing introns--and joining exons together. And it does this as a dance. First it identifies the beginning and the end of the intron by its nucleotides. Small proteins (snRNPs), bind to these ends of the intron and forms a loop. The loop is then removed leaving the two remaining exons to link together. In addition to this method, there are alternate splicing methods which create many different variations from the same gene. In 2000 S. Lawrence Zipursky and his colleagues at the University of California, Los Angeles (UCLA) identified that this alternate splicing resulted in "one gene–many polypeptides." From one template (gene) there are multiple ways of generating different proteins. How this is done is a mystery. But we know it is not a simple mechanistic process. This is a rhapsody that constantly repeats itself 37 trillion times in each of our cells.

And looking at this fathomless universe, you have to wonder, where does this leave the Amyloid Cascade hypothesis? If the music becomes faulty, then the dance becomes erratic. And we can see this not in one or two steps, but in a series of steps across the body. 

Imbalance

Protein mis-folding is continuous and “normal.”  The ribosome which reads the DNA to make the proteins makes mistakes in as many as 1 in every 7 proteins.  The gene splicing seems variable. Proteins can misfold through other mechanisms. For example, one of the amino acid might be deformed and eventually effect the whole protein. Or the protein is formed perfect but the conditions inside the cell—e.g. temperature or acidity—make it fold unconventionally. Sometimes the misfold is a required fold.  Perhaps the gene itself is dictating a misfold. We have to be careful with this concept of misfold and errors. These are moral judgments.  Especially when some combination of misfolded proteins--amyloids--are naturally produced to carry out necessary functions in the body.

Neal Hammer with the University of Michigan Medical school, and his colleagues, [12] reviewed cases where the amyloid has been shown to be a necessary feature. The authors conclude that “Despite over twenty years of [Alzheimer’s disease] AD research the nature of the toxic species of Aβ has yet to be conclusively identified and little is known about how Aβ polypeptide aggregation begins in vivo.“

We still do not know for certainty how many proteins there are in the body. The Human Proteone Project has so far identified 30,057 proteins. [13]  This figure might be revised to 100,000 unique types of proteins in humans. We also do not know the full extent, how often, and the overall consequence of misfolded proteins.  Aβ can be formed from 18 inappropriately folded versions of proteins naturally present in the body. But there are many more misfolded proteins that we have already identified, more remain to be identified. [14]  One thing that we have learned from nature is that errors are the salvation to immortality. Humans are the product of errors and the immortality of genes relies on the continuation of errors. Perhaps we should refrain from judging nature too early in our knowledge.

Amyloidosis in Alzheimer's disease.

The problem, we are told, is that when proteins fold incorrectly some become amyloids. And this happens so frequently that it becomes a disease all by itself called Amyloidosis. This physical expressions of the disease is determined by the type of protein that is misfolded and the organ or tissue it resides in. [15]  By studying amyloidosis it is now believed that certain misfolded small proteins called “seeds” can induce other proteins to fold—known as the study of proteopathy.  This is exactly what happens with the prion misfolded protein which causes a cascade of prion disease— Creutzfeldt–Jakob disease disease in humans. As with music that orchestrates the dance, the wrong tune will cause multiple wrong steps, and they are related to the same sheet of music. So that, as an example, Alzheimer’s disease is related, both clinically and also statistically, with type 2 diabetes, both seen as diseases of amyloidosis.  The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolds. There is some evidence that misfolded Aβ can induce tau to misfold, although this might be a symbiotic relationship, one promotes the other.

So the question is why—if the National Institute on Aging and Alzheimer’s Association truly believe in the Amyloid Cascade hypothesis—are they not looking at all of these other diseases of amyloidosis together rather than in silos?

And we know the answer to that question already. [16]

The second question that follows is more fundamental. If all these diseases share a common process, if by addressing the known cause of one can we delay or stop the cause of a secondary disease? Perhaps then, a public health approach to Alzheimer’s disease is warranted. [17]

There is a third and more radical question. If these misfolded proteins are in fact there for a reason and not as a result of error, then what are they protecting us from?

Perhaps we do not know the underlying disease of Alzheimer's yet. There is increasing evidence suggesting that the large amyloid plaques are developed to protect. [18] And science is bearing this out. It could be that although the small misfolds are dangerous because they are small enough to interfere with the workings of synapsis—-by clamping together they become too big to interfere with the small synaptic transmissions. They are likely protecting the brain. Like a scab on a wound.

A research cul de sac might remain as long as we remain in our silos of research. We need to venture out and explore. “Man cannot discover new oceans unless he has the courage to lose sight of the shore.”―André Gide. We need such intellectual honesty to understand the complexity of Alzheimer’s disease and to dig ourselves out of this research cul de sac.

Citations

​[1] Bianconi, E., Piovesan, A., Facchin, F., Beraudi, A., Casadei, R., Frabetti, F., ... & Perez-Amodio, S. (2013). An estimation of the number of cells in the human body. Annals of human biology, 40(6), 463-471.

[2] . With two common structures called “alpha helices,” like a slinky and “beta sheets” like folded paper fan–α-helices have 21 amino acids while β-sheets have 30 amino acids. There are many other types of shapes and varying levels of complexity of the final structure.

[3] Hardy, J. A. & Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

[4] Peptides are small proteins consisting of 2 or more amino acids. Oligopeptides have 10 or fewer amino acids. Polypeptides are chains of 10 or more amino acids, while polypeptides having more than 50 amino acids are classified as proteins.

[5] Iqbal K., Liu, F. & Gong, C.X. (2014). Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochemical pharmacology, 88(4): 631-639.

[6] Boche D., Donald J., Love S., Harris S., Neal J.W., Holmes C., et al. (2010). Reduction of aggregated tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol, 120: 13–20.

Gilman S., Koller M., Black R.S., Jenkins L., Griffith S.G., Fox N.C, et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64:1553–62.

[7] as defined by Braak & Braak stages:

Snowdon D. (1997). Aging and Alzheimer's Disease: Lessons From the Nun Study. The Gerontologist, 37(2):150-156

Snowdon D.A. (2003).Healthy aging and dementia: findings from the Nun Study. Annals of Internal Medicine, 139(5,2): 450–454.

Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997;277:813-817.

[8] (Crystal et al 2000; Polvikoski et al 2001)

[9] (Crystal et al, 1988; Polvikoski et al, 2001; Katzman et al, 1988; Tomlinson, Blessed & Roth 1970; Dickson et al, 1997).

[10] Hardy-Weinberg principle

[11] Some of these are:

Antisense RNA—asRNA, piRNA, micRNA—inhibits translation of mRNA by physically obstructing the translation of some of the nucleoids, germ cell and stem cell development, sperm production, and epigenetic process.
Natural antisense transcripts (NATs) are regulatory RNA involved in interference and inhibit gene expression (RNAi), alternative splicing, genomic imprinting, and X-chromosome inactivation
Long and Short non-coding RNA—ncRNA— perform multiple tasks related non protein transcription for four-fifths of all genome. The FANTOM3 project identified ~35,000 non-coding transcripts from ~10,000 distinct loci.

There are also parasitic RNA that we inherited from other retroviruses (in most cases.) But the most interesting are those RNAs involved in post-transcription. The message within each mRNA is edited—known as gene splicing—by other types of RNA. How they know what to delete and edit is a mystery. There are also some RNA that modifies our DNA replication.  Not just through epigenetic switches—which does not change the DNA—but through modification of our DNA itself.

[12] Hammer, N. D., Wang, X., McGuffie, B. A., & Chapman, M. R. (2008). Amyloids: friend or foe?. Journal of Alzheimer's Disease, 13(4), 407-419.

[13] Kim et al. A draft map of the human proteome. 2014. Nature. 509, 575-581.

[14]  Misfolded proteins:

1.              ABri

2.              ADan

3.              Amyloid A protein

4.              Amyloid β peptide

5.              Apolipoprotein AI

6.              Apolipoprotein AII

7.              Apolipoprotein AIV

8.              Atrial natriuretic factor

9.              Beta-2 microglobulin

10.            Calcitonin

11.            Crystallins

12.            Cystatin C

13.            Fibrinogen

14.            Fused in sarcoma (FUS) protein

15.            Gelsolin

16.            Glial fibrillary acidic protein (GFAP)

17.            Immunoglobulin heavy chains

18.            Islet amyloid polypeptide (IAPP; amylin)

19.            Keratoepithelin

20.            Lysozyme

21.            Medin (lactadherin)

22.            Monoclonal immunoglobulin light chains

23.            Notch3

24.            Prion protein

25.            Prolactin

26.            Proteins with tandem glutamine expansions

27.            rhodopsin

28.            Seipin

29.            Serpins

30.            Superoxide dismutase,

31.            Tau protein

32.            TDP-43

33.            Transthyretin

34.            α-Synuclein

[15] Amyloidosis Disease:

Amyloidosis—systemic
Primary systemic amyloidosis
Ig heavy-chain-associated amyloidosis
Secondary (reactive) systemic amyloidosis
Senile systemic amyloidosis
Hemodialysis-related amyloidosis
Hereditary systemic ApoAI amyloidosis
Hereditary systemic ApoAII amyloidosis
Finnish hereditary amyloidosis
Hereditary lysozyme amyloidosis
Hereditary cystatin C amyloid angiopathy
Amyloidosis—localized
Injection-localized amyloidosis
Hereditary renal amyloidosis
Senile seminal vesicle amyloid
Familial subepithelial corneal amyloidosis
Cataract
Medullary thyroid carcinoma
Neurodegenerative diseases
Alzheimer’s disease
Parkinson’s disease
Lewy-body dementia
Huntington’s disease
Spongiform encephalopathies
Hereditary cerebral hemorrhage with amyloidosis
Amyotrophic lateral sclerosis
Familial British dementia
Familial Danish dementia
Familial amyloidotic polyneuropathy
Frontotemporal dementias
Other diseases
Diabetes mellitus
Atherosclerosis
Sickle cell anemia

[16] Garrett MD (2015) Politics of Anguish: How Alzheimer's disease become the malady of the 21st century. Createspace. USA

[17] Garrett MD, & Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9.

Garrett MD &Valle RJ (2016).A Methodological Critique of The National Institute of Aging and Alzheimer’s Association Guidelines for Alzheimer’s disease, Dementia and Mild Cognitive Impairment. Dementia: The International Journal of Social Research and Practice,15(2) 239–254. DOI: 10.1177/1471301214525166

[18]  D.M. Walsh, I. Klyubin, J.V. Fadeeva, et al.Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo Nature, 416 (2002), pp. 535–539

P.M. Douglas, S. Treusch, H.Y. Ren, et al. Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc Natl Acad Sci USA, 105 (2008), pp. 7206–7211

© USA Copyrighted 2016 Mario D. Garrett

Complexity Theory and Alzheimer's disease: A Call to Action

The brain of a healthy person is constantly changing. Neurons and glial cells constantly die and get replaced with new cells. More than 30,000 proteins constantly misfold and get degraded, they are cleared from the brain. Constant mini injuries to the brain are accommodated without change in capacity. Where memories are constantly re-imaged and prioritized. Where cognitive functions are shifted from one area of the brain to another. All of these events define the daily functioning of our brain. The question that needs to be asked is why does this ongoing maintenance stops or becomes overwhelmed?

The emerging conclusion—that Alzheimer’s disease is a syndrome—derives from a century of anomalies in research. The National Institute on Aging’s and Alzheimer’s Association  (NIA/AA) new guidelines, based on the Amyloid Cascade hypothesis (Jack et al, 2011) are incomplete. Emerging evidence is elaborating a more complex process. More than one cause, or type of causes, may result in similar or different outcomes. The initial injury might or might not progress.  The neurological disease might or might not affect cognition. The chorus of scientists voicing this approach to Alzheimer’s disease is unremitting. These valid criticisms remain shunned from NIA/AA new research agenda.

So far, after a century of confusion in studying Alzheimer’s disease, it is time to stop repeating the same mistakes in the hope of coming up with new results. We need a new methodology that might provide different results.  This new approach comes from Complexity Theory. Complexity Theory is an open theory—many variables, some known others still unknown influence the outcome. The utility of broadening the theory is to allow for a more inclusive approach that allows diverse literature to be included rather than to remain ignored. A simplified view of the brain states that by looking at individual components you can understand the whole machine--as with the Amyloid Cascade hypothesis (Hardy & Higgins, 1992). Such a mechanistic approach—that harks back to the 14th century—is too limited to explain a behavioral disease such as Alzheimer’s disease.

Such models are useful in generating hypotheses but limited in furthering our understanding of how the brain functions.  Especially because of non-linear effects, a large change might result in a small effect and a small change a large effect. We cannot predict what the effect will be. In strokes for example—where a blockage in the blood vessels destroys an area/s of the brain—we might find a large stroke resulting in little diminished capacity or a small stroke with debilitating results. We cannot predict the outcome with certainty even if we know the area of the trauma. Each stroke is unique, as is Alzheimer’s disease.

Within this theory, systems or units exist, seemingly independent from each other that nevertheless rely on each other, communicating directly within a hierarchy of networks. We know these networks exist because of the presence of hormones, neurotransmitters and cytokines mediated in the body by hundreds of different types of lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases (Mohamed et al, 2005; Clarke & Sperandio, 2005).  Additionally, the system changes and evolves.

A Complexity Theory would address these variances and how the body maintains these systems in balance—a balance that is unique for each individual. This homoeostasis is based on an internal set of regulators, defined by both past experiences and unique adaptive responses to new stimuli from the environment. The theory would also need to refrain from separating our beliefs, expectations, and behavior from the wider social, political, and cultural systems in which we exist. These units interact within the whole system in (as yet) unknown ways (Doidge, 2015; Merzenich, 2013). In such an open system, both established and new external forces can, and do, impinge on its internal activity. The best example of this is psychosomatic illness where although the disease is caused by the psychology of the person—psychogenic—the physical effects are real (Shorter, 2008).

Because Complexity Theory utilizes input from a variety of disciplines, it is necessarily transdisciplinary (Albrecht et al., 1998). It may help address the philosophical complexity exposed by postmodernist philosophy (Cilliers, 1998; Henrickson & McKelvey, 2002). Complexity theory addresses situations where linear cause and effect do not apply. Examples of such complex theories have been applied to biology, management, computer science, psychology, and other fields. In medicine, Complexity Theory has been applied to immunology (eg. Efroni, Harelb & Cohenb, 2005). Brown & Moon (2002) note that the new public health has “advocated a multi-causal approach that saw infectious and chronic, degenerative disorders as being the result of a complex interaction between biophysical, social or psychological factors.” (pp. 362–363.

The theory’s “complexity” is because it is composed of many parts (sub-units) that interconnect in known and unknown ways (Sussman, 1999) and intricate ways (Moses, 2006), where cause and effect are subtle and change over time (Senge, 2014).

In Alzheimer’s disease research, Complexity Theory might explain why many causes may exist although the disease is expressed uniformly. It might also be that depending on where you are in your lifespan, the disease expresses itself differently, evolving across time (Coveney & Highfield, 1995). Complexity Theory attempt to reconcile the unpredictability of different systems—in this case, areas of the brain interact together in ways as yet unknown—with a sense of underlying order and structure (Levy, 2000). Complexity Theory can be the foundation for understanding all types of Alzheimer’s disease. It can easily be adapted to anomalies in research in a way that makes the theory predict outcomes. At the same time, the theory must be able to explain existing anomalies.

How does a theory of Alzheimer’s disease deal with such confounders? Under Complexity Theory these processes are inclusive, and can be mediated and moderated by other variables. For example, Alzheimer’s disease can be mediated by protecting against injuries (e.g. head injuries, toxicity, radiation). It might also be mediated by maintaining a healthy lifestyle (and the effect this has on supplying the brain with oxygen—cerebral perfusion), or eating a healthy balanced and varied diet that provides all the nutrients and bacterial flora that we require at older ages (Bredesen, 2014). While a century of work has looked at how plasticity, neurogenesis and capacity can delay or protect against Alzheimer’s disease. All these factors—injury, penumbra, perfusion, plasticity—become important processes and sub-units in discussing the etiology of the disease under a Complexity Theory.

But perhaps we are not the first to request this: ”….demonstrate to us in an impressive way how difficult it is to define disease solely with respect to their clinical features, especially in the case of those mental disorders which are caused by an organic disease process. (Alzheimer, 1912, p)  Fox, Freeborough & Rossor (1996) conclude by saying that “…no clear cut distinction exists between senile Alzheimer’s disease and normal aging as far as the clinical and anatomo-pathological elements are concerned” (p. 146). If this is true then we are back to square one with Alzheimer’s disease. It is a disease of old age.

Reference.

Garrett MD (2015). Politics of Anguish: How Alzheimer’s disease become the malady of the 21st century. http://www.amazon.com/Politics-Anguish-Alzheimers-disease-century/dp/1518892930

© USA Copyrighted 2016 Mario D. Garrett

Piaget's Missing Cognitive Stage: Socioemotional Selectivity in Older Adulthood

The Swiss psychologist Jean Piaget is a most prolific renaissance man, publishing in biology, psychology, morality, language and philosophy. His lasting legacy has however been his identification and definition of stages in children’s thinking. Each stage is marked by shifts in our understanding of the world, as though our brain clicks into a different qualitative mode of processing information. We cannot learn a specific concept if our mind has not yet developed the capacity to understand it. A theory "so simple only a genius could have thought of it" according to Albert Einstein. The same concept applies to animals, in that their brain is “intelligent’ enough to represent the world they live in to enable them to survive and prosper. The same constrains exist among humans as they develop. Piaget termed this as Genetic Epistemology; how we learn about our environment.

The stages include sensorimotor (up to age 2) preoperational (2-7) operational stage (7-11) formal operational (11+). These stages move us from learning about the environment by touching and moving objects through it, to the development of language where we begin to apply symbolism and acquiring the concept of an ideal world. From this stage we start making rational judgments about concrete or observable phenomena using language to manipulate symbols. At the last stage we develop hypothetical and deductive reasoning. Increasingly more complex processes are incrementally added to the previous stages established in earlier stages of our development.

The model that we build in our mind is similar to how scientists organize the world in terms of classes of objects or schemas.  Improving upon existing schemas through a process of logical assimilations or by changing the schema through accommodation this process aims for equilibrium--what Piaget terms “equilibration.”  The beauty of this type of thinking is that intelligence is a reflection of an active process. Our brain is forming a model of the outside world that helps us understand and predict the world. And there are specific developmental stages in how we do this.

But Piaget stopped at young adulthood and he stopped at the cognitive. In a world of “hypercognitive snobbery”—where cognition is prized above other equally valuable aspects of being identified in 2006 by Stephen Post p.223—we assume that thinking is the ultimate, but cognition is not comprehensive enough to explain our world. We also have an emotional component in living, perhaps more important, but surely as important.

As with the current thinking at the turn of the 20th century, “old age” was seen as a decline from a peak of early adulthood. Piaget, following this prejudice, did not think that much happens after attaining formal operational stage. But he was wrong.

There is, at least, another stage of reasoning that we can also identify.  The late Fredda Blanchard-Field with the Georgia Institute of technology promoted a stage of emotional development for older adults. What has developed into the socioemotional selectivity theory, this theory argues that we become more intelligent and mature about how we feel, where we select to remember positive experiences above negative ones. Pruning our social circles of friends or acquaintances and learning to let go of loss and disappointments are the external expression of this stage in thinking. But there is more. Our brain is wired so that the older we get the more that we focus and remember positive events while forgetting negative ones.

Psychologists Laura Carstensen—director of the Stanford Center on Longevity—and Charles Mather—with the University of California Santa Cruz—reported on neural mechanism that might be responsible for this selection of positive emotions. They identified cases where the amygdala—a small almond sized structure deep within the two sides of the brain—seems to be activated differently by younger versus older adults. Younger adults activate this structure more for negative images while older adults had higher activation for positive images.

But this did not explain why older adults remembered positive experiences better. It took a New Zealand psychologist Donna Addis and her colleagues to identify a possible mechanism. They asked young and older adults to view a series of photographs with positive and negative themes while recording their brain activity (fMRI). They found that in older adult brains, two regions that are linked to the processing of emotional content were strongly connected to regions that are linked to memory formation. Suggesting that older adults remember the good times well because the brain regions that process positive emotions also process memory.

Older adults experience an increase in positive thoughts and feelings, along with a decrease in negative emotions like anger and frustration. Living longer makes you remember positive emotions better because we are engineered that way—Genetic Epistemology. Like Piaget’s stages of cognitive development, this socioemotional stage involves a qualitative difference in how we process our environment.  Reclaiming older adulthood as a unique stage in our development—rather than seeing older age simply as a decline—dictates that we assign this socioemotional selectivity stage on equal basis with the other stages of development. We cannot learn a specific concept if our mind has not yet developed the capacity to understand it. We need to mature to learn how to interpret emotional reality.

References.

Isaacowitz, DM & Blanchard-Fields, F. (2012). Linking Process and Outcome in the Study of Emotion and Aging. Perspectives on Psychological Science, 7(1), 3-17

Piaget, J. (1970). Genetic Epistemology. New York: Norton.

Piaget, J. (1977). Gruber, H.E.; Voneche, J.J. eds. The essential Piaget. New York: Basic Books.

Piaget, J. (1983). Piaget's theory. In P. Mussen (ed). Handbook of Child Psychology. 4th edition. Vol. 1. New York: Wiley.

Post, SG. (2006). Respectare: Moral respect for the lives of the deeply forgetful. In J. C. Hughes, S. J. Louw, & S. R. Sabat (Eds.), Dementia: Mind, meaning, and the person (pp. 223–234). Oxford: Oxford University Press.

© USA Copyrighted 2016 Mario D. Garrett

The Fallacy of the Epidemiological Transition

​History dictates that with a changing population structure there is a parallel mirror process affecting health. The theory behind population change is called the demographic transition, while the historical change in mortality is called the epidemiological transition [1].   Epidemiological transition piggybacks on an established mathematical theory that argues that populations go through a cycle of high death and high birth rate, followed by declining death rate and declining birth rate.  Finally reaching a stage characterized by very low birth rate and low but fluctuating death rate.  The epidemiological transition posits that throughout this cycle mortality changes from infectious diseases to chronic disease. Finally reaching a stage of delayed chronic diseases. Unlike the distinct definitions of fertility and death rate that determine the demographic transition, the cut-off between an infectious disease and a chronic disease has become blurred.

In the United States, according to the Centers for Disease Control and Prevention (USA-CDC) more than seventy percent of all deaths are due to chronic diseases [2] .  Chronic diseases are characterized by Alzheimer’s disease, heart disease, diabetes and cancer. Since the causes of chronic disease was argued to be a combination of genetic, environmental, or lifestyle factors, public health was relegated as unimportant in dealing with chronic diseases. Public health is something that concerns only developing countries, until this year.

When an accountant managed water quality in Flint, Michigan, we very quickly saw a public health disaster enfold. Resulting in tainted water that marred the lives of a countless number of children for the rest of their lives. We created a chronic problem from a public health disaster.  So perhaps we need to revisit the epidemiological transition, since infectious diseases might also contribute to chronic diseases.  Especially since we are finding that chronic disease may apparently be infectious after all. If we can show that chronic diseases are infectious then the epidemiological transition becomes irrelevant.

An increasing number of chronic diseases are coming under scrutiny as possibly caused by infections. There are multiple examples to support the view that chronic diseases are in fact infectious diseases with a delayed expression. However, the search for bacterial, viruses, or environmental toxicity causes is difficult. Primary difficulty lies in detecting and replicating the causative agents in the laboratory. In most cases there are lags between the infection and the expression of the disease. Sometimes by the time the symptoms of the chronic disease appear, the causative agent is no longer present. But there are already strong signs that the three main chronic diseases have elements of infections: Alzheimer’s disease, cancer and heart disease.

Alzheimer’s disease

The initial infection that starts Alzheimer’s disease is unknown. As a chronic disease most of the research focuses on genetic mechanisms. But there is growing evidence that other, more relevant mechanisms exist, especially if we look at Alzheimer’s disease as a public health concern. These mechanism are: viral (HIV/AIDS, herpes simplex virus type I, Varicella zoster virus, cytomegalovirus, Epstein-Barr virus), bacteria (syphilis and Lyme-disease/borrelia), parasites (toxoplasmosis, cryptococcosis and neurocysticercosis), behavior (Alcohol, cigarette smoking, recreational drugs, concussion/mild/severe brain trauma) environmental elements (possibly aluminum), infections (possibly prions such as in Cretchfeldt-Jakobs disease), vascular causes (stroke, multiple-infarct dementia hydrocephalus, and injury or brain tumors, and emotional trauma. There are numerous studies that correlate all of these factors with Alzheimer’s disease, but surprisingly none of these factors appear in the federal “guidelines” for Alzheimer’s disease. [3]

As an example of the likely bacterium connection to Alzheimer’s is Lyme disease. Alois Alzheimer—who identified the disease in 1907—was primarily interested in syphilis. For centuries, other than just old age, syphilis was the main and only known cause of dementia. Although neurosyphilis is rare today, another bacterium gaining interest is Lyme disease. Lyme dementia has become a greater concern because it is the most common vector-borne disease in the northern hemisphere. Since there is no cure the expectation is that more patients will develop Lyme dementia in the near future [4].

Cancer

Other example where an infectious or an environmental substance contributes to chronic diseases is cancer. Viral causes of cancer are common enough that we call viruses that can cause cancer an oncovirus. These include human papillomavirus (cervical carcinoma), Epstein-Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leukemia virus-1 (T-cell leukemias).

Bacterial infection may also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma. Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma.)

The human papillomavirus, for instance, causes more than 90 percent of cervical cancer cases and is one of the most common cancers in the world especially in Asia. With childhood immunization programs, including the hepatitis B vaccine, this cancer will become less prevalent. Hepatitis C virus causes cirrhosis, end-stage liver disease, and liver cancer. Human herpesvirus 8 causes Kaposi’s sarcoma, a malignant complication of AIDS. Helicobacter pylori, a spiral-shaped bacterium, is the agent of peptic ulcers and gastric cancer and has an important  story of resistance, although not biologically but politically.

In 2005, two Australians, Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology for their pioneering work identifying the bacterium Helicobacter pylori as the cause of peptic ulcer disease. Overnight peptic ulcer disease was no longer a chronic disease but an infectious disease that can be cured by a short regimen of a pair of antibiotics. But despite evidence, it took more than ten years to persuade the scientific community. At the end, it took the primary author, Barry Marshall to infect himself with the bacteria to prove his point to a disbelieving scientific community. The long held view that peptic ulcer disease was a chronic disease wrestled against any competing views that it might be infectious.

Heart Disease

The relationship between heart disease and bacteria/virus is still sparse and interpretation of results is limited by potential biases. A large number of studies have reported on associations of human coronary heart disease and certain persistent bacterial and viral infections. One concluded that the relationship of heart disease with H pylori is weak, while for C pneumoniae, the evidence of association is stronger but still uncertain  [5].  Endocarditis is a disease characterized by inflammation or infection of the inner surface of the heart usually caused by a bacterial infection from the mouth that enters the heart.

And there are already evidence for the efficacy of an approach that looks at chronic disease as caused by infections. At the 2016 annual meeting of the American Association for the Advancement of Science, Stanley Riddell with Seattle's Fred Hutchinson Cancer Research Center, announced how T-cell therapy can help the human immune system fight off cancer cells the way it would attack foreign bacteria or a virus. This finding joins the arsenal of some vaccines to prevent cancer.

Such associations have been difficult to expose because the path from exposure of an infection to the expression of the chronic disease is usually not linear. There are other mediating or/and moderating factors. For example, the role of infection mediated through chronic inflammation is then associated with a variety of chronic diseases such as multiple sclerosis, rheumatoid arthritis, lupus, and other autoimmune diseases. But the pharmaceutical industry, despite their advantage at being able to “cure” chronic disease has been reticent in accepting the full force of this implication. It is not a clever economic strategy to cure diseases, only to manage them.

What we need is a broader approach to look at cancer, heart disease and Alzheimer’s disease more as a public health concern. Looking at chronic disease as a long-term assault from an external agent, whether this agent is a bacterium, virus or some toxic element. By re-addressing our priorities in research, perhaps this is the way out of this research cul-de-sac we find ourselves in. It is such radical thinking that is needed to hopefully start finding cures that have evaded us so far.

References

[1]   Omran, A.R (2005. First published 1971), "The epidemiological transition: A theory of the epidemiology of population change" The Milbank Quarterly 83 (4): 731–57, doi:10.1111/j.1468-0009.2005.00398.x

[2]  Centers for Disease Control and Prevention. Death and Mortality. NCHS FastStats Web site. http://www.cdc.gov/nchs/fastats/deaths.htm. Accessed December 20, 2013.

[3] Garrett MD, Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9.

[4] Blanc F,Philippi N,Cretin B,Kleitz C,Berly L,Jung B,de Seze J. Lyme Neuroborreliosis and Dementia. Journal of Alzheimer’s Disease 2014; 41(4):1087-1093.

[5] Danesh, J., Collins, R., & Peto, R. (1997). Chronic infections and coronary heart disease: is there a link?. The lancet, 350(9075), 430-436.

© USA Copyrighted 2016 Mario D. Garrett

A New Paradigm for Alzheimer's Disease Research

From lost hope emerges a new perspective. After more than a century of research into Alzheimer’s disease we have reached a research cul-de-sac. By eradicating the plaques and tangles from the brain, a series of studies reported that the disease worsened ^1,2. What this tells us is that the disease is more complex then just a build up of mis-folded proteins.

In panic, the National Institute on Aging, coopting the Alzheimer’s Association, published new guidelines for Alzheimer’s disease in 2011.³  These guidelines effectively transformed a clinical disease--a disease defined by its behavioral manifestations—into a pre-clinical disease. What this means is that now Alzheimer’s disease exists before there are any clinical manifestations. This seems counterintuitive given the studies showing that drugs that cleared the plaques and tangles—the only pre-clinical indicators--did not cure Alzheimer’s disease and in fact made it worse. But the increasing power of the pharmacological industry in establishing the research agenda seems limitless. Now pharmaceutical companies can experiment with patients before they even start showing symptoms of the disease. In effect, curing a disease before the clinical disease emerges. But so far, they have had little success. 

Since the early 1990 pharmaceutical companies have been attempting to halt early onset dementia among an unfortunate community in Medellin, Colombia. Discovered by Francisco Lopera in 1984, this heritable variant of Alzheimer's disease share a common ancestor—a 16th-century Spanish colonist who to this day has infected 5,000 patients in 25 families. ⁴  The reason why this approach—trying to find a biological cause of the disease--has been so resilient despite mounting evidence contradicting this approach, is that there has not been a competing theory to challenge it. Until now.

A crescendo of mounting criticism has established that Alzheimer’s disease is more complex than a cascade of misfolded proteins. That even though people might have the plaques and tangles, some do not express the disease, while some who express Alzheimer’s disease have been shown to have no significant plaques and tangles. In addition, with older adults, multiple studies have shown that the correlation between plaques and tangles and Alzheimer’s disease declines with age. One way to explain these anomalies is to broaden the study of Alzheimer’s disease. One such approach is to see it as a public health disease. ⁵

A public health perspective argues that there are multiple traumas to the brain. Some of these can be a virus or bacteria, while some are physical (like a concussion). We are seeing more and more how physical trauma causes dementia among NFL football players. But sometimes this trauma is managed and contained. A good example of this process is looking at stroke victims where we see more than 30 percent improving. In such cases, the penumbra—the protective cells that surround the initial trauma—is contained and the death of cells remains localized. Two factors promote this healthy brain. One is blood supply—Perfusion, while the other is growing your brain--Plasticity.

Perfusion allows for the brain to receive adequate nutrients and energy to heal itself. Having a healthy brain improves the chances that a trauma is contained. Plasticity on the other hand ensures that there is enough flexibility in the brain that if the brain needs to contain an area that other parts can take over that lost function. Without these two factors the penumbra will continue to grow and affect larger areas of the brain—and such damage will go beyond plaques and tangles. This broader public health interpretation of Alzheimer’s disease assimilates both the traditional Amyloid Cascade hypothesis and explains the increasing number of studies showing how external factor influence the incidence of Alzheimer’s disease.

The beauty of this public health approach is that we do not have to wait another hundred years before we realize that we are in a research cul-de-sac. We can start implementing programs that reduce and lower the exposure to traumas. Reduction of concussions (in sport, military, recreational activities) should be made a priority. Programs that educate on the effects of smoking and heavy drinking on the brain need to be promoted, as well as programs that address environmental toxicity both in the air and in our water. For perfusion, city walkability programs, and social engagement programs all promote walking, swimming, light exercise, gardening among other activities. While improving plasticity involves social activities, dancing, music and other cognitive exercises.

Pharmaceutical influence can determine federal research policy, but with knowledge, individuals can protect themselves and their family from exposure to this deadly disease that we still do not fully understand.

A version of this article can be found in:

Garrett MD & Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9. Page 2 of 9.

A complete story of this blog can be found in my recently published book: 

Garrett MD (2015).The Politics of Anguish: How Alzheimer’s disease became the malady of the 21st century.

References.

1. Gilman S., Koller M., Black R.S., Jenkins L., Griffith S.G., Fox N.C, et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64:1553–62.

2. Boche D., Donald J., Love S., Harris S., Neal J.W., Holmes C., et al. (2010). Reduction of aggregated tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol, 120: 13–20.

3. Jack  C.R., Albert M.S., Knopman D.S., McKhann G.M. Sperling R.A., Carrillo M.C., ... & Phelps C. H. (2011). Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia, 7(3):257-262.

4. Lopera F., Ardilla A., Martínez A., Madrigal L., Arango-Viana J.C., Lemere C.A., ... & Kosik K.S. (1997). Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. Jama, 277(10): 793-799.

5. Garrett MD & Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9. Page 2 of 9

© USA Copyrighted 2016 Mario D. Garrett