Proposed Causes and Treatment of Primary Progressive Aphasia (PPA)
Dennis N. Crouse
February 16, 2021
Primary Progressive Aphasia (PPA) is a type of neurodegenerative condition that symptomatically is a slow deterioration of language ability (i.e., aphasia). PPA is associated with other neurodegenerative diseases such as Alzheimer’s (i.e., 1/3 of PPA cases) and frontotemporal lobar degeneration (i.e., 2/3 of PPA cases). PPA is therefore called a neurological syndrome.
The primary symptom of PPA is slowly progressing aphasia occurring as the dominate feature and lasting for at least the first two years of the disease. The first symptoms of PPA are declining speech and language capability followed later by memory loss manifesting itself as difficulty with word finding and object identification (i.e., anomia) and in many cases, finally progressing to a nearly total inability to speak (i.e., mutism). PPA is slowly progressive unlike other forms of aphasia that arise suddenly from stroke or brain injury. PPA is also unlike Alzheimer’s disease as PPA patients have aphasia as the dominant symptom before memory loss and can take care of themselves, maintain their daily living skills, and even remain employed.
Bird Watching as a Test for PPA
In later life I have resumed the hobby of bird watching that I first began in my early teens. Warblers are my favorite group of birds as they can be easily identified by their plumage and nuanced songs. The art of being a successful warbler watcher hinges on the ability to spot the bird either visually and/or audibly (i.e., sensory processing), identify the name of the warbler from a memorized lexicon of key features (i.e., semantic processing), and finally call out the name of the warbler to others (i.e., articulation). In my teens this three-step process could be carried out in less than a second. But as I have grown older it has been slowed by what is called a “tip-of-tongue delay” caused by temporary anomia. If this delay becomes progressively longer and more frequent over a two-year period it could be a symptom of PPA.
Brain Atrophy as a Causal Factor of PPA
Brain atrophy (e.g., cortical thinning) of specific areas of the brain is correlated with different symptomology in both patients with PPA and language variants of frontotemporal lobar degeneration (FTLD) as shown in table 11,2.
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Table 1. Variants of PPA and FTLD, Symptoms, and Location of Brain Atrophy1,2 |
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|
PPA Variant |
Primary Symptom |
Location of Brain Atrophy |
|
Agrammatical (PNFA) |
Effortful and Halting Speech |
Left inf. frontal lobe & ins. cortex |
|
Semantic (SemD) |
Anomia |
Bilaterally in ant. temporal lobes |
|
Logopenic |
Impaired Single Word Retrieval |
Left pos. temporal & parietal lobes |
PNFA = Progressive Nonfluent Aphasia; SemD = Semantic Dementia; inf. = inferior; ins. = insular; ant. = anterior; pos. = posterior
As PPA or language variants of FTLD progress, brain atrophy extends to other lobes of the brain following a distinct pattern that depends upon the variant2. Brain atrophy is also a characteristic of AD, with brain atrophy observed in the frontal and entorhinal cortexes and hippocampus3.
Brain atrophy in AD is due to the programmed death of neurons during what is called neuronal cell cycle events (CCEs)4. The cause of this programmed death is a cytokine modulated cascade that starts with a xenobiotic chemical or pathogen infecting the brain and causing inflammation. Tumor necrosis factor (TNF-alpha) is the primary cytokine responsible for CCEs4. TNF-alpha is a cytokine released by both some white blood cells, called macrophages, and microglial cells in the brain to alert the immune system of an infective agent, such as a toxic metal or pathogen, and induce the process of inflammation.
Higher than normal levels of microglial derived TNF-alpha may play a central role in pathogenesis of Alzheimer’s disease4,5, late stage dementia6, and have been documented in the cerebrospinal fluid of patients with frontotemporal dementia7. Therefore, because PPA is associated with both Alzheimer’s and frontotemporal dementia, excess TNF-alpha is also likely involved with brain atrophy observed in PPA1,2.
Blood-Brain Barrier as the Brain’s Leaky Roof
The blood-brain barrier acts as a protective roof over the brain to keep environmental factors, such as toxic metals and pathogens, from leaking into the brain. This roof becomes leaky due to chemically or physically induced trauma(s). Chemical trauma includes environmental toxins and oxygen deprivation (i.e., hypoxia) caused by stroke or white matter hyperintensities. Physical trauma includes traumatic brain injury due to a blow to the head. Leaks are sporadic and result in localized brain atrophy due to chronic exposure to leaking toxins.
Aluminum Induces TNF-alpha Expression
TNF-alpha is deadly to neurons because with the enzyme JNK a self-amplifying loop is created that induces the generation of reactive oxygen species (ROS) that kills neurons8. Toxic metals also induce the production of reactive oxygen species (ROS) in microglial cells of the brain that can kill neurons. The metal that tops the list for ROS production in microglial cells is aluminum as shown in table 29.
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Table 2 - Metal Ion Induction of ROS in Human Microglial Cells9 |
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|
Metal Sulfate |
Relative Induction of ROS |
|
Aluminum |
10 |
|
Iron |
6 |
|
Manganese |
4.5 |
|
Zinc |
4 |
|
Nickel |
3.5 |
|
Lead |
3.5 |
|
Gallium |
3 |
|
Copper |
3 |
|
Cadmium |
3 |
|
Tin |
2 |
|
Mercury |
1.5 |
|
Magnesium |
0 |
|
Sodium |
0 |
In 1999 it was discovered that aluminum in drinking water (i.e., 0, 5, 25, and 125ppm) for one month enhances the expression of TNF-alpha in mice in a dose-dependent manner .This increased expression due to aluminum was only observed in the cerebrum not in peripheral cells suggesting that microglial cells were the source of increased TNF-alpha10. Five years later in 2004 this discovery was duplicated by another group. Aluminum lactate in drinking water (i.e., 0.27, 2.7, and 27ppm of aluminum) for 10 weeks up-regulated TNF-alpha expression, and enhanced reactive microglia in the striatum of mice11. Therefore, aluminum induces the production of TNF-alpha and ROS resulting in a deadly cocktail for neurons causing PPA, AD, and frontotemporal lobar degeneration.
Aluminum Induces Brain Atrophy in AD
Aluminum hotspots in the AD brain were first observed in 197312. Aluminum hotspots in the brain are dependent upon where aluminum leakage across the blood-brain-barrier occurs. The location of these hotspots can be random making PPA, AD, and frontotemporal lobar degeneration all primarily sporadic diseases. The sporadic location of aluminum hotspots can account for the variability in symptoms and disease diagnosis of PPA as shown in table 1. Likewise, the locations of aluminum hotspots coincide with the locations of brain atrophy in AD as shown in tables 3 and 43,13.
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Table 3. Brain Atrophy in Humans with AD and Non-demented Controls During 1 Year3 |
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Regions of Brain Analyzed |
AD Longitudinal % Change |
Controls Longitudinal % Change |
|
Entorhinal Cortex |
-2.42 |
-0.55 |
|
Hippocampus |
-3.75 |
-0.84 |
|
Frontal Cortex (caudal) |
-1.60 |
-0.40 |
|
Frontal Cortex (ventral) |
-1.06 |
-0.38 |
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Table 4. Brain Aluminum in Humans with AD and Non-demented Controls13 |
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|
Regions of Brain Analyzed |
AD (Al mcg/g of brain tissue) |
Controls (Al mcg/g brain tissue) |
|
Entorhinal Cortex |
10.2 + 9.0 |
1.5 + 0.6 |
|
Hippocampus |
4.9 + 3.0 |
1.4 + 0.6 |
|
Frontal Cortex (caudal) |
6.8 + 4.3 |
1.8 + 0.6 |
|
Frontal Cortex (basal/ventral) |
6.4 + 2.9 |
2.5 + 0.7 |
Autopsy and analysis of 242 brains of people diagnosed with AD, as reported in six studies, have revealed that in all cases AD brains have higher than normal levels of aluminum13,14,15-18. Autopsy and analysis of brains from people with early13,14,18 or late onset AD13,14,15-17 and with familial15,16, sporadic13,14,17 or occupational AD18 all had higher than normal levels of aluminum. Because of the role played by aluminum in brain atrophy, it could be theorized that it may also play a role in PPA and frontotemporal dementia. However, there are no studies of aluminum in the brains of patients who had been diagnosed with either frontotemporal dementia or PPA prior to death.
Synaptic Loss in PPA
The loss of synapses in neurodegenerative diseases, such as AD, is better correlated with cognitive decline than is neuronal loss19,20. Synaptic loss impairs the ability of neurons to communicate and underlies the cognitive deficits seen in those with PPA21. This loss of synapses was observed in Broca’s area of the brain in a patient with PPA21. Impaired cortical synaptic connections in the part of Broca’s area with synaptic loss could account for the symptoms of PPA seen in the patient21.
The loss of synapses (e.g., synaptic integrity) is correlated with the loss of synaptophysin, a major synaptic vesical protein. The pathological severity of AD is negatively correlated with the amount of synaptophysin mRNA in temporal cortex neurons22. In addition, the amount of synaptophysin was reduced by 30% of normal levels in the prefrontal cortex of those with severe AD23,24. Synaptic vesicle formation in vitro and therefore the amount of synaptophysin at synapses is inhibited by aluminum fluoride commonly found in fluoridated drinking water25.
Therefore, aluminum not only causes the loss of neurons but also aluminum bonded to fluoride causes the loss of synapses by inhibiting synaptic vesicle formation as seen in those with PPA21,25.
Treatment of PPA
Because of the role played by TNF-alpha in brain atrophy, it has been suggested that TNF-alpha inhibitors, such as Etanercept, could be used to treat PPA26,27 and Alzheimer’s disease28. Although published results in 2008 looked good on the basis of a single case of PPA26, there has not been a published duplication of this case study on a larger number of PPA cases with controls.
Aluminum accumulation in the brains of those with
PPA could be targeted for detox with orthosilicic acid (OSA) in drinking water29.
There are no published studies of OSA treatment of patients with PPA. However,
OSA in drinking water has been shown to improve cognition in some AD patients
and has been shown to remove aluminum from the brains of rats30-32.
In addition, drinking OSA rich water is correlated with a lower risk of AD as
shown in an epidemiological study33.
Conclusion
Primary Progressive Aphasia (PPA) is a neurological syndrome associated with either Alzheimer’s disease (AD) or frontotemporal lobar degeneration (FTLD). Neuronal and synapse atrophy, along with higher-than-normal levels of the cytokine tumor necrosis factor (TNF-alpha), has been observed in patients with PPA, AD and FTLD symptoms. Aluminum in drinking water enhances the expression of TNF-alpha in mice and is a putative causative factor of AD. Both aluminum and TNF-alpha are associated with increased ROS generation in glial cells of the brain that can result in neuronal and synapse atrophy. Since orthosilicic acid (OSA) in drinking water facilitates the removal of aluminum in rat brains and can improve cognition in AD patients, it is hypothesized that OSA in drinking water can also decrease symptomology in PPA patients.
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