Abstract
Alzheimer’s disease (AD) is the number one neurological disease in America and is the most common form of dementia. The side effects of this disease are devastating to the patient, the family and the community where they reside. This paper investigates 3 new treatments for AD, TMS with cognitive training, deep brain stimulation, and insulin therapy. All show signs of slowing the progression of AD but insulin therapy has the most promise because it is non-invasive, has better results and less time consuming than the other therapies.
Alzheimer’s Disease from a Neurological Perspective
Alzheimer’s disease (AD) is the number one neurological disease in America and is the most common form of dementia. (“Changing the trajectory of Alzheimer’s disease; A national imperative,” 2011) The side effects of this disease are devastating to the patient, the family and the community where they reside. Alzheimer’s disease robs the patient of their memory, identity, initiative, judgment, mood regulation, higher cognitive function and language and replaces it with paranoia, confusion, embarrassment, mood disruptions and fixations. It is idiopathic and terminal, meaning there is no known cause or cure. (Nordeen, 2004) It is the sixth leading cause of death in the country. (“Changing the trajectory of Alzheimer’s disease; A national imparative”) From onset to death is roughly 14 years, this lengthy decline is where the disease’s nick name “the long goodbye” is derived. (Ballenger, 2006) Current treatments for this disease, typically medications designed to replace neurotransmitter loss, are useless as a cure and do not slow its progression. This paper will investigate new treatments for AD from a neurological perspective through first, setting the background by delineating the changes in the brain and then, presenting three studies that move AD research forward.
The changes in a brain with AD are defined by significant neuron loss throughout the brain however; it is most prominent in a few areas. The first areas to degenerate are the entorhinal cortex and the hippocampus. Loss in these areas results in disturbances in learning and memory, consolidation of memory during sleep, and short term, episodic and declarative memory. (Nordeen, 2004) The neocortex, the highest functioning and latest to evolve undergoes massive neuron loss. This deficit is marked by faulty judgment, changes in the brain’s ability to process information, loss of long term memory, and decreased initiative. Significant neuron loss in the amygdala inhibits processing of emotional content and information. (Nordeen)
The next three nuclei discussed are unique in that they use neurotransmitters to project to the cortex without the customary relay through the thalamus. Nucleus basalis of meynert in the reticular formation uses acetylcholine to project directly to the cortex. In every case that this nucleus is damaged some form of dementia results. (Nordeen, 2004) The nucleus locus coeruleus, often called the blue nucleus is located in the pons. This nucleus also uses neurotrasmitters, in this case norepinephrine, to project directly to the cortex. Degeneration within this nucleus effects the regulation of blood flow to the brain, the extraction of oxygen and glucose in the brain, selective attention regulation, and regulation of sleep, wake cycles. (Nordeen)The raphe nuclei serotonergically projects to the cortex. This is the cell group that antidepressants target because it is critical in the regulation of mood. Loss in this area would impair the brain’s ability to govern disposition.
Other hallmarks of this disease are widespread neurofibrillary tangles and plaques. Neurofibrillary tangles are abnormal filaments that form within the neuron destroying it. Plaque forms in the extracellular space using β amyloid. (Nordeen, 2004) This mass of plaque damage and destroy adjacent neurons. Glial cells respond to the invasion by surrounding the plaque thereby, adding to the mass of it, further damaging the contiguous neurons. An expected result of the massive neuron destruction is the loss of the dendrites and synapses associated with them. It is estimated that 100,000 are lost per day. (Nordeen)
Another byproduct of β amyloid is abnormal deposition of the blood vessels in the brain. Amyloid destroys the blood vessel walls eventually causing a brain hemorrhage. This is the most common cause of death for AD patients. (Nordeen, 2004)
Finally, AD breaks down the blood brain barrier, one of the body’s most unique defenses. This allows toxins and metals such as aluminum to be deposited in the brain, further breaking down and destroying neurons. (Nordeen, 2004)
To summarize, the massive neuron loss caused by AD produces widespread dysfunction in learning, memory, behavior, executive function, and language. Alzheimer’s is idiopathic and terminal. Current treatments fall woefully short to slow the progression of this disease.
Transcranial magnetic stimulation (TMS) combined with cognitive training (Bentwich, Dobronevsky, Aichenbaum, Shorer, & Peretz, 2011)
The theory for this pilot study is based on brain plasticity, specifically, long term potentiation. By alternately stimulating the brain with TMS and cognitive training repeatedly over 4 ½ months, the researchers hoped to strengthen the neuronal connections in the cortex. The newly reinforced connections would then result in long term higher cognitive function. Either TMS or cognitive training is currently used with some success for the treatment of AD. This is the first study in which both are employed. The idea being, where one is good, two is better.
TMS is also used with some success in the treatment of Parkinson’s disease, depression, mania, OCD and PTSD. It has also been linked to improvements in executive function and learning and memory. The fact that it is noninvasive, painless, and has no known side effects endears it to participants and researchers alike.
Participants had to have a probable diagnosis of early to moderate AD, an MMSE score of 18-24, a clinical dementia score of 1, and a caregiver, to be included in this study. Conversely, some exclusionary items were alcohol or drug abuse, mentally instability, being uncooperative, severe agitation, or if they had medical condition such as epilepsy. Eight participants were selected one dropped out for medical reasons unrelated to the study. All but two were on Cholinesterase inhibitors during this study.
An MRI was used to map the brain regions of interest and to confirm scans were consistent with an AD diagnosis. The mapping of these areas also assisted in the positioning of the TMS for the stimulation. The six brain areas of interest were, Broca and Wernicke’s areas, the right and left dorsolateral prefrontal cortexes (RDLPFC and LDLPFC respectively), and the right and left parietal somatosensory association cortex. For safety purposes, these six areas were broken down into two treatment groups, Broca’s area, RDLPFC and LDLPFC in one group, and Wernicke’s, RPSAC and LPSAC in the other. The treatment of these groups was alternated daily.
The cognitive stimulation section of the study was outsourced meaning an outside company designed cognitive tasks to specifically target and stimulate the goal brain areas. These tasks were presented to the participants by computer. The brain areas were separated into two groups and each group had alternate days of stimulation for safety purposes. For the first 5 weeks of the study, participants were treated five days a week for approximately 45 m (15 m per brain area. After that, the participants were treated twice a week for three more months.
Participants were measured on a variety of standardized test to quantify any cognitive and practical changes. Baseline measures were taken using the Alzheimer Disease Assessment Scale – Cognitive and Activities of Daily Living (ADAS -cog, and ADAS –ADL respectively) the Hamilton Scale for Depression, the Neuropsychiatric Inventory (NPI) and an MMSE three weeks before the study began. A Clinical Global Impression of Change scale was also used. Comparison measurements were taken 6 weeks and 4 ½ months after treatment began.
Due to the fact that this study has few participants (N = 7) significance was difficult to assess in some tasks. Despite that, ADAS – cog and ADAS –ADL both showed significant improvement at 6 weeks and 4.5 months over the baseline measure. The CGIC, MMSE and the NPI were all statistically nonsignificant. The Hamilton approached significance (p = .056) This means there is strong evidence to suggest that TMS and cognitive training has potential to slow or even reverse some of the symptoms of AD. Specifically, reduction of cognitive impairment, increases in daily functioning and lessening of depression. The benefits of this pilot study remain: it is noninvasive, and has no known side effects. The time investment ( 45 m a day 5 days a week for 6 weeks followed by 2 days a week for 4 ½ months) for this study would be major drawback. This study was limited by the sample size, length of treatment, and did not account for practice effects. For future research, lengthening the treatment duration from 4 ½ months to one year or beyond would give more time for the effects to be fully realized. Increasing the sample size would increase the power to detect changes over time and give a more precise measurement of the treatment effects. Regardless, this treatment deserves more investigation.
Deep brain stimulation (Laxton, et al., 2010)
All brain areas are interconnected and work together to perform functions, when one area of the brain is degenerated by AD it affects all the rest. This is the basis for the study. Researchers theorized that modulating the damaged pathways through deep brain stimulation will normalize their function and thereby reverse the effects of AD. Deep brain stimulation has shown success in treatment of Parkinson, Huntington disease, and depression. It has been used to modulate memory in that; stimulation specifically to the hippocampus has shown to increase declarative memory. The researchers, therefore, hypothesized that stimulation of the fornix in the hippocampus would change the temporal memory circuits. Specifically, it would raise scores on the MMSE, Alzheimer Disease Assessment Scale – Cognitive (ADAS –cog) and change glucose utilization in the brain, measured via PET scan.
Only early stage AD patients were selected for this study because as the disease progresses, brain structural integrity decreases and could not tolerate the electrode’s invasion. Further inclusionary specifications are as follows: They had to be between the ages of 40 and 80 years old, had to receive a diagnosis of AD within the past two years, patients had to have a Clinical Dementia Rating score of 0.5 or 1.0, the had to have a score between 18 and 28 on the MMSE, they had to be taking cholinesterase inhibitors for a minimum of 6 months. They were excluded if they had any of the following: preexisting structural brain abnormalities, other neurological or psychiatric diagnosis, or had medical comorbidities that would prohibit them from a surgical procedure. Six patients were selected for inclusion in the study.
An MRI was used for electrode placement measurements. The electrodes were surgically placed bilaterally using a fluoroscope while the patient was awake. Electrodes were then connected to internal pulse generators located in the patient’s chest under general anesthesia. A second MRI scan was used to confirm electrode placement. Patients were discharged from the hospital between 1 and 3 days post-operative. Two weeks after discharge patients were checked and the stimulators were turned on. All patients were constantly stimulated for 12 months with 3 – 3.5 V, 130 Hz, for 90 ms in duration. The time interval between stimulations was not mentioned. They were measured on the previously mentioned tests at 1, 6, and 12 months post-operative.
Preoperative PET scans were obtained as a baseline for glucose metabolism using the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose (F18). All normal protocols were followed. They were re-measured at 1 month, and 12 months postoperative. Study patients were matched demographically to control subjects. Also, a standardized low-resolution electromagnetic tomography (LORETA) was used to track the stimulation effects of the electrodes. Specifically, to make sure that the temporal memory circuits were in fact being stimulated. The results were positive.
The results of the ADAS –cog from one month post-operative showed slight improvement in three out of four patients, at 6 months, four patients improved with an average drop in scores of 2.65. After 12 months, only one patient continued to improve. All of the score improvements came from the recall and recognitions section of the ADAS –cog assessment. Overall it is very encouraging results because the average gain for AD patients is 6-7 points per year.
MMSE results also showed positive changes. The rate of decline from one year pre-operative to the one year post-operative showed a 1.44 point average decrease compared to 3 points for a normal rate of decline. This shows a slowing of the disease progression.
PET scans showed significant improvement in glucose metabolism in the temporal and parietal cortical areas and the primary sensory motor regions. At one year post op, these changes persisted.
In sum, deep brain stimulation does not work for all patients but the average rates of decline do appear to slow overall. Glucose metabolism also increases as a result of this treatment improving brain function. This study was very lengthy (12 months) which shows the effects are long term. Some of the limitations of this study are: First, this extremely invasive surgical procedure is a huge commitment for the patient. Even though these patients tolerated the procedure well, the health and cognitive risks are vast. Second, the practice effects for the cognitive measures may interfere with result interpretations. Third, the small sample size (N = 6) could have reduced significance. Finally, they did not control for placebo effect.
Insulin therapy (Craft, et al., 2011)
The brain uses insulin in a number of functions, for instance, insulin is used to remodel synapses, and to metabolize glucose, the brain’s main energy source. Insulin receptors are densely located in the hippocampus and the entorhinal cortex and aids in learning and memory functions. It also protects the brain from β amyloid protein buildup. Therefore, AD is often a result of ineffective regulation of insulin in the brain. The theory of the researchers is that restoring insulin levels in the brain will slow the pathological progress of AD.
Inclusionary parameters for this study were as follows: Participants had a Clinical Dementia Rating score between 0.05 and 1.0, an MMSE of 15 or higher, and a probable AD diagnosis. Participants had to be free from psychiatric disorders, alcoholism, severe head trauma, diabetes, among other things. Participants also needed a caregiver to be enrolled in this study.
Participants were randomized into three treatment groups, placebo (n = 30), 20 IU of insulin (n = 36), and 40 IU insulin group (n = 38). An intranasal insulin delivery system was chosen over regular shot delivery because of its rapid deployment (it only takes 60 minutes for insulin to reach the cerebral spinal fluid), and it does not affect blood insulin levels.
This study controlled for body mass, sex, AD medications, and E(APOE)Ɛ4 allele. Parallel versions of cognitive and functional test were used to control for practice effects. Participants received insulin or saline treatments in the morning and evening for 4 months.
The cognitive measures of interest for this study were a delay story recall task, and the Dementia Severity Rating Scale (DSRS). The story task consisted of presenting a story with 44 informational elements once. Then the participant was asked to recall the story immediately and after a 20 m delay. The ADAS –cog, and the ADAS –ADL were also utilized.
Forty participants (placebo n = 15, 20 IU n = 13, and 40 IU n = 12) also received a PET scan before treatment and after 4 months of treatment to tract glucose hypo-metabolism. Participants were scanned 35 m after injection of F18. Results of the PET scan show increased metabolism in the right and left frontal cortex in both insulin groups compared with the placebo group (20 IU = .04, 40 IU, p = .03) and in the left parietal only for the 40 IU group (p = .05). Specifically, the 20 IU dose of insulin showed significant increases in the inferior occipital cortex (left), the lateral temporo-occipital cortex (right), precuneus (right), superior temporal cortex (right), lateral occipital cortex (left), and the orbital frontal cortex. The 40 IU dose of insulin showed increases in the orbital frontal cortex, inferior occipital cortex (left), inferior parietal cortex (left), precuneus and cuneus regions (right), lateral occipital cortex (left), medial frontoparietal cortex (left), and the caudate (right).This indicates that insulin treatment increases glucose metabolism in some brain regions.
The cognitive functioning tasks also showed fewer declines in the insulin conditions. The delayed story recall condition showed significant improvement over time in the 20 IU condition (p = .02, Cohen f = 0.36) but not the 40 IU condition. The researchers believe that the 40 IU dosage, for this measure, surpassed the ideal insulin dose and therefore was not different from the placebo condition. The Dementia Severity Rating Scale also showed significant improvement in both the 20 IU and 40 IU conditions (p = .01, Cohen f = 0.38 and 0.41 respectively). The ADAS –cog task results showed a smaller amount of decline in both insulin conditions (20 IU, p = .04, Cohen f = 0.27, 40 IU p = .002, Cohen f =0 .40) over the placebo condition. Finally, the ADAS –ADL scores showed significantly less decline in the insulin groups (20 IU, p = .01, Cohen f = 0.2640 IU p = .02 Cohen f = 0.39)
In sum, this study displays strong evidence that insulin treatment slows cognitive decline and increased glucose metabolism in AD patients. It is non-invasive and has few minor side effects. This was a well-designed study that had few limitations. The only improvements to this study would be to test how long the effects last and add participants.
Conclusion
In these three studies all showed improvements in cognition or at least a slowing of the rate of decline. Out of the three studies, insulin treatment is the most promising because it isn’t invasive, it is less time consuming and it shows larger improvements over time. A recent study published by the Alzheimer’s Association shows that by 2050 the total costs for AD will rise to $1,078 billion dollars. That staggering amount can be reduced to $631 billion if we can slow the progress or delay onset of AD by five years. (“Changing the trajectory of Alzheimer’s disease; A national imparative,” 2011) The insulin treatment has the best chance to achieve that goal.
References
Ballenger, J. F. (2006). Health politics of anguish. In Self, senility, and Alzheimer’s disease in modern America: A history. Baltimore, MD: Johns Hopkins University Press.
Bentwich, J., Dobronevsky, E., Aichenbaum, S., Shorer, R., & Peretz, R. (2011). Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease: A proof of concept study. Dementias.
Changing the trajectory of Alzheimer’s disease; A national imperative. (2011). Alzheimer’s Association.
Craft, S., Baker, L. D., Montine, T. J., Minoshima, S., Watson, G. S., & Claxon, A. (2011). Intranasal insulin therapy for Alzheimer’s disease and Amnestic mild cognitive impairment. American Medical Association.
Laxton, A. W., Tang-Wai, D. F., Mary Pat McAndrews, Zumsteg, D., Wennberg, R., & Karen, R. (2010). A phase 1 trial of deep brain stimulation of memory circuits in Alzheimer’s disease. American Neurological Association.
Nordeen, J. (2004). Understanding the brain. The teaching company.