Dementia and Mild Cognitive Impairment: Widespread but Reversible Diseases
By Eric Braverman, M.D.
Director, PATH Medical
Introduction: Mild Cognitive Impairment is a Widespread and Heterogeneous Disease
Mild or moderate cognitive impairment (MCI) is a heterogeneous disorder. It affects different people in different ways. Some cases of MCI turn into Alzheimer’s dementia, some remain mildly impaired for life, and others are reversed. With the discovery of neurogenesis – regeneration of brain cells – the idea that we can recover full intellectual capacities as we age seems possible along with a new vision of the future that growing older might mean growing smarter and increasing intellectual faculties.
Dementia takes 15 to 20 years to develop and begins with MCI. Pre-MCI, which is asymptomatic, may take another 15 to 20 years of development prior to the discovery of the first MCI symptoms. Although MCI is usually defined as mild cognitive impairments, most high functioning individuals would consider these individuals moderately impaired. Hence earlier stages – or pre-MCI – occur, in which there are even milder forms of cognitive impairment. MCI begins in the 30s to the 40s. By 80-85, 50% of Americans are demented. Dementia may be an accelerated form of brain aging. However, cognitive impairment without dementia is more prevalent in the United States than dementia, and its subtypes vary in prevalence and outcomes.
Alzheimer’s disease affects more than five million Americans and is the fourth-leading cause of death in the United States. Yet, by many accounts, only 50% of the cases are diagnosed, and only 25% of patients receive the medication they need. In 40 years, more than 15 million Americans may have the disease. However, before full-blown dementia hits, patients may have been suffering MCI for decades.
Measuring Cognitive Functioning: Current Techniques
There are several instruments used to measure cognitive function and to predict the conversion from MCI to dementia. Neuropsychological tests, such as the Test of Variables of Attention (TOVA), CNS Vital Signs (CNSVS), Wechsler Memory Scale, and the Randt-Brown Memory Test measure memory and executive functions. Neuroradiological techniques include the quantitative EEG evoked potentials, volumetry (hippocampus, entorhinal cortex, and the whole brain), SPECT, PET, magnetic resonance spectroscopy, and diffusion-weighted MRI. Blood panels include an extensive medical and hormonal battery. In elderly and impaired subjects, a test for APOE4 is necessary as well as dopamine genotypes, and beta amyloid protein, and possible analysis of the CSF (for beta amyloid and tau proteins) which are biomarkers.
In the current conventional view, diagnosing cognitive impairment is done by the combination of a skillful clinical interview plus a judicious use of neuropsychological tests. However, so far there are no standardized tests for the evaluation of MCI. We are proposing a new standard based on the work of Clark Randt, whose research helped establish the connections between neurotransmitters and memory functioning, and many others.
The BEAM Method: Our Standard, a Similar Approach to Cardiology
Using the Brain Evaluation & Assessment Method (BEAM), we “brain print” each patient. This helps us to identify the degree of cognitive impairment. The more specific the analysis, the more specific the repair. A similar method is employed in cardiology. The core cardiac domains that are analyzed are blood work/cholesterol, C reactive protein; blood pressure; electrophysiological: EKG, Holter, etc.; Echocardiogram: valves, ejection fraction; coronary arteries: CT angiogram. The core brain domains that we propose become the standard for routine medical testing are: electrophysiology, memory, attention, temperament and type, axis 1&2, IQs.
The progression of heart disease, like cognitive impairment, is a heterogeneous process. Heart disease can progress via high LDL cholesterol and low HDL, weight gain and poor exercise tolerance, high blood pressure, valve disease, heart attack, arrhythmia, heart failure. The progression to brain disease can occur via slow speed, low energy/voltage, anxiety/blues/mood problems, decreasing verbal and visual memory, decreased attention, decreased working memory, and decreased IQs.
Some of the challenges we face before reaching the point of a more widespread usage of measurements of brain functioning involve the establishment of norms, both ipsative and normative. At this point, patients do not have adequate cognitive baselines. Many forms of cognitive decline that show up on tests relate to learning differences and different aptitudes that occur naturally in each patient. However, if we begin to “brain print” each patient, especially from early ages onward, we can begin a data bank of cognitive baselines for individuals and populations. Brain printing may be the solution to $100,000,000,000 plus problems, including obesity, addiction, neuropsychiatric problems, violence, and cognitive impairments.
P300 latency and brain speed
Although cognitive decline is a heterogeneous disorder, the first abnormality associated with cognitive impairment is a decline in electrophysiological processing speed. This sets off a whole cascade of changes leading to declines in memory, attention, IQ, and changes in temperament. Brain speed can be measured by the P300 wave on a q EEG. The P300 wave is an event-related potential that can be recorded via EEG as a positive deflection in voltage at a latency of roughly 300+ age msec. The presence, magnitude, topography, and time of this signal can measure processing speed. The generation of the P300 event-related potential is influenced by the glutamatergic, GABAergic, cholinergic, noradrenergic, dopaminergic, and serotonergic systems. P300 latency is dominantly cholinergic, whereby decreased latency (increased processing speed) is associated with a well-functioning cholinergic system. The psychotropic medications used to treat dementia interact with these neurotransmitter systems. For example, Donepezil, an acetylcholinesterase inhibitor used in the treatment of Alzheimer’s, improves P300 latency. Clark Randt showed that catecholamines help memory, and impact brain voltage and speed to a degree. Brain speed, as measured by P300 latency, changes throughout the life cycle.
Infants have high voltage (as measured by P300 amplitude) cognitive impairment – having voltage as high as 20 millivolts, and P300 speed as slow as 400 msec. Around age 13 brain speed is given a jolt when teenagers get injected with their own steroids. Between ages 12 and 30, their brain speeds up to a maximum speed of 300+age, or 320 msec.
The parameters of electrophysiology that are measured by the qEEG and that correlate with the different neurotransmitter systems are speed, voltage, rhythm, and synchrony. Cognitive impairment can affect any of these parameters of the EEG. Furthermore, cognitive impairment can manifest as impairment in verbal, visual/spatial, immediate, or working memory, in addition to long-term memory. It can manifest as impairments in attention: with omission errors, commission errors, and abnormalities in response time, response variability, and complex attention.
Hormonal Therapies for Enhancement of Brain Function
Hormone replacement enhances brain speed. Many of the same hormones associated with increases in processing speed are also associated with neurogenesis, or growing new brain cells. These hormones may make it possible to grow smarter as we grow older. Antidepressants are also known stimulants of neurogenesis. The following paragraphs discuss specific hormone changes with aging and the effects of hormone replacement.
Parathyroid hormone levels increase with age. We have found a positive correlation between P300 latency and parathyroid hormone levels. Control of PTH levels may be an important factor in protecting against age-induced dementia. Hyperparathyroidism and osteoporosis can lead to calcifications throughout the body, and also in the brain. Calcification in the brain, which is sometimes associated with hyperparathyroidism, is correlated with impaired processing speed. Bone loss has been shown to predict cognitive decline in older, osteoporotic women, which may be mediated by calcifications in the brain. The field of medicine dealing with the bones, the brain, and behavior is now called neuropsychosteology.
Estrogen replacement therapy in menopausal women has led to a significant improvement in information processing as indexed by a significant shortening of P300 latency. Estrogen has been shown to interact with the cholinergic system and influence cognition in animal models. Estrogen pretreatment attenuated the anticholinergic drug-induced impairments on tests of attention. During oophorectomy, 10 msec of processing speed is lost. MCI and menopause are dynamically related. Hormonal factors explain why women have increased rates of cognitive decline and dementia.
In men, one “normal” consequence of aging is a robust decline in circulating and brain levels of the sex steroid testosterone. Androgens including testosterone help us to regulate beta-amyloid protein, which accumulates in Alzheimer’s patients. Androgen therapy may thus be used to prevent Alzheimer’s dementia and other forms of cognitive decline.
In women, DHEA-S levels have been shown to be associated with better cognitive function. Higher endogenous DHEA-S levels are independently and favorably associated with executive function, concentration and working memory.
Thyroid hormones have been shown to modulate adult hippocampal neurogenesis in studies on rats. Hypothyroidism is associated with poor concentration, memory disturbances, depression, and decreased cognitive function. Hypothyroidism is linked to increased P300 latency.
In patients with growth hormone (GH) deficiency, GH replacement therapy decreased P300 latency after 6 months. Low IGF-1 correlates to delayed processing speed, a loss of 10-20 msec. GH replacement also enhances neurogenesis in rats, and it is hypothesized that its effects on cognitive function.
Melatonin deficiency deprives people of antioxidant protection, and also results in loss of sleep/poor sleep quality. Sleep deprivation leads to increased P300 latency. Administration of melatonin may improve some cognitive impairments.
Decline in Attention
Cognitive decline also leads to a decline in attention. In 2004, 112,012 Americans died due to attention-related accidental injuries. Loss of attention after age 30 is part of MCI.
The Test of Variables of Attention (TOVA) is a computerized test of attention that assists in the screening, diagnosis, and treatment monitoring of attention disorders, like ADHD. Delays in response time, and commission errors may indicate a decline in processing speed. In males, commission errors are the most common abnormality, and are indicative of anxiety. In females, reaction time abnormalities are most common, indicative of depression.
Approximately 50% of all adults partially fail attention tests. If you’re failing 2-3 of the attention parameters measured by TOVA (commission errors, omission errors, response time variability, and response time), your brain has slowed down by at least 20 msec. Since most of us think over a period of only 100 msec, losing 20% of our processing speed is enormous. Attention and memory problems lead to deficits in IQs, including abstract logical, creative, emotional, common sense, and IQ flexibility.
Cognitive Decline and Other Diseases
Cognitive decline has been associated with almost every medical illness, including diabetes, sickle cell disease, thyroid disorders, metabolic syndrome and cancer, to name a few. Sarcopenia, osteopenia, poor nutrition, and disease-related disabilities are stumbling blocks on the road to longevity.
The P300 test of brain speed is functionally the cholesterol test of the brain. Someday we envision that just as how most Americans know their cholesterol levels, everyone will know their brain age, how many years they are away from dementia. Cholesterol, the first precursor to the steroid hormone pathway and a marker of decline in our steroid manufacturing, is a tremendous global marker of both heart disease and physical wellbeing. Brain processing speed delay is antecedent to both memory and attention decline, and will become the marker that every human being wants to know.
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Eric R. Braverman, M.D.
Dr. Braverman is a Summa Cum Laude and Phi Beta Kappa graduate of Brandeis University and NYU Medical School, did brain research at Harvard Medical School, and trained at an affiliate of Yale Medical School. He is acknowledged worldwide as an expert in brain-based diagnosis and treatment, and he lectures to and trains doctors in anti-aging medicine.