Music as Medicine: Using Music to Help Dementia and Alzheimer’s Patients

Summary: Music could have unexpected benefits for those with Alzheimer’s disease.

Source: Ithaca College.

Music and voice major Jessica Voutsinas ’18 was singing the classic song “Over the Rainbow” to a resident at Longview — an adult residential facility near the Ithaca College campus — when the woman unexpectedly lit up and began telling stories about her life and children in a breakthrough of memory recall.

Voutsinas started visiting Longview as part of a new course at Ithaca College called Exploring Music as Medicine, which teaches students how to perform for dementia and Alzheimer’s patients and then assigns them to local nursing homes to bring music to residents. Since the launch of the program, dozens of patients in Tompkins County have experienced its benefits.

“You play familiar music,” lecturer and course cofounder Jayne Demakos ’78 says. “That’s really what people with Alzheimer’s and dementia will respond to.”

“The class was a transformative experience for me,” says Voutsinas. “It seemed unbelievable that music could do something that pills can’t. But after witnessing this and experiencing it for myself, my whole perception of music changed.”

Ryan Mewhorter ’19, a voice and performance major, was introduced to the idea of the healing power of music when he heard School of Music Dean Karl Paulnack speak about the program at the beginning of his first year at IC.

Having lost his grandfather to Alzheimer’s disease, Mewhorter immediately wanted to become involved in the project. By his second semester on campus, he had founded a student organization called Healing through Musical Companionship. The club now has 50 members who visit Beechtree Center for Rehabilitation and Nursing in downtown Ithaca each week to play recorded music for patients. Using recorded music allows students who are not musicians to help trigger residents’ memories and encourage positive emotional responses.

During her first visit to Beechtree in February 2016, club member Kathryn Kandra ’19 met a woman who was slumped in her wheelchair, head tucked down toward her lap. Kandra began playing the show Annie on an iPod, and within minutes the woman started singing along and conducting the music. Halfway through act one, she began asking Kandra about her life at Ithaca College.

“When I met her, she was completely nonverbal,” Kandra says. “It was amazing that I could give her at least 10 minutes of this lucidness and companionship.”

Mewhorter also loves bringing that feeling to Alzheimer’s and dementia patients, although he found that the live music program through the music course allowed him to make a more direct connection with residents.

Image shows a volunteer playing music for an alzheimer's patient.

“Live music has this feeling that is more personal,” he says. “When you put headphones on a resident, there isn’t a whole lot of room to communicate. When you perform music for them, they can sing along and make eye contact with you and follow the beat.”

Seeing the incredible enthusiasm for both the Exploring Music as Medicine course and Healing through Musical Companionship club has sparked talk of expanding the programs. Paulnack says it is possible that the School of Music may consider creating a major or minor in music as medicine that would emphasize both a high level of musicianship and the healing power of music. The program would involve the departments of music, recreation and leisure studies, gerontology, speech-language pathology and audiology, occupational therapy, and writing.

“We don’t claim to know what we’re doing yet,” says Paulnack. “We just want to jump in with both feet and explore it.”


Source: Dan Verderosa – Ithaca College
Image Source: image is credited to Robyn Wishna/Ithaca College.
Original Research: We will report on the findings of this research once the study is complete.

The Way The Brain Processes Speech Could Serve as a Predictor of Early Dementia

Summary: Noticeable communication problems may be an early sign of mild cognitive impairment, a new study reports.

Source: Baycrest Center For Geriatric Care.

Early dementia is typically associated with memory and thinking problems; but older adults should also be vigilant about hearing and communication problems, suggest recent findings in a joint Baycrest-University of Memphis study.

Within older adults who scored below the normal benchmark on a dementia screening test, but have no noticeable communication problems, scientists have discovered a new potential predictor of early dementia through abnormal functionality in regions of the brain that process speech (the brainstem and auditory cortex).

These brain regions are thought to be more resilient to Alzheimer’s. However, this discovery demonstrates changes occur early in the brain’s conversion of speech sound into understandable words. This finding could be the first sign of decline in brain function related to communication that presents itself before individuals become aware of these problems.

Their research technique of measuring electrical brain activity using an electroencephalogram (EEG) in these brain regions also predicted mild cognitive impairment (MCI), a condition that is likely to develop into Alzheimer’s, with 80 per cent accuracy. This test could be developed into a cost-effective and objective diagnostic assessment for older adults.

The study, published online in the Journal of Neuroscience prior to print publication, looked at older adults with no known history of neurological or psychiatric illnesses with similar hearing acuity.

The brain activity within the brainstem of these older adults demonstrated abnormally large speech sound processing within seven to 10 milliseconds of the signal hitting the ear, which could be a sign of greater communication problems in the future.

“This opens a new door in identifying biological markers for dementia since we might consider using the brain’s processing of speech sounds as a new way to detect the disease earlier,” says Dr. Claude Alain, the study’s senior author and senior scientist at Baycrest’s Rotman Research Institute (RRI) and professor at the University of Toronto’s psychology department.

“Losing the ability to communicate is devastating and this finding could lead to the development of targeted treatments or interventions to maintain this capability and slow progression of the disease.”

The study involved 23 older adults between the ages of 52 and 86. Participants were separated into two groups based on their results on a dementia screening test, the Montreal Cognitive Assessment (MoCA). Researchers measured brain activity in the brainstem while participants were watching a video. They measured brain activity in the auditory cortex while participants were identifying vowel sounds. Statistical methods were used to combine both sets of brain activity to predict MCI.

“When we hear a sound, the normal aging brain keeps the sound in check during processing, but those with MCI have lost this inhibition and it was as if the flood gates were open since their neural response to the same sounds were over-exaggerated,” says Dr. Gavin Bidelman, first author on the study, a former RRI post-doctoral fellow and assistant professor at the University of Memphis. “This functional biomarker could help identify people who should be monitored more closely for their risk of developing dementia.”

The next steps involve studying whether those individuals who already have dementia or convert early from MCI to dementia also demonstrate these same changes in brain activity when they hear speech.

Research for this study was conducted with support from the Grammy Foundation, the Canadian Institutes of Health Research, the FedEx Institute of Technology and the Center for Technologies and Research in Alzheimer’s Care, which supported the staff and equipment needed to conduct the study.

With additional funds, researchers could explore developing a portable, reliable and easy-to-use alternate diagnostic test for MCI that incorporates the body’s different senses.

“MCI is known to cause changes in different senses, such as vision or touch,” says Dr. Alain. “If we could incorporate these changes into a wireless EEG test, we could combine all this information and develop a better biomarker. One day, doctors could administer a short, 10-minute assessment and instantly provide results.”

“This could offer a new diagnostic assessment that tests a person’s cognitive abilities, such as their ability to communicate, and objectively measure physiological changes in the brain that reflect early signs of dementia,” says Dr. Bidelman.


The research team included Jill Lowther (University of Memphis) and Sunghee Tak (Seoul National University).

Funding: Funding for this research was provided by Grammy Foundation, Canadian Institutes of Health Research, FedEx Institute of Technology, Center for Technologies and Research in Alzheimer’s Care.

Source: Scott LaFee – Baycrest Center For Geriatric Care
Image Source: image is in the public domain.
Original Research: Abstract for “Mild cognitive impairment is characterized by deficient brainstem and cortical representations of speech” by Gavin M. Bidelman, Jill E. Lowther, Sunghee H. Tak and Claude Alain in Journal of Neuroscience. Published online March 7 2017 doi:10.1523/JNEUROSCI.3700-16.2017

Baycrest Center For Geriatric Care “The Way The Brain Processes Speech Could Serve as a Predictor of Early Dementia.” NeuroscienceNews. NeuroscienceNews, 15 March 2017.
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Mild cognitive impairment is characterized by deficient brainstem and cortical representations of speech

Mild cognitive impairment (MCI) is recognized as a transitional phase in the progression toward more severe forms of dementia and is an early precursor to Alzheimer’s disease. Previous neuroimaging studies reveal MCI is associated with aberrant sensory-perceptual processing in cortical brain regions subserving auditory and language function. However, whether the pathophysiology of MCI extends to speech processing prior to conscious awareness (brainstem) is unknown. Using a novel electrophysiological approach, we recorded both brainstem and cortical speech-evoked brain potentials (ERPs) in older, hearing-matched human listeners who did and did not present with subtle cognitive impairment revealed through behavioral neuropsychological testing. We found MCI was associated with changes in neural speech processing, characterized as hypersensitivity (larger) brainstem and cortical speech encoding in MCI compared to controls in the absence of any perceptual speech deficits. Group differences also interacted with age differentially across the auditory pathway; brainstem responses became larger and cortical ERPs smaller with advancing age. Multivariate classification revealed that dual brainstem-cortical speech activity correctly identified MCI listeners with 80% accuracy, suggesting application as a biomarker of early cognitive decline. Brainstem responses were also a more robust predictor of individuals’ MCI severity than cortical activity. Our findings (i) suggest that MCI is associated with poorer encoding and transfer of speech signals between functional levels of the auditory system and (ii) advance the pathophysiological understanding of cognitive aging by identifying subcortical deficits in auditory sensory processing mere milliseconds (<10-ms) after sound onset and prior to the emergence of perceptual speech deficits.


Mild cognitive impairment (MCI) is a precursor to dementia marked by declines in communication skills. Whether MCI pathophysiology extends below cerebral cortex to impact speech processing prior to conscious awareness (brainstem) is unknown. By recording neuroelectric brain activity to speech from brainstem and cortex, we show that MCI hypersensitizes the normal encoding of speech information across the hearing brain. Deficient neural responses to speech (particularly those generated from the brainstem) predicted the presence of MCI with high accuracy and prior to behavioral deficits. Our findings advance the neurological understanding of MCI by newly identifying a subcortical biomarker in auditory-sensory processing prior to conscious awareness, which may be precursor to declines in speech understanding.

“Mild cognitive impairment is characterized by deficient brainstem and cortical representations of speech” by Gavin M. Bidelman, Jill E. Lowther, Sunghee H. Tak and Claude Alain in Journal of Neuroscience. Published online March 7 2017 doi:10.1523/JNEUROSCI.3700-16.2017

Prolonged Sleep May Predict Dementia Risk

Data from the Framingham Heart Study has shown that people who consistently sleep more than nine hours each night had double the risk of developing dementia in 10 years as compared to participants who slept for 9 hours or less.

The findings, which appear in the journal Neurology, also found those who slept longer had smaller brain volumes. It is believed that the number of Americans with Alzheimer’s disease and other dementias will grow each year as the size and proportion of the U.S. population age 65 and older continues to increase. By 2025 the number of people age 65 and older with Alzheimer’s disease is estimated to reach 7.1 million.

A large group of adults enrolled in the Framingham Heart Study (FHS), were asked to indicate how long they typically slept each night. Participants were then observed for 10 years to determine who developed dementia, including dementia due to Alzheimer’s disease. Researchers from BUSM then analyzed the sleep duration data and examined the risk of developing dementia.

COM-sleeping man

“Participants without a high school degree who sleep for more than 9 hours each night had six times the risk of developing dementia in 10 years as compared to participants who slept for less. These results suggest that being highly educated may protect against dementia in the presence of long sleep duration,” explained co-corresponding author Sudha Seshadri, MD, professor of neurology at BUSM and FHS senior investigator.

According to the researchers the results suggest that excessive sleep may be a symptom rather than a cause of the brain changes that occur with dementia. Therefore, interventions to restrict sleep duration are unlikely to reduce the risk of dementia.

“Self-reported sleep duration may be a useful clinical tool to help predict persons at risk of progressing to clinical dementia within 10 years. Persons reporting long sleep time may warrant assessment and monitoring for problems with thinking and memory,” added co-corresponding author Matthew Pase, PhD, fellow in the department of neurology at BUSM and investigator at the FHS.

The researchers believe screening for sleeping problems may aid in the early detection of cognitive impairment and dementia. The early diagnosis of dementia has many important benefits, such as providing a patient the opportunity to more activity direct their future plans and health care decisions.

Prolonged Sleep May Predict Dementia Risk

Posted 6 days ago on Thursday, February 23rd, 2017 in Featured, Research


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Alzheimer’s Risk Factors By Dr Daniel Amen

Alzheimer’s Risk Factors By Dr Daniel Amen

O One family member with Alzheimer’s or dementia 3.5
O More than one family member with Azheimer’s or dementia 7.5
O A single head injury with loss of consciousness 2
O Several head injuries without loss of consciousness 2
O Alcohol dependence or drug dependence in past or present 4.4
O Major depression or ADD/ADHD diagnosed by a physician in past or present (female) 4
O Major depression or ADD/ADHD diagnosed by a physician in past or present (male) 2
O Standard American diet 2
O Being obese 2
O History of stroke 10
O Heart disease or heart attack 2.5
O Pre-hypertension or hypertension 2.3
O pre-diabetes or diabetes 3.4
O Cancer chemo 3
O Parksinson’s disease 1.5
O Sleep apnea 3
O Less than a high school education 2
O Limited exercise, less than twice a week 2
O Jobds that do not require new learning 2
O Periodontal disease 2
O Presence of inflammation in the body (e.g., high homocysteine or C-reactive protein) 2
O Smoking cigarette or 10 years or longer 2.3
O Low estrogen in females or low testosterone in males or femailes 2
O Within the age range of 65 to 74 years old 2
O Within the age range of 75 to 84 years old 2
O Over 85 years old 38
Total Score

Two common classes of drugs linked to dementia

Recent reports have linked two common classes of drugs to dementia. Fortunately, there are alternatives to both.

If you’re worried about developing dementia, you’ve probably memorized the list of things you should do to minimize your risk—eating a healthy diet, exercising regularly, getting adequate sleep, and keeping your mind and soul engaged. In the past year, we’ve learned that some of the drugs you may be taking to help you accomplish those things could increase your risk of dementia. In two separate large population studies, both benzodiazepines (a category that includes medications for anxiety and sleeping pills) and anticholinergics (a group that encompasses medications for allergies and colds, depression, high blood pressure, and incontinence) were associated with an increased risk of dementia in people who used them for longer than a few months. In both cases, the effect increased with the dose of the drug and the duration of use.

Image: Thinkstock

These findings didn’t come entirely as a surprise to doctors who treat older people. “The Beer’s List published by the American Geriatrics Society has long recognized benzodiazepines, antihistamines, and tricyclic antidepressants as potentially inappropriate for older adults, given their side effects,” says Dr. Lauren J. Gleason, a physician in the Division of Aging at Harvard-affiliated Brigham and Women’s Hospital. Such drugs are on the list because they share troubling side effects—confusion, clouded thinking, and memory lapses—that can lead to falls, fractures, and auto accidents.

What the studies found

It’s important to note that neither of these studies was a randomized controlled clinical trial, so neither proved that either type of drug causes dementia.

The anticholinergic study. Researchers tracked nearly 3,500 men and women ages 65 or older who took part in Adult Changes in Thought (ACT), a long-term study conducted by the University of Washington and Group Health, a Seattle health care system. They used Group Health’s pharmacy records to determine all the drugs, both prescription and over-the-counter, that each participant took in the 10 years before starting the study. Participants’ health was tracked for an average of seven years. During that time, 800 of them developed dementia. When the researchers examined medication use, they found that people who used anticholinergic drugs were more likely to have developed dementia than those who didn’t use them. Moreover, dementia risk increased along with the cumulative dose. Taking an anticholinergic for the equivalent of three years or more was associated with a 54% higher dementia risk than taking the same dose for three months or less.

The University of Washington study is the first to include nonprescription drugs. It is also the first to eliminate the possibility that people were taking the drugs to alleviate early symptoms of undiagnosed dementia. For people who took anticholinergic bladder medications, the increased risk was just as high as for those taking tricyclic antidepressants, which are also anticholinergics.

The benzodiazepine study. A team of researchers from France and Canada linked benzodiazepine use to an increased risk of being diagnosed with Alzheimer’s disease. In the study, the greater people’s cumulative dose of benzodiazepines, the higher their risk.

The researchers relied on a database maintained by the Quebec health insurance program. From it, they identified nearly 2,000 men and women over age 66 who had been diagnosed with Alzheimer’s disease. They randomly selected more than 7,000 others without Alzheimer’s who were matched for age and sex to those with the disease. Once the groups were set, the researchers looked at the drug prescriptions during the five to six years preceding the Alzheimer’s diagnosis.

People who had taken a benzodiazepine for three consecutive months or less had about the same dementia risk as those who had never taken one. But those who had taken a benzodiazepine for three to six months had a 32% greater risk of developing Alzheimer’s, and those taking one for more than six months had an 84% greater risk than those who hadn’t taken one.

The type of drug taken also mattered. People who were on a long-acting benzodiazepine like diazepam (Valium) or flurazepam (Dalmane) were at greater risk than those on a short-acting one like triazolam (Halcion), lorazepam (Ativan), alprazolam (Xanax), or temazepam (Restoril).

Why these drugs have a stronger effect in older people

As we age, our ability to process medication changes. The kidneys and liver clear drugs more slowly, so drug levels in the blood remain higher for a longer time. People also gain fat and lose muscle mass over time. Both these changes affect the way drugs are distributed to and broken down in body tissues. And because these drugs are stored in body fat, they can continue to produce effects days after people stop taking them, especially in people with a higher proportion of body fat. In addition, older people tend to take more prescription and over-the-counter medications, each of which has the potential to suppress or enhance the effects of the others.

Why the drugs affect your mind

Both anticholinergics and benzodiazepines affect the activity of neurotransmitters—chemical messengers that work in the central nervous system—but the drugs work in slightly different ways.

Anticholinergic drugs block the action of acetylcholine. In the brain, acetylcholine is involved in learning and memory. In the rest of the body, it stimulates the autonomic nerves—those that regulate contractions of blood vessels, airways, and our cardiovascular and digestive systems. The strongest anticholinergic drugs include some antihistamines, tricyclic antidepressants, medications to control overactive bladder, and sleeping pills.

Benzodiazepines boost another neurotransmitter’s effectiveness. They make gamma-aminobutyric acid (GABA)—which slows the activity of neurons in the brain-—more potent. For that reason, they are used to calm anxiety and help people sleep.

If you take one of these drugs

Dr. Gleason suggests having a thorough discussion with your doctor to review the potential benefits and harms of these medications—and all the others you take. If a drug appears problematic, the two of you can explore alternatives by considering the reason it was prescribed and seeing if there is a different type of drug that can be used as a replacement.

Don’t stop taking the drugs on your own. It isn’t safe to quit most benzodiazepines and anticholinergic drugs “cold turkey.” Work with your clinician to develop a plan for tapering off them.

Medications to avoid or use briefly

Common drugs that might increase dementia risk Possible alternatives
Allergies, colds Anticholinergics

brompheniramine (Dimetapp)

carbinoxamine (Palgic)

chlorpheniramine (Chlor-Trimeton)

diphenhydramine (Benadryl)

hydroxyzine (Atarax, Vistaril)

cetirizine (Zyrtec)

desloratadine (Clarinex)

fexofenadine (Allegra)

loratadine (Claritin)

Anxiety Benzodiazepines

alprazolam (Xanax)

chlordiazepoxide (Librium)

clonazepam (Klonopin)

clorazepate (Tranxene)

diazepam (Valium)

flurazepam (Dalmane)

lorazepam (Ativan)

oxazepam (Serax)

bupropion (Wellbutrin)

buspirone (Buspar)

citalopram (Celexa)

fluoxetine (Prozac)

paroxetine (Paxil)

sertraline (Zoloft)

venlafaxine (Effexor)

Depression Anticholinergics

amitriptyline (Elavil)

clomipramine (Anafranil)

doxepin (Sinequan)

imipramine (Tofranil)

trimipramine (Surmontil)

bupropion (Wellbutrin)

buspirone (Buspar)

citalopram (Celexa)

fluoxetine (Prozac)

paroxetine (Paxil)

sertraline (Zoloft)

venlafaxine (Effexor)

Insomnia Anticholinergics

mirtazapine (Remeron)

nefazodone (Serzone)

trazodone (Desyrel)


estazolam (Prosom)

quazepam (Doral)

temazepam (Restoril)

triazolam (Halcion)


Nondrug approaches

practicing relaxation techniques

avoiding alcohol and heavy meals before bedtime

exercising vigorously early in the day

Urge incontinence Anticholinergics

darifenacin (Enablex)

fesoterodine (Toviaz)

flavoxate (Urispas)

oxybutynin (Ditropan)

solifenacin (Vesicare)

tolterodine (Detrol)

trimipramine (Surmontil)

trospium (Sanctura)

Nondrug approaches

bladder training

physical exercise

weight loss for overweight or obese women

Minimally invasive procedures

Botox injections

implantable bladder stimulators

Sources: DeGage SB, et al. “Benzodiazepine use and risk of Alzheimer’s disease: Case-control study,” BMJ (Sept. 9, 2014), Vol. 351, published online; Salahudeen MS et al. “Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: A systematic review,” BMC Geriatrics (March 15, 2015), Vol.15, No.31, published online.

Depression to Dementia


  • (i) Individuals who develop depression at any point in their lives, sustain minimal or no depression-related neuropathology (eg, glucocorticoid neurotoxicity), and who have stable, normal cognitive functioning;
  • (ii) Individuals who develop depression at any point and who experience depression-related neuropathology that results in MCI that is stable (unless they experience additional depressive episodes);
  • (iii) Individuals who accumulate AD neuropathology over many years and who develop late-life depression (related or unrelated to AD pathology), that lowers brain reserve capacity, and results in expression of MCI earlier than otherwise would be the case, and given the underlying neuropathology, progress to AD;
  • (iv) Individuals who accumulate AD neuropathology over many years along with co-occurring cerebrovascular disease, which damages the frontostriatal circuitry, leading to late-life depression. The total neuropathologic burden, combined with depressed mood, lowers brain reserve capacity, leads to expression of MCI (eg, memory and executive dysfunction) earlier than otherwise would be the case, and, given the underlying neuropathology, progresses to AD along with co-occurring cerebrovascular disease;
  • and (v) Individuals who develop cerebrovascular disease (with variable neuropathologic burden), that damages the frontostriatal circuitry, leading to late-life depression and MCI (eg, executive dysfunction), that, will follow the course of the underlying cerebrovascular disease.
AD Alzheimer’s disease
CAD coronary artery disease
HPA hypothalamic-pituitary-adrenal
MCI mild cognitive impairment
MDE major depressive episode
WMH hyperintense white matter regions

ad-depGlucocorticoids contribute to hippocainpal atrophy and learning/episodic memory impairment

Depression is associated with neuroendocrine changes similar to those observed in animal models of chronic stress, including abnormalities within the hypothalamicpituitary-adrenal (HPA) axis. Most notably, depressed subjects have been shown to exhibit, increased HPA central drive with elevated corticotrophin-releasing hormone (CRH) and vasopressin production by cells of the hypothalamic paraventricular nucleus (PVN); impaired negative feedback regulation due to decreased expression of corticosteroid receptors in the hypothalamus and pituitary as well as upstream CNS regulatory centers; and adrenal hypertrophy (reviewed in ref 25). The net effect of these changes in HPA function is chronic elevation of adrenal glucocorticoid production with impaired negative feedback and abnormal homeostatic regulation. Such HPA dysregulation is clinically detectable (via dexamethasone nonsuppression or elevated 24-hour urinary Cortisol) in about, half of patients with major depression.2526 HPA dysregulation may be more common among older depressed individuals, as suggested by the finding of a significant correlation between age and post-dexamethasone Cortisol levels in individuals with late-life depression.27

Adrenal glucocorticoid/cortisol regulates HPA activity through both direct, negative feedback at the pituitary and hypothalamus and indirect, mechanisms involving higher central nervous system (CNS) centers. The human hippocampus, for example, contains large numbers of corticosteroid receptors and plays a critical role in downregulating CRH release via a multisynaptic pathway terminating in y-aminobutyric acid (GABA)-ergic output to the paraventricular nucleus (reviewed in ref 28). At. the same time, HPA disturbances causing prolonged hypercortisolemia may promote hippocampal atrophy and functional decline, such that HPA regulation is further compromised. ‘Iliis interaction may underlie the observed association between hypercortisolemic disease states such as Cushing’s syndrome and depression, and both hippocampal atrophy and impairment, in the verbal and spatial memory functions subserved by the hippocampus.29,30

Animal studies suggest that high-stress conditions or exogenous glucocorticoids can cause hippocampal neuronal damage31 and memory impairment.32 These changes have been observed concurrent with stress or exogenous glucocorticoid administration, and appear to progress over a lifetime of stress or glucocorticoid excess (see review in ref 33). Human studies in older adults likewise suggest that hippocampal size and function are diminished in the setting of elevated glucocorticoids,3435 and in proplemiaortion to duration of prior hypercortisolemia.36

On the basis of these findings, many have hypothesized that glucocorticoids may promote hippocampal cell injury and death when chronically elevated, as in the setting of hypercortisolemica associated with major depression. Glucocorticoid-induced cellular damage may be mediated through effects on several biochemical substrates. Postulated mechanisms include decreased glucose uptake and ATP generation, elevated intracellular calcium with increased free radical production and degradative enzyme activity, and impaired uptake of glutamate from hippocampal synapses resulting in excitotoxicity.28,37 In addition, hypercortisolemia has been linked to a decrease in neurogenesis in the dentate gyrus.38 While the combination of cell death and decreased neurogenesis may theoretically contribute to hippocampal cell loss over time, recent, evidence suggests at. most a minor role for this mechanism in hypercortisolcmic human subjects in the absence of cooccurring insults.39 Animal and human studies support the idea that glucocorticoids contribute to hippocampal atrophy and functional deficits predominantly through more subtle alterations, including reduced synapse number,40 atrophy of pyramidal cell dendrites,41derangement, of glial cells,42 and other changes.

The loss of hippocampal volume and memory function observed in some elders with late -life depression suggests the possibility that depression may be a predispositional risk factor for AD in particular. Indeed, lower hippocampal volumes independently predict subsequent AD in groups of MCI and cognitively normal elderly subjects.52 Likewise, deficits in verbal learning and memory, similar to those described in cuthymic patients with history of major depression,30 also predict AD (eg, ref 53). While a primary causal role for depression in AD pathogenesis seems unlikely, depression-associated hypercortisolemia leading to decline in hippocampal size, connectivity and cognitive function may represent one of multiple links between depression and dementia as described below.

Brain and cognitive reserve are often used interchangeably, but in fact, have subtle but. distinct differences in meaning.119 Nevertheless, either may account, equally well for the relationship between depression and dementia. Tltic concept of brain reserve capacity, first proposed by Satz120 varies across individuals such that those with greater neuronal redundancy are able to tolerate more cell loss than those with less redundancy, before manifesting clinical symptoms. The concept of redundancy refers to the notion that, circuits contain more than the minimum number of neurons needed to perform an operation. Redundancy is evident when individuals incur substantial neuronal loss before the appearance of clinical symptoms. Thus, brain reserve capacity posits that individual differences in neural redundancy translate into differences in thresholds for vulnerability to or protection from clinical symptoms after brain damage. The concept of cognitive reserve developed by Stern (eg, refs 121 ,122) is similar but rather than being based on differences in brain size or neuronal count, emphasizes differences in the efficiency or manner in which tasks are performed or information is processed.

Both brain reserve and cognitive reserve explain the role of risk and protective factors for cognitive impairment (including progressive decline into dementia), associated with brain damage. For example, higher educational attainment, larger head size, larger brain volume,123 social engagement, 124 physical activity,125 and leisure cognitive activity126,127 may result in greater redundancy and/or efficiency and therefore reserve, thereby offering protection against exhibiting clinical symptoms of dementia. Similarly, lower levels of these protective factors may reduce neuronal or functional redundancy leading to earlier dementia symptom onset for a given level of CNS damage.

While certain mechanisms may alter an individual’s risk to develop (or change the rate of development of) ADrelated pathology (eg, P-amyloid deposition), other mechanisms alter the strength of association between these biological changes and the time to develop clinical disease. We propose that depression alters an individual’s risk of cognitive dysfunction, shortening the latent period between the development, of AD neuropathology and the onset, of clinical dementia, thus increasing the incidence and prevalence of AD among older adults with depression.

About Glucocorticoids

Glucocorticoids (GCs) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor (GR),[1] that is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure (see structure to the right). A less common synonym is glucocorticosteroid.

GCs are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as reduction of inflammation. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. GCs have many diverse (pleiotropic) effects, including potentially harmful side effects, and as a result are rarely sold over the counter.[2] They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. This includes: inhibitory effects on lymphocyte proliferation as in the treatment of lymphomas and leukemias; and the mitigation of side effects of anticancer drugs.

GCs affect cells by binding to the glucocorticoid receptor (GR). The activated GR complex, in turn, up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression).[2]

Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. In technical terms, “corticosteroid” refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for “glucocorticoid.” Glucocorticoids are chiefly produced in the zona fasciculata of the adrenal cortex, whereas mineralocorticoids are synthesized in the zona glomerulosa.

Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.