If the recent crisis over malpractice (or, more precisely, professional liability) insurance seems vaguely familiar, it is because the crisis is not new. Rather, this year's round of premium rate increases, hospital service curtailments and physician anguish is only the latest struggle of a protracted war between the insurance industry and the segment of the legal community once known as trial lawyers but now self-named as the plaintiffs' bar.

As in previous years, the victims are patients, who have virtually no control over the events that affect their ability to obtain medical services, and health care professionals, who must either find the means to absorb ever-larger premiums for their liability insurance or seek other careers.

According to the American Hospital Association (AHA), physicians' premiums have increased as much as 81% in Pennsylvania, 67% in West Virginia, 58% in Indiana and Montana, and 57% in Texas. The U.S. Department of Health and Human Services (HHS) reported that premiums increased as much as 113% in Virginia and 112% in Arkansas this year.

Even more devastating, however, has been an exodus of carriers from the professional liability marketplace, making it difficult for physicians and hospitals to find coverage at any price. The St. Paul Group of Companies, with a 9% share of the market, announced last year that it intended to stop writing malpractice insurance. A spokesperson told the trade magazine 

 that St. Paul had lost nearly $1.5 billion on professional liability in the preceding four years.

Other companies were overexposed in professional liability, and several of them were forced into insolvency. Physicians Insurance Company and PHICO in Pennsylvania, PIE in Ohio, and Frontier Insurance in New York were taken over by regulators. Another insurance company, MIIX, withdrew from 11 states to concentrate on its home market of New Jersey, and SCPIE Holdings dropped out of the malpractice market in Texas and Florida to concentrate on its home market in  California. Other carriers have been downgraded by ratings agencies--usually a sign of financial weakness--or have followed St. Paul's lead and left the market.

Members of the American Psychiatric Association got a taste of the impact of the country's malpractice crisis in May when Legion Insurance Company was taken over by Pennsylvania regulators. Legion provided coverage for over 7,600 APA members. A new plan underwritten by commercial insurance giant American International Group will cost 30% more per year.

Psychiatrists generally pay significantly smaller premiums than high-risk specialists. One comparison study showed that the average premium for psychiatrists in Dade County, Fla., who do not utilize electroconvulsive therapy was $29,045--a fraction of the $200,000 plus for cardiovascular surgeons,  neurosurgeons and obstetrician-gynecologists.

Because insurance is regulated by states, rates can vary widely based on location. For example, a psychiatrist in Los Angeles could pay as little as $7,000 a year for $1 million to $3 million in coverage. Earlier this year, similar coverage would have cost $6,724 in Long Island, N.Y.; $16,559 in Wayne County, Mich.; and $11,981 in West Virginia.

"It becomes difficult to talk about rates in general because there are so many variables," according to Martin Tracy, president of Professional Risk Management Services Inc., which manages the APA-endorsed professional liability program. Tracy told 

, "There is a 'book rate,' but the rate an individual doctor actually pays depends on [their] claims history, what subspecialties [they] may have, and what state they're located in. Most companies give a premium credit to doctors who are in the early years of their careers. It's possible that two psychiatrists with the same kind of practice in the same building could wind up paying different premiums."

Psychiatrists can reduce their premiums in many states by taking an approved risk management course.

"Most states do recognize that doctors who receive some kind of risk management education are better risks," Tracy said.

Some carriers also charge a higher premium for psychiatrists who utilize ECT. "Some companies perceive ECT as being a higher-risk procedure," Tracy explained. "The carrier that we have used over the years and the carrier we have switched most of the business to have accepted our perception that ECT is not a high-risk procedure. They do not charge any additional premium, but it's not unusual to see it with other carriers."

Norman E. Alessi, M.D., a professor in the department of psychiatry at University of Michigan, sees another potential fallout from the emphasis on malpractice insurance.

"Many of my colleagues live in a state of not wanting to push the envelope that far, because they fear the consequences if they're not successful," he told 

. "People feel an enormous sense of vulnerability. We're not even allowed to develop relationships with patients anymore in the managed care environment, which is what psychiatry was all about. People aren't taught those skills anymore. I believe that's one of the contributing factors to the lawsuits--we don't get to know our patients," he added. 

"With many of the big commercial carriers fleeing the market, the carriers that are left have more new business than they can take," Lawrence E. Smarr, president of Physician Insurers Association of America (PIAA), told 

Twenty-seven percent of hospitals responding to an AHA survey said that physicians were retiring or moving out of state because of premium increases or a shortage of coverage. One hospital in five reported curtailing some services due to liability insurance problems.

The current crisis is, in some ways, a replay on a national scale of the events of the mid-1970s in California. Doctors in the southern part of the state stopped accepting new nonemergency patients as malpractice rates soared. That crisis ended with the passage of legislation limiting the amount of noneconomic damages that could be awarded in malpractice cases and with the creation of physician-owned mutual insurance companies--known in the trade as 

--to fill the gap left by the departure of commercial insurers from the professional liability market.

The next major skirmish occurred in the early 1980s when rates began to increase across the country. Eventually, 46 states passed tort-reform legislation designed to hold down damage awards, and by 1985 the number of claims being tried had begun to decline. Companies such as St. Paul recognized the need in the market for new capital and rushed to fill the breach. Some bedpan mutuals, such as SCPIE, began writing business outside their traditional home bases.

"About 1984, there was a drop-off in claims frequency, but because it takes five years on average for a claim to be paid after it surfaces, carriers were reluctant to say that there was a reversal in the trend," according to Smarr. "As a result, rates stayed at a higher level in the late 1980s. The companies didn't know they were making higher profits until the coverage losses paid themselves out."

The economic boom of the 1990s meant insurers were receiving high returns on their investments, largely in high-grade corporate bonds. As a result, companies relied less on premium income to realize a profit. They made their earnings goals on the interest income on their cash flow. "We had a very competitive marketplace during the latter half of the '90s," Smarr said, "and carriers lowered rates to unprofitable levels in order to get business."

At the end of the decade, as the Federal Reserve began cutting interest rates to stimulate the economy, insurance company portfolios yielded lower returns, which as Smarr told a congressional hearing last June, increased the need for premium revenues. 

An AHA study found that the return on investments for the property and casualty insurance industry--which includes malpractice insurers--declined from a high of 11.5% in 1997 to an estimated 4.3% in 2000.

At the same time, claims frequency began returning to its previous levels. More damaging, however, was an increase in claims severity--the amount of money paid out. "Severity has been rising at 5% to 8% a year since the 1980s," Smarr explained. "The average paid claim has risen by 6.9% a year through the 1990s, compared to an inflation rate of 2.6% during that period." Combined with declining interest rates and price competition, the increasing claims costs made malpractice an unprofitable line for many companies.

Insurers' combined ratio--a figure that consists of paid losses and overhead expenses divided by premium income--for medical malpractice was 140% in 2001, according to Pete Moraga of the Insurance Information Network of California. In other words, for every dollar of premium income, malpractice carriers paid out $1.40 in claims and overhead.

"The higher claims costs come from higher jury awards," Moraga told 

. "The median jury award in malpractice cases reached $1 million in 2000. That's up 110% from 1996, when the median was just $474,536. That also raises the bar on those cases that get settled. A lot of cases are settled before ever going to the jury."

According to a study released in July by HHS, the cost of litigation is a principle driver in the malpractice crisis. But only a handful of cases ever get to court. The HHS found, "Only 1.53% of those [patients] injured by medical negligence even filed a claim. Most claims--57-75%--result in no payment to the patient. When a patient does decide to go into the litigation system, only a very small number recover anything. One study found that only 8-13% of cases filed went to trial; and only 1.2-1.9% resulted in a decision for the plaintiff." The HHS termed the current legal system a litigation lottery.

Insurers believe the cure for the malpractice woes is a cap on noneconomic damages. They point to California, which enacted a cap in 1975. According to a study by the National Association of Insurance Commissioners, malpractice premiums in California have increased 167% since 1976, when the state's cap went into effect, compared with an increase of 505% for the rest of the country during the same period. 

"It makes no sense to deprive American citizens who have had the right to trial by jury for 225 years of that right," countered Carlton Carl, a spokesperson for the Association of Trial Lawyers of America, told 

. "What makes sense is having insurance companies resolve more claims without contesting them. Insurance companies go to court every day to fight the payment of legitimate claims in malpractice cases, auto cases and all sorts of cases. What does it profit anyone to deny people who have been injured, through no fault of their own, reasonable compensation for their injury?"

According to the lawyers, insurance company mismanagement and the quest for higher profits have contributed to the country's malpractice woes. "St. Paul lost $108 million with the collapse of Enron," Carl said. "There's a group of doctors in West Virginia who have filed suit against St. Paul for allegedly illegally transferring assets to subsidiaries that supposedly were reserved for claims. We're seeing potentially the same kinds of accounting shenanigans as we've seen in other corporations. Not to mention the industry's track record: They made their greatest profits through most of the'90s through medical malpractice premiums--earning a windfall in the stock and bond markets. As soon as the economy turns sour, they decide to raise rates. The same thing happened in the '80s and back in the '70s."

The Center for Justice and Democracy, argued, "To buy [the insurers'] position, one would have to accept the notion that jury awards were high in the mid-1970s, then low for a decade, then high in the mid-1980s, low for 17 years and are now high again. This is ludicrous  The average claims payout by medical malpractice companies is about $30,000 per claim and has been virtually unchanged for the last decade."

So far, the lawyers are finding little support for their position. Legislators in several states are considering caps on pain and suffering awards, and in the U.S. Congress the House passed a bill that mirrors California's 25-year-old law. In a press statement, the PIAA said the Congressional Budget Office believes the House measure would save the federal government $14.1 billion over the next 10 years in lower payments to providers. Proponents of the House-passed measure concede that it probably will take another year to get it through the Senate. "We're not going to let up," Richard Corlin, M.D., immediate past president of the American Medical Association, told the press. "If it doesn't have a cap on pain and suffering, it's not tort reform."

(On Oct. 9, Mississippi Gov. Ronnie Musgrove signed a bill that sets caps on pain-and-suffering damages for malpractice suits in that state--Ed.) 

Articles

As the economic boom of the'90s slows down, more and more insurance companies are realizing less profit. As a result, physicians find it more difficult to get the malpractice insurance they need; when they do find it, it is usually at a higher cost.

Health Care Faces Malpractice Crisis

The patient with whom I am exchanging pleasantries and sports scores is a second-generation pedophile. It is only a small exaggeration to say that he is on every medication known to man. Brutally and repeatedly sodomized by his stepfather through childhood and adolescence, he is himself a gentle person who experiences his deep aquifers of rage only when they spout forth under pressure in threatening auditory hallucinations. His own brief career as a sex offender followed the same quiet, obsequious, ingratiating style, and he inflicted no physical violence on the boys involved. It ended in a trip to the state prison, a dangerous place for convicted pedophiles, particularly for this slight and timid individual. I can make some fairly safe assumptions about what happened to him there.

Although I have known this patient for a number of years, my formal role with him in the clinic setting where I work part-time is limited to writing his prescriptions. If I really did all the paperwork I am supposed to do in connection with this, we would have no human interaction whatever. As it is, the mental health center's assigned clinician does the frontline work, and each new clinician chooses one of two basic tacks when my patient's name is transferred to their caseload. Some, focusing on his "major mental illness" diagnosis of schizoaffective disorder, concentrate on the management aspect, filling his weekly medication caddies or getting him to the cooking group. Others, usually inexperienced or idealistic or both, take on his posttraumatic stress disorder and his history with varying degrees of skill and intuitive common sense (few have meaningful supervision--their supervisor usually only shows them which forms to fill out and when). 

Ontogeny recapitulates phylogeny in the careers of this second group of clinicians, as it did in my own. Regardless of what any of us may have read, each generation of would-be therapists has to make Freud's original mistake of uncovering too much with the wrong patients and making them worse. This is the foremost vulgar error of psychodynamics, and the reason why many clinicians, trying to play it safe, thereafter avoid "content" altogether, or learn to see it only as something to be replaced by more adaptive cognitive schemata.

In this case, with sensitive history-taking and puzzling through recurrent nightmares, my patient's most recent idealist (an unusually gifted one) succeeded in precipitating a florid psychotic episode with command hallucinations both suicidal and homicidal. Perhaps some different, adaptive schema would not have been such a boring idea after all. The newly re-stabilized patient is fresh from the hospital.

Needless to say, with what influence I have, I try to support the management-minded clinicians' efforts and to dampen the idealists, but either way, clinicians only last at most a year or two. I am always left, as now, with my pedophile and his ongoing quest to be as numb as possible.

For the sake of emphasis, I will recite his medication list, with total daily doses (most are divided into fours, as frequent dosing is reassuring to him; the caddy boxes are reliable friends). Clonazepam 5 mg, oxcarbazepine 600 mg, risperidone 12 mg, trifluoperazine 20 mg, valproate 2000 mg, fluoxetine 80 mg and trazodone 200 mg at bedtime. And there may be more. Not to mention his insulin and oral hypoglycemic, his ACE inhibitor, his COX-2 inhibitor, his statin, his triptan, his proton-pump inhibitor, his inhalers. And the occasional zolpidem or oxycodone thrown in by a well-meaning on-call general physician. Altogether, a lot of things are being inhibited here. And God knows what interactions are going on beyond the binary scope of my software.

This man is younger than I am, and he can hardly move. Sometimes after seeing him, I walk up and down the hills across the street as fast as I can until I am sweating and breathless just to prove that movement is possible.

Academics, chief residents, inpatient docs, scoff all you want. I defy anyone with a serious public outpatient practice to tell me you do not have at least one, usually several, patients like this. They are one of psychiatry's ill-kept secrets, and I recall discovering them among my attendings' clientele when I was an on-call resident years ago. Luckily, my attendings were of a philosophical generation. Their explanations went straight to the big picture and skipped any attempt to make pharmacological sense or to apologize. These are broken people, they told me. Their lives are unbearable if experienced with any clarity. We help them to stay numb as an alternative to having them, or someone else nearby, get physically hurt or die. And then, over the years, we find something in them to appreciate or to make contact with, some little bit of life left within them. Such appreciation, such contact, must be seen as having value in itself and not as a means to an end. 

While dampening the idealism of the clinicians, I have myself practiced a sort of psychopharmacologic idealism. Every single psychotropic on the previous list has been tested with a taper since I inherited this patient several years ago. I have had small victories: buspirone is gone, oxcarbazepine has replaced carbamazepine. But any attempt at the big ones--fluoxetine, valproate, clonazepam, the antipsychotics--inevitably results in emergency department visits, phone calls from a frightened wife, broken windows, punctured walls. 

At first I thought we were having a symbolic dialogue about dependency and autonomy through his drastic reactions to any change I would make. I spent lots of phone time reassuring him and getting him to try and hang on, to wait some medically respectable interval before reinstating his former dosage. But after I stopped questioning his regime, there were no further problems until the latest therapist rocked the boat. The patient has taught me, and now he trusts me completely. Our contract is that I will keep him numb. He watches the sports channel and dozes periodically; sports is our topic today. His face is flat, his speech a bit slurred; his half-smiles, though, are still worth the wait.

On my desk beyond him is the latest issue of 

 in which Elio Frattaroli, M.D., speaks from his new book 

 (Viking, 2001). His words are an eloquent compensation for today's symptom-driven, mindless psychiatry. He speaks of unconscious conflicts and symptoms as an opportunity for spontaneous growth. True believer in psychotherapy that I am, I still find myself playing with ironic titles of my own. 

No, there is nothing mysterious here, no hidden conflict to reflect upon in the situation of my pedophile patient. The horror is mostly above board, and if we go looking for more, he lands in the hospital. 

Reflection, growth, awareness: such noble statements of value are necessarily one-sided; they always leave something important out. I still hide the newspaper's morning headlines from my 9-year-old, the suicide bombings, child abductions and rapes. From my 17-year-old, I do not. I suppose the difference is that I expect him by now to have developed his capacity for numbness. I must have been teaching him right all along.

Perhaps the Enron and WorldCom executives learned that lesson too well, oblivious to the future pain of the people from whom they stole even as these same people typed their memos and brought them their coffee. But clearly, we all learn adaptive numbness. It is a universal and essential complement to awareness. They must exist in some shifting equilibrium for us to survive in this sometimes hostile and overwhelming, sometimes hospitable and nurturing world.

 language) we are considering here parallels physical processes like hibernation and dormancy. Each seems to allow the organism to await better conditions (why else would my patient brighten while discussing sports scores?); each may end either in death or in a reawakening. I do not delude myself that even with all the time in the world I could "facilitate the maturational process" (Frattaroli, paraphrasing Winnicott) in some idealized psychotherapy with my patient. If his soul is healed, it will be by a Power greater than myself--by a change in the conditions within which he lies dormant. Both forms of psychiatry, biological and psychodynamic, may function as vast defense mechanisms against the recognition of just how bad life can be, and how helpless we are before that fact.

Today I paddle out onto my little lake at sunrise. It is as good a place for awareness as any. The loons are much tamer than they were when I was a boy: numb to the traffic noise from Route 302 that is already beginning to build, numb to me as I approach. Withdrawing to rocky coves, they will retain their numbness even as the noisy jet-skis invade, long after I go to work. Yet these indifferent-appearing loons are acutely aware of fish down deep in the cooler water, diving for them periodically. When I add my noise to the inbound traffic, I will be trying in the midst of my numbness to stay aware of the possibilities in my patient's gentle half-smile and his soul under the numbed-out surface.

How does a clinician deal with those patients for whom they can ultimately do nothing but help them stay numb for the majority of their days?

Numbing Out

Is history repeating itself? Has China taken up the political abuse of psychiatry by adopting the methods that made the Soviet Union infamous? That is the claim now being made by human rights groups who are calling on organized psychiatry to intervene. There is no doubt that China is persecuting members of the Falun Gong sect who are the followers of Master Li Hongzhi.

Police and security forces have broken up peaceful demonstrations by the Falun Gong; members of the sect have been beaten, they have been imprisoned, they have been sent to the Chinese labor camp--equivalents of the Soviet Union's gulags--and, yes, some have been sent to psychiatric hospitals. All of this persecution has been confirmed by reliable journalists, by human rights groups and by the friends and families of Falun Gong members who are laboring to enlist support in the West.

The outgoing president of the World Psychiatric Association (WPA), Prof. Juan J. Lopez-Ibor Jr., M.D., reported that over 500 complaints have been submitted to their Committee for the Review of Abuse of Psychiatry. The WPA met in Yokohama, Japan, this past August and voted to send an investigative team to China. The delegation of Chinese psychiatrists to the WPA supported this proposal. British and American psychiatrists had proposed stronger measures.

The exact parameters of the WPA investigation are unclear; we do not yet know what the Chinese government will allow. The Asia division of Human Rights Watch has already criticized the WPA for not playing hardball and for failing to threaten expulsion if China did not adopt effective remedies.

Based on the evidence currently available, I believe that some members of the Falun Gong indeed have been placed in psychiatric hospitals, not because they have serious mental disorders or because they pose a danger to themselves or others, but because they persist in their deep commitment to Falun Gong and to peaceful demonstrations.

China's severe treatment of the Falun Gong is not about political ideology. The Falun Gong is not a political critic of China's government, and, according to knowledgeable political observers, the Chinese government is now best characterized as a "non-ideological authoritarian" regime. The Chinese authorities are apparently threatened by any group that can mobilize a large demonstration. In 1999, when thousands of Falun Gong members completely surprised the Chinese government by assembling in a peaceful demonstration in front of the leadership compound in Beijing, the police and security forces cracked down ruthlessly. The persecution has only continued.

Human Rights Watch has every reason to be concerned about China's current regime, which has dealt ruthlessly with many of its citizens, as well as the Falun Gong. But there remains a critical consideration for organized psychiatry even if we, as individuals, stand shoulder-to-shoulder with human rights groups in condemning China's violations of human rights. Are China's psychiatrists playing an active role in the political abuses of psychiatry, as Human Rights Watch claims? Or are they fearfully and passively acquiescing to the authorities? I believe the answer to that question should guide organized psychiatry's response to our colleagues in China.

There is a reliable anecdotal account that, in my opinion, gives a partial answer to the question. It comes from a Chinese graduate student of physics now studying in Texas. He reports that his mother, a devoted Falun Gong member, was sent to a psychiatric hospital. Her psychiatrist told family members that his mother was not mentally ill, but that both the psychiatrist and family would get in trouble with the authorities if the mother persisted in going to Beijing to protest. Psychiatrists who know the situation in China believe this is the typical pattern. Psychiatric care in China is limited, and psychiatrists have little professional, political or economic power. They certainly do not have the resources to challenge a regime's oppressive measures.

It is certainly possible that some Chinese psychiatrists are actively and unethically cooperating with the authorities, rather than passively acquiescing or courageously resisting and risking retribution. Robin Munro, the chief spokesperson for Human Rights Watch, asserts that China's psychiatrists have been playing an active role in the persecution of political dissidents in China since the days of Chairman Mao.

It is, of course, well-known that under Mao, China engaged in horrific abuse of its citizens. During the Cultural Revolution, the totalitarian psychological methods of "Thought Reform" were imposed on anyone who opposed Mao or Maoism. Social scientists, psychiatrists, psychologists and other scholars around the world have studied the methods of Thought Reform.

Now Munro claims to have discovered that an influential cadre of forensic psychiatrists were directly involved in those abusive practices beginning in Mao's day and continuing to the present. His reconstruction, in the Human Rights Watch publication 

, of what he calls "the shadowy history of the political misuse of forensic psychiatry in the People's Republic of China" has become the basis of claims that Chinese psychiatrists, and particularly forensic psychiatrists, have adopted the methods of Soviet psychiatry.

Munro has no training in psychiatry and no direct knowledge of psychiatry in China. Nor is his claim based on new documents or recently available archives. He has gleaned his putative evidence from his reading of the published Chinese psychiatric literature. His is a tendentious reading, and he writes about the political abuses of judicial psychiatry in China during decades when there were no judges, no courts, no independent legal system and no forensic psychiatrists. The claim that there is a cadre of Chinese forensic psychiatrists who have adopted Soviet-style political abuses of psychiatry and who wield political power and misuse psychiatry seems without foundation in fact.

It is important to emphasize that even Munro, in condemning China's forensic psychiatrists for decades of political abuse, acknowledged that they were not involved in the recent measures taken against the Falun Gong. This is an important distinction that has been overlooked in the resolutions of organized psychiatry and in the media, where the claims are lumped together under the banner of Soviet-style abuse. There is very good evidence that police and security forces are abusing their plenary powers to relegate some members of the Falun Gong to psychiatric hospitals. There is none to support Munro's claim of Soviet-style abuse.

Based on that distinction, I believe the WPA has taken the right first step in voting to send an investigative team to gather more information. The evidence now available is insufficient to condemn Chinese psychiatrists or to threaten them with expulsion from the WPA.

Human Rights Watch and other groups are reporting significant increases in China's violations of its citizens' rights. Nothing I have written here is meant to diminish those very real concerns.

Is history repeating itself? Has China taken up the political abuse of psychiatry by adopting the methods that made the Soviet Union infamous? That is the claim now being made by human rights groups who are calling on organized psychiatry to intervene. 

Commentary Investigating Psychiatric Abuses

blunt trauma indigo
walled below pale blue eyes,

the biopsy site healed 
in a straight red line.

in this world where 
bruise is not a metaphor.

Here the body's art
conspires with destruction,

and violence surprises
with beauty so intense

the eyes of all beholders
must learn to be blind.

Wounds

Accurate and early diagnosis of Alzheimer's disease (AD) is vital to ensure patients receive the proper treatment, research is targeted correctly, and prevention and cures are found. However, it can be difficult to distinguish between AD and other forms of dementia, or even from other reversible disorders. The Alzheimer's Association has compiled an outline of the 10 most common symptoms associated with AD (Table 1) to help alert patients, caregivers and clinicians so that they can take action at the earliest signs of the disease. The earlier AD is diagnosed, the more treatable it is. The following is a review of some current tools used for diagnosis, and an update on research into promising new techniques for AD assessment.

The standard tools for assessing AD include neuropsychological or cognitive evaluation, physical exam, neurological exam, laboratory testing, neuroimaging, behavioral assessment, and patient history. Many of these tests have been used for several years, and the question has been raised as to which are most effective. 

 and those from the National Institute of Neurologic, Communicative Disorders and Stroke-AD and Related Disorders Association (NINCDS-ADRDA) have proven to be reliable resources for clinicians. 

A recent meta-analysis of the diagnostic accuracy of these tests compared to neuropathologic confirmation from several studies revealed that both guidelines achieved an average of 81% sensitivity for a diagnosis of "probable" AD (Knopman et al., 2001). A diagnosis of "possible" AD achieved a very high sensitivity of 93%. Specificity for both diagnoses was lower, at 70% and 48%, respectively. 

With respect to neuroimaging, magnetic resonance imaging, computed tomography (CT), single photon emission computed tomography (SPECT) and positron emission tomography (PET) have all been used to assist in the diagnosis of AD. In a study cited by Knopman and colleagues (2001), when compared to neuropathologic confirmation, CT scans were 95% sensitive and 40% specific for diagnosing AD based on the width of the medial temporal lobe in 86 autopsied cases. The researchers also assessed the value of SPECT in two large studies of autopsy-confirmed diagnoses of AD. The SPECT results revealed sensitivities ranging from 86% to 95%, and specificities ranging from 42% to 73% when comparing patients with AD and non-AD dementia. In a smaller study, PET scans were reported to have a sensitivity of 93% and a specificity of 63%. Knopman and colleagues cautioned that imaging should be used in conjunction with other tests to increase the likelihood of an accurate diagnosis. Only noncontrast CT or MRI scans were recommended for use in routine initial evaluation of dementia patients. Neither SPECT nor PET imaging have proven to be superior to clinical criteria for AD.

Cognitive assessment is essential to the diagnosis and treatment of AD. There are several neuropsychological tests to assess the patient's cognition as well as their overall clinical condition. It is also important to measure their function in activities of daily living. Finally, caregiver-based interviews or questionnaires are useful for assessing behavioral disorders. A list of these assessment scales can be found in Table 2.

Genetic (e.g., apoliproprotein E genotyping) and cerebrospinal fluid markers have been used when assessing patients for AD. However, Knopman and colleagues do not recommend using these or other genetic markers to diagnose AD, primarily because clinical criteria are more sensitive. Comorbidities, such as depression, vitamin B

 deficiencies and hypothyroidism, should be evaluated.

One of the greatest challenges of assessing AD is whether the patient's symptoms reflect true AD, some other dementia or a different disorder altogether. The tools previously mentioned can assist in differential diagnosis, but it is important for clinicians to be aware of the subtle differences and characteristics that distinguish AD. The Alzheimer's Association provides a "Differential Diagnosis in AD Algorithm" outlining step-by-step procedures for diagnosing AD. It is available at <www.alz.org/PhysCare/Diagnose/procedure.htm>. 

A majority of dementias such as vascular dementia (VaD), frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) are a result of vascular and degenerative brain diseases (Waldemar et al., 2000). In addition, inflammatory diseases, intra-cranial tumors and normal pressurehydrocephalus are rare symptomatic causes of dementia. According to the Alzheimer's Association, disorders that are associated with "reversible" dementia include depression, medication-induced dementia, hypothyroidism, B12 deficiency and systemic infections.

Lack of personal concern, disinhibition, indifference, compulsion and repetitive stereotyped behaviors demonstrate particular behaviors of FTD but are not typically seen in AD (Waldemar et al., 2000). Waldemar and colleagues also noted that early symptoms of DLB can include delusions and hallucinations. According to the Alzheimer's Association, VaD differs from AD in that the cognitive changes are typically associated with an onset within three months following a stroke, abrupt deterioration in cognitive functions or fluctuating, stepwise progression of cognitive deficit. Depression in elderly patients can manifest itself as confusion, memory disturbance and impaired attention, all of which are typically not seen in younger depressed patients. Alzheimer's disease may also coexist with depression, with each disorder exacerbating the other.

As mentioned earlier, patients with suspected dementia would benefit from structural neuroimaging studies such as MRI or CT in order to rule out brain diseases that can cause dementia. In the early stages of AD, changes in medial temporal lobe volume can be seen on MRI scans and, at times, on CT scans. In addition, MRI scans may show abnormalities of white matter or basal ganglia, which can affect diagnosis and/or prognosis of AD (Waldemar et al., 2000). Functional brain imaging such as SPECT and PET may be helpful when a clinical diagnosis of AD is questionable, but should not be used in place of a competent and confident clinical diagnosis (Knopman et al., 2001). 

Although some studies find PET imaging useful for providing a differential diagnosis of dementia (e.g., Coleman, 2001; Silverman et al., 2001), researchers are still trying to find ways of improving imaging for use in AD. The latest research in PET imaging found that a new agent can help clinicians detect the actual plaques that cause AD. Prior to these findings, researchers could only detect plaques at autopsy. Jorge R. Barrio, Ph.D., professor of molecular and medical pharmacology at University of California, Los Angeles, and his colleagues came across this discovery during an attempt to locate proteins in the brain. They developed a molecule called 2-(1-(6-[(2-[18F]fluoro-ethyl)(methyl)amino]-2-naphthyl) ethylidene)malononitrile ([18F]FDDNP), which binds to the neurofibrillary tangles (NFTs) and ß-amyloid plaques (APs) in the brains of living patients with AD (Shoghi-Jadid et al., 2002). The researchers studied nine patients with AD and seven healthy controls. All subjects received neurologic, psychiatric and neuropsychological evaluations. They then were injected with [18F]FDDNP and subsequently scanned with fluorodeoxyglucose-PET (FDG-PET). The researchers' findings revealed that brain areas with low glucose metabolism, as a consequence of damage from NFTs and APs, were matched with high retention and localization of [18F]FDDNP. This correlated with lower scores on memory performance. In addition, the death of one patient allowed the researchers to compare the PET scan with brain tissue. They found that the patient had damage to the areas suggested by the PET scan. 

The researchers hope that PET imaging with [18F]FDDNP will be used to detect neuronal damage before symptoms appear. "[Alzheimer's disease] remains silent for many years. By the time memory deficits appear, the disease is already advanced," Barrio told 

. As exciting as this discovery is,    it also raises some issues. One is the question of who should be tested. If the idea is to catch the disease before symptoms appear, then anyone appearing normal should be tested. This method is not practical for obvious reasons. Second, once a patient is tested, the appearance or absence of plaques does not guarantee or dismiss a diagnosis. According to Barrio, healthy adults can have plaques in their brains without ever developing AD. Finally, if a patient is found to have a substantial number of plaques in their brain, what actions should be taken? "It's not a good idea to only provide early diagnosis and no hope," said Barrio. "The pharmaceutical industry is working very hard to develop drugs that will prevent formation of plaques." In addition, Barrio and his team are working on 25 to 30 additional compounds to optimize the resolution in the scans.

With the intent of determining predictors of AD, findings from a study  published in 

 may also provide tools for diagnosing AD (Marquis et al., 2002). Researchers at University of Alberta in Canada studied 108 adults 65 years or older who were healthy at the start of the study. After an average of 3.7 years, 48 of these subjects progressed to questionable dementia. The researchers found that those with dementia entered the study with three traits in common: slower gait, lower scores on memory tests and minor shrinkage in the hippocampus as measured by MRI. Each of these changes was very subtle, but physicians may want to take these traits into consideration when evaluating older patients.

With the multitude of tools available for diagnosing AD, physicians need to be selective in choosing the methods that are right for them and their patients. Time, cost, accuracy and convenience are factors physicians and researchers need to take into consideration. Fortunately, as more tools become available, physicians will have a better chance of accurately diagnosing AD. Most important, physicians must take care to diagnose their patients early in the disease and treatment process.

 Coleman RE (2001), Positron emission tomography in the evaluation of dementia. Presented at the 48th Annual Meeting of the Society of Nuclear Medicine. Toronto; June 23.
 

 Knopman DS, DeKosky ST, Cummings JL et al. (2001), Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56(9):1143-1153 [see comments].
 

 Marquis S, Moore MM, Howieson DB et al. (2002), Independent predictors of cognitive decline in healthy elderly persons. Arch Neurol 59(4):601-606.
 

 Shoghi-Jadid K, Small GW, Agdeppa ED et al. (2002), Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 10(1):24-35.
 

 Silverman DH, Small GW, Chang CY et al. (2001), Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 286(17):2120-2127 [see comments].
 

 Waldemar G, Dubois B, Emre M et al. (2000), Diagnosis and management of Alzheimer's disease and other disorders associated with dementia. The role of neurologists in Europe. European Federation of Neurological Societies. Eur J Neurol 7(2):133-144 [see comment].

New developments in neuroimaging and effective diagnostic tools can help obtain early diagnosis of and timely treatment for Alzheimer's disease.

An Overview of Diagnostic Tools

Dementia is defined as an acquired persistent impairment of intellectual function with compromise in at least three of the following spheres of mental activity: language, memory, visuospatial skills, emotion or personality, and cognition. 

Despite recent advances in our understanding of the pathophysiology of Alzheimer's disease (AD) and other dementing illnesses, current treatments for these disorders often fall short of expectation. Patients, family members and caregivers often find themselves unable to resist the lure of using so-called natural products to treat or prevent memory impairments and their behavioral and psychological symptoms. This article will focus on providing an overview of the current scientific evidence of commonly used supplements for memory impairment. 

Lecithin is found in many animal and vegetable sources (e.g., peanuts, cauliflower, oranges, eggs, steak and beef liver). Commercial sources can come from soybeans, eggs and other animal sources. Lecithin is a choline-containing phospholipid and a major dietary source of choline. It is postulated to accelerate the synthesis of acetylcholine in the brain (Higgins and Flicker, 2000). 

A review of 12 studies of dementia of the Alzheimer's type (DAT) to determine the efficacy of lecithin showed an overall relative deterioration of activities of daily living (ADLs) and no improvement of cognition or global impairment (Higgins and Flicker, 2000). In that same review, one trial of Parkinson's dementia showed a nonsignificant improvement in orientation and memory tests. There was no evidence of an effect on functional performance. However, the reviewers did find possible statistical improvement in one trial of subjective memory complaints.

The proposed lecithin dose is 1.2 g/day to 2.4 g/day. Possible adverse reactions include gastrointestinal (GI) pain, nausea or diarrhea. No adverse interactions have been reported.

Also known as tocopherol and tocotrienol, vitamin E occurs in oils, fats, nuts and other seeds, as well as a variety of animal foods. Alpha-tocopherol, the medical form used, is fat-soluble, and can therefore enter the brain. Vitamin E functions biologically as an antioxidant, inhibiting the process of lipid peroxidation. 

One study using 1000 international units (IU) bid of vitamin E over two years in subjects with moderate DAT found no difference in survival time. The combination of vitamin E (2000 IU/day) and selegiline (Eldepryl) (10 mg/day) was shown to reduce the rate of decline of functions in patients with AD. However, combined therapy was not superior to either agent alone (Sano et al., 1997). 

Data from the Honolulu-Asia Aging Study suggested that vitamins E and C have a protective effect for vascular and mixed dementias and may improve cognitive function in late life (Masaki et al., 2000). 

The proposed dose of vitamin E is 1000 IU bid. While possible adverse reactions are rarely reported, vitamin E may cause GI disturbances, blurred vision, headaches and fatigue. 

Theoretically, vitamin E might increase the risk of bleeding in people with vitamin K deficiency or bleeding tendencies. It may theoretically have an additive interaction with antiplatelet and anticoagulant medications. 

, which is present in cereal grains, nuts, meats and legumes, in treating alcoholic amnesia is well established. Animal studies both suggested that vitamin B

 might facilitate the presynaptic release of acetylcholine and bind to nicotinic receptors enhancing anticholinesterase activity. These may have a role in the management of AD. 

 as a treatment for AD are mostly small with fewer than 50 subjects. Most studies used subjects with mild-to-moderately severe AD and measured cognition and behavior as the primary outcomes. Overall results showed no improvement in cognition; however, results should be considered as inconclusive due to poor design and small number of subjects (Rodriguez-Martin et al., 2001). 

 may cause a hypersensitivity reaction or dermatitis. Loop diuretics may increase urinary B

 excretion resulting in a deficiency that can affect cardiac function. 

 is an Ayurvedic herbal used for mental illness, epilepsy and cognitive enhancement. 

Steroidal saponins derived from the leaves are the active principle ingredient thought to enhance nerve impulse transmission, and hence to improve memory and cognition. Animal and human studies conducted in India in the early 1980s reported memory enhancing effects with improved concentration and working memory (Singh and Dhawan, 1982; Singh and Singh, 1980). Further studies are needed to explore the pharmacology and clinical usefulness of this supplement.

The proposed dose of Bacopa monniera is 12 g/day of the dried plant in syrup. Possible adverse effects and interactions are unclear from the literature available.

Perhaps the most widely recognized plant in folk medicine, ginseng (

) refers to several different species originating in different countries. The root is considered the most valuable in traditional medicine and has been used in the treatment of a great number of symptoms and diseases. The contents of the particular root are dependent on the species, age, location of plant, and method and timing of harvest and processing. Over the last decades, laboratory and human studies have documented a range of pharmacological effects from the ginsenosides, the steroid-like compounds found in ginseng. Ginseng is known as an adaptogen. Animal studies report a reversal of scopolamine-induced memory deficits in rats, an increase in acetylcholine uptake and improved learning performance. In humans, two randomized, controlled trials reported some improvement in cognitive function over eight and 12 weeks of ginseng use. Another study, looking specifically at 50 elderly subjects, reported improvement over baseline measures (Vogler et al., 1999). 

The proposed ginseng dose is 400 mg/day. Possible adverse effects from taking ginseng include headache, hypoglycemia, tremor, sleep disorders and GI disorders. Ginseng may interact with warfarin (Coumadin), diabetic agents and insulin, diuretics, digoxin, phenelzine (Nardil), and alcohol.

An endogenous substance that participates in cellular energy production, acetyl-l-carnitine is structurally related to acetylcholine; hence it may enhance cholinergic neurotransmission. It may also promote mitochondrial membrane stabilization. 

Several animal and laboratory studies suggested a possible role in delaying cognitive decline. A large-scale study enrolled 229 subjects with probable AD between 45 years of age and 65 years of age. Subjects were randomized to 1 g tid or placebo. No differences in the rate of decline of cognitive function were noted (Thal et al., 2000). This finding is contrary to outcomes reported in previous smaller studies that indicated a slowing of cognitive decline. Further studies are needed to evaluate the possible role of acetyl-l-carnitine in the management of memory impairment.

The proposed dose of acetyl-l-carnitine is 1.5 g/day to 4 g/day divided in three doses. Possible adverse reactions may include confusion, depression, agitation or aggression in patients with AD. No adverse interactions have been reported.

 extracts are prepared from the green leaves of the maidenhair tree. More than 40 individual components of ginkgo have been identified so far. Actions of the components of ginkgo include antioxidant properties, vasodilation, antagonism of platelet-activating factor and an increase in density of muscarinic receptors. 

A recent review of nine randomized, double-blind, controlled studies suggested that ginkgo extract is more effective than placebo in delaying the deterioration of AD, vascular dementia and mixed types. A small effect was observed after six months in a meta-analysis looking at subjects with mild-to-moderate AD (Ernst and Pittler, 1999). Wettstein (2000) compared placebo-controlled studies of available cholinesterase inhibitors with studies of the standardized ginkgo extract EGb 761 and found similar periods of delay in disease progression, although  another well-designed study failed to find any benefit in elderly subjects with mild-to-moderate dementia (van Dongen et al., 2000). Large doses of ginkgo (>600 mg) resulted in subtle improvement in speed of information processing but not in other cognitive functions. Overall, studies looking at memory improvement in nondemented healthy adults have been inconclusive.

The proposed dose of ginkgo is 120 mg/day to 240 mg/day divided in three doses of the standardized extract containing 24% flavonoids and 6% terpenoids. Possible adverse reactions include headache, dizziness, palpitations, restlessness, weakness, central nervous system hemorrhage and seizures. Ginkgo should be used with caution with medications that inhibit clotting or enhance bleeding.

An alkaloid extracted from a moss, huperzine A (

) is used in Chinese medicine for a variety of conditions including memory problems. It is currently being sold in the United States as an over-the-counter dietary supplement to enhance cognition for people with memory loss. 

Research has shown huperzine A to be a selective and reversible inhibitor of acetylcholinesterase. It also has been shown to lessen neuronal toxicity caused by glutamate. Initial small investigations reported improvement in cognitive functions of subjects with AD (Xu et al., 1999; Xu et al.,1995). Further evaluations are warranted. 

The proposed dose of huperzine A is 30 mcg to 200 mcg bid. Possible adverse reactions include blurred vision, GI effects, hyperactivity, anorexia and bradycardia. Use of huperzine A might worsen overflow incontinence.	

Theoretically, huperzine A could have an additive effect on cholinergic and acetylcholinesterase inhibitors and interact adversely with anticholinergic drugs. 

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) are secreted by the adrenal glands and are the precursors of androgens. Their exact effect on cognition is unclear, but some authors attribute it to neurotransmission. Levels of DHEA peak at puberty and fall slowly as people get older (Schneider et al., 1992). Restoring low levels of DHEA has been reported to improve the overall well-being of older adults (Huppert et al., 2000). 

Two prospective studies of 833 community-dwelling men and a middle-class cohort of 270 men, respectively, found no association between levels of DHEA-S and cognitive decline (Barrett-Connor and Edelstein, 1994; Moffat et al., 2000). Other studies reported similar findings among men and women. A clinical observational study of patients with AD found no association between cognition and DHEA-S level. Huppert et al. (2000) concluded that the data offered no support for an improvement in memory or other aspects of cognitive function in normal older people.

Commercial products are manufactured from a wild yam extract. The proposed dose of DHEA or DHEA-S is 25 mg/day to 250 mg/day qid. Determination is based on measured blood levels. Possible adverse reactions include acne, hair loss, hirsutism, decreased high-density lipoproteins, insulin resistance, mania, hypertension, abdominal pain, liver dysfunction and menstrual irregularity. 

Since DHEA inhibits cytochrome P450 3A, it can potentially affect all drugs metabolized through this mechanism. Caution is required for people with diabetes as DHEA may increase insulin resistance. Individuals with hormone sensitive neoplasm, liver disease and bipolar disorder should avoid DHEA. Theoretically, soy may decrease the effect of DHEA. 

A broad-spectrum antibiotic previously used for the treatment of tuberculosis, D-cycloserine is a structural analogue of the amino acids glycine and D-alanine.

There is accumulating evidence that supports an important role for N-methyl-D-aspartate (NMDA) receptors in learning and memory through long-term potentiation. The activity of NMDA receptors can be modulated by the activity of glycine. These glycine receptors are also stimulated by the antibiotic D-cycloserine. Hence, it has been suggested that D-cycloserine might improve memory and other cognitive processes. An initial study using low doses of D-cycloserine reported a reversal of scopolamine-induced memory impairment in healthy young subjects (Laake and Oeksengaard, 2002). 

In a review of four studies (two large and two small) using varied doses in subjects with different levels of memory impairment, Laake and Oeksengaard (2002) found no evidence of differences with placebo in the measurement of Clinical Global Improvement Scale (CGI), mini-mental state exam (MMSE), and other cognitive and functional scales. The number of dropouts was much higher in the treatment group than in the placebo group. 

The proposed D-cycloserine dose is 10 mg to 200 mg divided into two doses per day. Adverse reactions are dose-related and include ankle clonus, confusion, dysarthria, headache, hyper-reflexia, irritability, nervousness, paranoid reactions, psychotic states with suicidal tendencies, vertigo, paresis, seizures and tremor. No adverse interactions have been reported.

An amino acid found in green tea, theanine is a glutamate analog. Theoretically it can provide neuroprotection by antagonizing the effect of glutamate and NMDA receptors. 

Animal studies indicate a possible protective effect of ischemic neuronal death (Kakuda et al., 2000). No human studies were located for this review.

No typical dose in humans has been proposed and the possible adverse reactions are unknown. Theanine can interact adversely with catecholamine and cause vasoconstriction, so it should be used with caution in people with hypertension.

Most studies of the phospholipid phosphatidylserine used bovine brain sources, but, due to concerns about mad cow disease, soy or cabbage sources are now available. Phosphatidylserine is active at cell membranes, including synaptic membrane zones. Partial improvement of learning and recall capacity was noted in subjects with age-related cognitive decline (Crook et al., 1991). 

The proposed dose is 100 mg/day to 300 mg/day. Possible adverse reactions include GI upset and insomnia at high doses. Phosphatidylserine may interact with uric acid and alanine aminotransferase (ALT/SGPT) lab tests. There have been no reported adverse interactions.

Among the many dietary supplements used for memory impairment, several have shown some evidence of effectiveness. Others are still awaiting proof through well-designed studies. Despite the great interest in and use of dietary supplements, the collection of scientific evidence on their efficacy is still in its infancy, and better-designed studies are needed to provide us with answers. For now, clinicians need to use caution in interpreting available information and in counseling their patients. 

 Barrett-Connor E, Edelstein SL (1994), A prospective study of dehydroepiandrosterone sulfate and cognitive function in an older population: the Rancho Bernardo study. J Am Geriatr Soc 42(4):420-423.
 

 Crook TH, Tinklenberg J, Yesavage J et al. (1991), Effects of phosphatidylserine in age-associated memory impairment. Neurology 41(5):644-649.
 

 Ernst E, Pittler MH (1999), Ginkgo biloba for dementia: a systematic review of double-blind, placebo-controlled trials. Clinical Drug Investigation 17(4):301-308.
 

 Higgins JP, Flicker L (2000), Lecithin for dementia and cognitive impairment. Cochrane Database Syst Rev (2):CD001015.
 

 Huppert FA, Van Niekerk JK, Herbert J (2000), Dehydroepiandrosterone (DHEA) supplementation for cognition and well-being. Cochrane Database Syst Rev (2):CD000304.
 

 Kakuda T, Yanase H, Utsunomiya K et al. (2000), Protective effect of gamma-glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils. Neurosci Lett 289(3):189-192.
 

 Laake K, Oeksengaard AR (2002), D-cycloserine for Alzheimer's disease. Cochrane Database Syst Rev (2):CD003153.
 

 Masaki KH, Losonczy KG, Izmirlian G et al. (2000), Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54(6):1265-1272 [see comment].
 

 Moffat SD, Zonderman AB, Harman SM et al. (2000), The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 160(14):2193-2198.
 

 Rodriguez-Martin JL, Qizilbash N, Lopez-Arrieta JM (2001), Thiamine for Alzheimer's disease. Cochrane Database Syst Rev (2):CD001498.
 

 Sano M, Ernesto C, Thomas RG et al. (1997), A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 336(17):1216-1222 [see comments].
 

 Schneider LS, Hinsey M, Lyness S (1992), Plasma dehydroepiandrosterone sulfate in Alzheimer's disease. Biol Psychiatry 31(2):205-208.
 

 Singh HK, Dhawan BN (1982), Effect of Bacopa monniera Linn. (brahmi) extract on avoidance responses in rat. J Ethnopharmacol 5(2):205-214.
 

 Singh RH, Singh L (1980), Studies on the anti-anxiety effect of the medyha rasayana drug, Brahmi (Bacopa monniera Wettst.). J Res Ayur Siddha 1:133-148.
 

 Thal LJ, Calvani M, Amato A, Carta A (2000), A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 55(6):805-810 [see comment].
 

 van Dongen MC, van Rossum E, Kessels AG et al. (2000), The efficacy of gingko for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc 48(10):1183-1194.
 

 Vogler BK, Pittler MH, Ernst E (1999), The efficacy of ginseng. A systematic review of randomised clinical trials. Eur J Clin Pharmacol 55(8):567-575.
 

 Wettstein A (2000), Cholinesterase inhibitors and Gingko extracts-are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration. Phytomedicine 6(6):393-401.
 

 Xu SS, Cai ZY, Qu ZW et al. (1999), Huperzine-A in capsules and tablets for treating patients with Alzheimer disease. Acta Pharmacologica Sinica 20(6):486-490.
 

 Xu SS, Gao ZX, Weng Z et al. (1995), Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer's disease. Acta Pharmacologica Sinica 16:391-395.

The promise of natural products as possible sources of new treatments for Alzheimer's disease and other dementing illnesses is on the rise. Scientific evidence for the 13 dietary supplements most commonly used for memory impairment is analyzed and evaluated.

Using Complementary Treatments

Alzheimer's disease (AD) is a devastating and debilitating neurodegenerative condition, and the most common cause of dementia among the elderly. Despite considerable advances in the cellular and molecular biology of AD, however, little progress has been made in identifying the causes of the disease. Both the canonical plaques and tangles correlate poorly with the extent of cognitive decline, and it is unclear whether they themselves are the primary culprits or rather markers of a later stage in a disease process (Joseph et al., 2001). If the latter is true, then concomitant pathologies such as cerebrovascular disease may be significant contributors to the disease even if they are neither necessary nor sufficient for plaque and tangle formation. Indeed, AD and cerebrovascular disease frequently overlap (de la Torre, 2002; Kalaria and Ballard, 1999; Moody et al., 1997), and the presence of such pathology contributes synergistically to the severity of cognitive impairment, beyond what would be predicted on the basis of the AD pathology alone (Nagy et al., 1997). In this context, recent epidemiological evidence for an association of AD with elevated serum total homocysteine (tHcy) and low levels of B vitamins is of considerable interest (Clarke et al., 1998; Seshadri et al., 2002; Snowdon et al., 2000). 

Elevated tHcy is a recognized risk factor for vascular disease (Boushey et al., 1995; Clarke et al., 1991), cerebrovascular disease (Brattstrom et al., 1984; Yoo et al., 1998), stroke (Bostom et al., 1999a) and all-cause morbidity (Bostom et al., 1999b). Homocysteine is a non-protein-forming, sulfur-containing amino acid, produced by the body as it metabolizes the essential amino acid methionine. Homocysteine is metabolized by two pathways: methylation, in which methionine is synthesized using folate and vitamins B

, and transsulfuration, in which vitamin B

 is a cofactor in the degradation of homocysteine (see Figure, as well as Selhub [1999] or Finkelstein [1990] for review). 

Homocysteine metabolism is regulated by the cell to maintain a balance between the methylation and transsulfuration pathways and to maintain low levels of this potentially cytotoxic amino acid (Brattstrom et al., 1994; Brattstrom et al., 1988; Finkelstein, 1990). Barring kidney malfunction, the occurrence of hyperhomocysteinemia indicates that homocysteine metabolism has been disrupted and that the export mechanism is disposing excess cellular homocysteine into the blood. This response prevents toxicity to the cell, but leaves vascular tissue exposed to the potentially harmful effects of excess homocysteine.

Hyperhomocysteinemia can occur as a result of a nutritional deficiency of one or more of the vitamins that participate in homocysteine metabolism. Excess dietary methionine, found primarily in meat and dairy products, can also raise plasma homocysteine levels. 

In a longitudinal case-control study, Clarke et al. (1998) calculated a risk ratio of 4.5 for histologically confirmed AD associated with serum total homocysteine in the upper third of homocysteine values, after controlling for age, sex, social class, smoking and apolipoprotein E (APO E)/

4 genotype. When also controlling for folate and B12, the risk ratio rose to 5.1, suggesting that homocysteine's effects were (at least partially) independent of vitamin status. Homocysteine values were found to be relatively stable during three annual follow-ups compared with values at enrollment, were not related to duration of illness or to the severity of dementia prior to enrollment, and predicted the extent of medial temporal lobe atrophy. 

We have enlarged these observations in a prospective study of incident AD in 1,092 subjects from the Framingham cohort. In nondemented subjects, plasma tHcy levels of >14 µmol/L at baseline nearly doubled the risk of incident dementia eight years later (Seshadri et al., 2002). After adjusting for age, sex, APO E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6, the relative risk for all-cause dementia was 1.4 per standard deviation increase in tHcy, either at baseline or eight years earlier. Corresponding relative risks for AD were 1.8 and 1.6, respectively. The risk of AD attributable to a plasma tHcy in the highest age-specific quartile of our population was 16%, which is comparable to the population-attributable risk of having at least one APO E4 allele (Brookmeyer et al., 1998). 

Our findings supported a strong graded association between plasma tHcy levels and the risk of developing dementia and AD. These findings may have even broader significance in light of repeated observations associating hyperhomocysteinemia with mild cognitive impairment and poor performance on neuropsychological tests in dementia-free subjects (Duthie et al., 2002; Morris et al., 2001; Nilsson et al., 2001).

These epidemiological observations are consistent with the view that vascular dementia and AD share some common pathological mechanisms. The role of hyperhomocysteinemia is particularly interesting in this context, because plasma homocysteine can be safely lowered by relatively inexpensive nutritional intervention and vitamin supplements, which could conceivably reduce the associated risk (Homocysteine Lowering Trialists' Collaboration, 1998; Selhub et al., 2000b). However, association does not prove causality. Alternative explanations include the possibilities that these associations are secondary to disease-related metabolic disturbances, or the trivial explanation that they reflect a reduction in dietary intake with increasing severity of cognitive decline and dementia (Riviere et al., 1999). Even the early rise in homocysteine levels, which seems to increase the likelihood of subsequent dementia, could be secondary to other disease-related processes (Brattstrom and Wilcken, 2000). Nevertheless, elevated plasma homocysteine apparently reflects an early involvement of impaired one-carbon metabolism in AD (Figure). 

In order to validate homocysteine as a causative risk factor for AD, two conditions must be satisfied: the epidemiological association must be shown to be causal, and the pathological mechanism underlying this association must be elucidated. Satisfying both conditions requires the application of complementary epidemiological and biochemical approaches to the problem.

Demonstrating causality can only be done in an experimental study by reducing the exposure of a treatment population to homocysteine while holding all other factors constant. Currently, several trials are planned or underway to test the benefit of B vitamin supplementation in lowering homocysteine and, in turn, preventing dementia or slowing its progression. Successful outcomes will support a causal role for homocysteine in AD and point to a considerable public health benefit of homocysteine-lowering. If, however, the trials successfully lower homocysteine without preventing cognitive decline, the relation of homocysteine to AD will remain uncertain. 

A variety of theoretical mechanisms have been invoked to account for the association of homocysteine with AD and cognitive decline (see Selhub et al. [2000a] for a review). Homocysteine might contribute to thromboembolism of large vessels through damage to the endothelial cells that line the vessels, or by harming the brain capillaries (composed of a single layer of endothelial cells) that make up the blood-brain barrier. Homocysteine might also poison groups of neurons that have N-methyl-D-aspartate receptors (e.g.,  hippocampal pyramidal cells that are particularly vulnerable to AD pathology) (Lipton et al., 1997). There is considerable experimental evidence (largely in vitro) supporting such cytotoxic effects of homocysteine, but their relevance in vivo is uncertain, particularly in the brain where they have never been tested. 

Alternatively, elevated plasma homocysteine might reflect the accumulation in the cells of its precursor, S-adenosylhomocysteine (SAH), a potent inhibitor of methylation reactions. Several important neurological processes require methylation, which, if disrupted significantly, could have a profound impact on neurological function. Furthermore, impaired one-carbon metabolism has also been linked to DNA damage (Duan et al. 2002; Kruman et al., 2002; Kruman et al., 2000) and altered metabolism of biogenic amines (e.g., dopamine, norepinephrine, serotonin) (Gospe et al., 1995; Hamon et al., 1986). Folate and vitamin B12 are necessary cofactors for normal brain metabolism, and severe deficiencies of either one will directly impair neurological function. This necessity, together with their intimate metabolic relationship to homocysteine, makes it difficult to dissociate the putative toxicity of homocysteine from the potentially harmful effects of inadequate folate or vitamin B12 status. 

These and other questions will need to be addressed in order to fully understand the observed epidemiological relation of impaired one-carbon metabolism (elevated homocysteine and deficient B vitamins) to AD, and to justify widespread screening for tHcy and population-based vitamin intervention.

 Bostom AG, Rosenberg IH, Silbershatz H et al. (1999a), Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med 131(5):352-355.
 

 Bostom AG, Silbershatz H, Rosenberg IH et al. (1999b), Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med 159(10):1077-1080.
 

 Boushey CJ, Beresford SA, Omenn GS, Motulsky AG (1995), A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274(13):1049-1057 [see comments].
 

 Brattstrom LE, Hardebo JE, Hultberg BL (1984), Moderate homocysteinemia-a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke 15(6):1012-1016.
 

 Brattstrom LE, Israelsson B, Jeppsson JO, Hultberg BL (1988), Folic acid-an innocuous means to reduce plasma homocysteine. Scan J Clin Lab Invest 4(3):215-221.
 

Alzheimer's disease (AD) is a devastating and debilitating neurodegenerative condition, and the most common cause of dementia among the elderly. Despite considerable advances in the cellular and molecular biology of AD, however, little progress has been made in identifying the causes of the disease.

Psychiatric Times Vol 19 No 11