Posted 9 June 2009

7th Annual Mild Cognitive Impairment (MCI) Symposium: Focus on Early Alzheimer’s Disease and Non-Alzheimer’s Prodromal Dementia

March 27-28, 2009
Miami, Florida

View Powerpoint Slide Index (Links to presentations also appear in the summary below.)

In the past decade, the concept of mild cognitive impairment (MCI) has provided a way of identifying people at elevated risk of developing Alzheimer disease. MCI has been difficult to put in practice at times, but all the same has opened a window of opportunity for early detection, intervention, and some clinical trials. At the 7th Annual MCI Symposium, held 27-28 March in downtown Miami, Florida, 24 speakers covered the waterfront on this topic. Nineteen of the speakers graciously made their slides available to the Alzforum community, enabling writer Pat McCaffrey to bring you a comprehensive virtual conference report.

Dementia Prodromes Take the Stage in Miami

8 June 2009. Early detection improves the prospects for treatment for most diseases, and Alzheimer disease is no exception. In the past decade, the concept of mild cognitive impairment—a diminution of mental function, usually including memory domains, that falls short of frank dementia but exceeds the normal changes of aging—has provided a way to identify people at a higher risk of developing AD and opened a window of opportunity for intervention. The MCI construct has enabled imaging and other studies of earlier and earlier stages of AD. In setting the agenda for the 7th Annual Mild Cognitive Impairment (MCI) Symposium, host Ranjan Duara, Director of the Wien Center for Alzheimer’s Disease and Memory Disorders at Mount Sinai Medical Center in Miami Beach, Florida, aimed to offer participants the latest in a broad range of MCI research, in AD as well as in other dementias. Twenty-four speakers in four sessions covered topics ranging from the imaging and neuropathology of what are now recognized as many subtypes of MCI, to the prodromal manifestations of non-AD dementias, to the important question of the role of vascular factors in dementia and its prevention. View Duara Presentation [.ppt] (1.15 MB).

The symposium this year marked the tenth anniversary of keynote speaker Ronald Petersen’s seminal publication on the clinical characterization of MCI (Petersen et al., 1999). Petersen and colleagues at the Mayo Clinic in Rochester, Minnesota, described MCI in older people who reported memory complaints and showed a measurable cognitive decline but had preserved overall function and no dementia. While not all researchers agree with the characterization of MCI in that paper, it stimulated a blossoming of research into MCI, Petersen said.

A continuing challenge for MCI researchers has been standardizing and operationalizing the definition of MCI so that clinical determinations are robust and reproducible. Even so, different epidemiological studies in the past decade show that, consistently, about 15 percent of elderly fit the criteria of MCI. The number of new cases of MCI each year is two to three times higher than the new cases of dementia, making MCI “a significant public health issue,” Petersen said.

Not everyone with MCI goes on to develop AD or dementia, and another challenge is how to distinguish those patients who will progress. Back in 1999, the available data indicated that MCI progresses to dementia at a rate of 12 percent per year, compared to 1-2 percent of the general elderly population who develop AD. This number has stood the test of time, Petersen said, although it appears slightly higher in clinical groups of people who show up at the doctor’s with a memory complaint (10-15 percent per year) versus epidemiological studies of the general population (7-10 percent per year). Over the past decade, multiple factors have been discovered that predict progression, including clinical severity of impairment, ApoE genotype, and MRI measures of ventricular expansion and hippocampal atrophy. FDG-PET and amyloid imaging, as well as CSF biomarkers can also contribute to predicting progression, and combining these measures leads to higher-quality predictions.

Predicting which subjects with MCI are headed for AD is key to successful clinical trials in early AD. Current trials are powered based on a 15 percent conversion rate per year, but most trials have not achieved that rate, Petersen says. The progression rate is affected by the source of subjects, study design, cutoff scores, diagnostic procedures, and other variables, and lower rates mean that positive drug effects may be difficult to see. So far only the ADCS trial of donepezil posted a 15 percent conversion, Petersen said, noting that trial showed some hint of positive effects in the first one to two years (see ARF related news story). The ADNI project, which replicates the ADCS recruitment protocol, is recording an annual progression rate to AD of 16 percent.

When MCI is not a precursor to AD, it may offer an early warning of other neurological or neurodegenerative conditions. Since 1999, the MCI picture has become more complicated, with MCI now split into two broad subtypes. Amnestic MCI (aMCI) involves deficits in memory only, while non-amnestic MCI is defined by deficits in other cognitive areas. MCI has been further subdivided into single-domain or multi-domain types, but always falling short of being considered dementia. While the etiology of MCI subtypes is not completely clear, most studies point to amnestic MCI as a precursor to AD, while naMCI is likely to have a non-AD origin (e.g., vascular). However, there are many other causes of cognitive impairment, including other dementing neurological disorders (frontotemporal dementia, Lewy body disease), psychiatric causes (depression), and somatic factors like vitamin B12 deficiency, medications, etc. Many questions remain about the pathological underpinnings, epidemiology, and predictive value of MCI subtypes, and those questions were the fodder for the presentations and discussion periods for the two days of the symposium.

The Many Faces of MCI
In the first session, Katie Palmer of the Santa Lucia Foundation IRCCS in Rome, Italy, talked about her epidemiological studies of amnestic versus non-amnestic MCI syndromes in the Kungsholmen district of Stockholm. The prevalence of MCI can be a moving target, depending on the definition used, and Palmer found that the prevalence of amnestic MCI in her study was quite low (1.8 to 3.4 percent, depending on criteria used). She found that naMCI was actually two to four times more prevalent than aMCI in this population. As expected, people with amnestic MCI were at double the risk for progression to AD over three years, while those with single-domain, naMCI had no increased risk of AD. The highest risk was seen in people with MCI affecting multiple domains, who had 11 times the risk of progressing to AD compared to normal healthy subjects. Consistent with the idea that aMCI and naMCI are etiologically different, Palmer identified significant risk factors for MCI that were not risks for the development of AD. These included hip fracture, taking more than five medications, and history of psychosis. One important point Palmer raised from a meta-analysis of conversion studies was that conversion rates were not linear: Conversion in the first one to two years after diagnosis was higher than in later years. In addition, she showed that attrition can skew results in longitudinal studies, meaning it is important to account for the inevitable loss of elderly subjects in these studies.

Palmer showed some new data on neuropsychiatric factors affecting progression from MCI to AD. Despite the fact that one-third of subjects with amnestic MCI displayed signs of depression, it did not put them at higher risk for progressing to AD over four years. In some patients, treating depression reversed cognitive deficits. On the other hand, apathy was less prevalent (seen in 7 percent of amnestic MCI and 14.7 percent of multi-domain MCI), but was associated with a 6.5 times higher risk of progression to AD, and predicted a more rapid progression.

Studies like this that link progression with other clinical manifestations may provide hints to the etiology of MCI subtypes. Palmer made the point that many somatic conditions, for example vitamin B12 and folate deficiency, elevated homocysteine, TSH levels, recent hip fractures, use of benzodiazapines, diabetes, hypercholesterolemia, cerebrovascular and cardiovascular disease, congestive heart failure, myocardial infarction, hypertension, and stroke can all cause changes in one or more cognitive domains that would lead to a diagnosis of MCI, though not necessarily amnestic MCI. Many, but not all of these factors are also early markers for AD, and the challenge will be to sort out how each contributes to MCI and to the progression to AD or other forms of dementia. View Palmer Presentation [.ppt] (1 MB).

Amy Borenstein of the University of South Florida in Tampa presented data from two epidemiological studies that compared the outcomes for people diagnosed with amnestic MCI versus non-amnestic MCI. Her data further supported the idea that people diagnosed with amnestic MCI were more likely to progress to AD, while non-amnestic MCI tended to stem from vascular factors. From the Florida Alzheimer’s Disease Research Center cohort, the risk factors Borenstein and colleagues identified for aMCI and naMCI were different: ApoE genotype, years of education, and medial temporal atrophy were significant predictive factors for aMCI, while years of education, age, male sex, and hypertension were risk factors for naMCI. Progressive impairment over one year (a decline in test scores) occurred faster for those with aMCI than naMCI.

Borenstein also showed unpublished data from the Nun Study that was consistent with a different pathological basis for aMCI and naMCI. Out of a group of 165 elderly nuns who were cognitively normal at baseline and followed for over 13 years, 98 died, of which 57 remained cognitively normal, 23 showed their first impairment in memory, and 85 showed a first impairment in a non-memory domain. Brain autopsies revealed that Braak stage (AD pathology) was highest among the women who first presented with aMCI. Those presenting with naMCI had no significant increase in AD pathology compared to normals. Borenstein concluded that naMCI appears to be a more benign condition than aMCI, and that the two represent clinical correlates of different pathological processes. View Borenstein Presentation [.ppt] (175 KB).

David Loewenstein of the Wein Center spoke about how to measure MCI. Clinicians need to be able to detect cognitive impairments as early as possible, he said, as the stage of MCI as it is currently defined may already be too late to intervene. That means researchers need to develop tests that can detect subtle changes in cognitive function years or decades before clinical diagnosis. Many of the neuropsychological measures now in use were originally designed to test deficits after head injury, Loewenstein said. They have been adapted for dementia, but may not be suitable for use in MCI or, more to the point, pre-MCI. For example, a simple test of free recall of a list of related items measures simply the rate of forgetting, and is good at identifying dementia, but not necessarily MCI. In contrast, the Florida Brief Memory Scale goes beyond delayed recall and introduces cued recall and interfering information. The three-minute test is based on knowledge of medial temporal lobe function and is highly sensitive for aMCI, which shows up when the subjects cannot use cue information to help them recall (Loewenstein et al., 2009). The test becomes even more sensitive when subjects are given a second list of items in the same category and then asked to recall the first list. The point, Loewenstein said, is that researchers need to focus on developing tests based on understanding of brain function. “Detecting pre-MCI will take new approaches and new paradigms, and only research will show if they are useful,” he said. View Loewenstein Presentation [.ppt] (210 KB).

Beyond cognition, Liana Apostolova from the David Geffen School of Medicine at UCLA talked about psychiatric symptoms in AD and MCI, which can include hallucinations and delusions. Often underappreciated, these symptoms stress caregivers and can lead to nursing home placement, she said. In some studies, up to 50-75 percent of people with AD show high levels of apathy, dysphoria, irritability, and anxiety. The presence of these symptoms in non-demented elderly people increases the likelihood of progression from normal to MCI or from MCI to AD. This is not unique to patients with memory issues, since Apostolova showed new data indicating that patients with aMCI or naMCI experienced similar levels of different psychiatric symptoms. View Apostolova Presentation [.pdf] (152 KB).

Jennifer Whitwell of the Mayo Clinic in Rochester, Minnesota, described her work on neuroimaging of MCI subtypes. She found that people with aMCI who progressed to AD show progressive atrophy and changes in brain metabolites consistent with AD. In contrast, MRI of the non-progressors revealed little AD-related pathology. Subjects with naMCI showed normal hippocampal volume and metabolite levels, but a high proportion of cortical infarcts. Subjects with aMCI plus deficits in multiple cognitive domains also show more cortical infarcts, indicating a role for vascular factors in non-memory cognitive domains. Non-amnestic MCI with a single affected domain was associated with grey matter changes in brain regions corresponding to the affected domains (language or attention, for example). Although the number of subjects looked at for each domain was too small to make any conclusions, Whitwell speculated that these people might progress to other non-AD dementias, such as frontotemporal dementia (FTD) or dementia with Lewy bodies (DLB), depending on the earliest affected domains. Half of the subjects with aMCI showed amyloid load by PET-PIB imaging, but few with naMCI were PIB-positive. “The majority of subjects with aMCI most likely have underlying AD, although vascular disease may also play a role. Subjects with naMCI, and perhaps a minority of subjects with aMCI, will most likely progress to non-AD degenerative dementias, or may even show non-progressive memory impairment,” Whitwell concluded. View Whitwell Presentation [.ppt] (25 MB).

In the afternoon session, Joseph Parisi of the Mayo Clinic in Rochester, Minnesota, continued the analysis of the neuropathology of MCI. He reviewed data on 15 very old (81-94 years of age) patients who had died while in the MCI stage, and found they had a wide range of pathology. All had medial temporal lobe tau pathology, though most scored low probability of AD by the NIA Reagan criteria. Most showed additional changes as well: seven had argyrophilic tau inclusions, five had infarcts, three had hippocampal sclerosis, one had Lewy bodies and two had tau but no amyloid pathology. In addition, he described 34 patients who had MCI, and eventually died with dementia. Nearly three-quarters turned out to have autopsy-confirmed AD, but that left a substantial number who did not, and who also showed a range of pathologies. New data on six cases of naMCI revealed again a range of pathologies including AD with relative hippocampal sparing, early AD plus infarcts and agyrophilic grain disease.

The complexity of the pathologic picture might in part be due to the old age of the group, Parisi said. He thinks that the pathologies all go on together, but advance at different rates. “If one could back up ten years, the pathology would probably be more simple and clear cut,” he said. Also, he pointed out that vascular pathology is a big confounder, and remains very hard to quantify.

The MCI Diagnosis: The Patient’s Perspective
The first day of this conference also featured a panel discussion on the topic of disclosing the diagnosis of MCI. Brian Carpenter from Washington University, St. Louis, Missouri and William Haley, University of South Florida, Tampa, each described their studies on the experience of patients receiving an MCI or dementia diagnosis. Carpenter asked if a diagnosis of dementia triggered catastrophic emotional reactions, by quizzing patients and caregivers pre-disclosure and one year after. He found that levels of depression or anxiety did not change in the days after diagnosis or over the year, and in fact that many people experienced less anxiety after the diagnosis. Haley found a similar situation, where having a diagnosis of MCI was comforting to people who suspected already they were somehow slipping. Both patients and caregivers minimized the likelihood of progression to AD, Haley found, and focused on lifestyle factors they thought would forestall further decline. Information from focus groups of caregivers suggested that what patients and caregivers really need is information and counseling on how to deal with the impact of cognitive impairment on their lives and relationships. View Carpenter Presentation [.ppt] (406 KB). View Haley Presentation [.ppt] (819 KB).

The lack of catastrophic reactions to the diagnosis of MCI is in contrast to the disclosure of genetic information. This can be more problematic, according to Deborah Blacker of Massachusetts General Hospital/Harvard Medical School. Blacker made the point that genetic tests for early-onset familial forms of AD are conclusive in telling people that they will get AD, but do not answer the important question of when. For late-onset disease, the presence of risk genes like ApoE gives a probability, but does not tell whether an individual will get the disease. In both cases, testing introduces uncertainty. This is very different from early recognition, which is ultimately the goal of MCI, biomarkers, and imaging. In that case, positive results tell people that the ‘when’ is soon, which lets patients take control of preparations. Also, although there are currently no effective ways to stall progression, once such interventions become available, early recognition will be critical for deploying them most effectively. View Blacker Presentation [.ppt] (8.57 MB).

One point that came up in discussion was the lack of physicians with expertise in AD who will be available to handle these thorny problems. In fact, most patients receive the news of cognitive impairment from a general practitioner or general neurologist. Some of the audience members thought that with AD prevalence growing, the lack of doctors with specialized training will become a problem. Blacker opined that with the sheer number of people projected to get AD, it is likely that most of the responsibility for them will have to fall to primary care physicians.

MCI in Lewy Body Disease
Moving on from AD, the next session dealt with α-synuclein diseases, which include Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB, see also Alzforum series). Owen Ross of the Mayo Clinic in Jacksonville, Florida, introduced the audience to the genetics of Parkinson disease, Lewy Body disease and AD. The identification of familial forms of these diseases, and genetic risk factors have helped in understanding the mechanism of disease. While there are no genetic tests for the sporadic forms of these diseases, the hope is that one day genetics will be able to give an early warning of impending disease and a chance at prevention. View Ross Presentation [.ppt] (9.9 MB).

Bradley Boeve from the Mayo Clinic in Rochester, Minnesota, talked about cognitive prodromes of DLB. In contrast to aMCI as a precursor to AD, patients with DLB tend to show impairment of other domains, most often attention/executive functioning and visiospatial functions. Language is preserved, but memory can be variably affected. The conclusion Boeve made is that any MCI subtype can evolve into DLB.

One fascinating prodrome of DLB that does not involve memory is REM sleep behavior disorder (RBD), a state where people are physically active during REM sleep. Normally, in REM sleep skeletal muscle activity is suppressed, but in RBD this inhibition lifts and patients appear to act out their dreams, sometimes putting their bedfellows at risk of being kicked or punched to the point of injury. In 45 cases of RBD associated with neurodegenerative disese that Boeve has studied at the Mayo clinic, 38 occurred in Lewy body disease, 5 in multiple system atrophy, and 1 in AD. In the synucleinopathies (LBD and MSA), the RBD occurred long before disease became apparent. In some cases, patients showed nighttime disturbances as early as in their 20’s, perhaps representing the earliest manifestations of DLB.

Boeve hypothesized that patients who have both RBD and MCI likely represent evolving Lewy body disease. To study that question, he looked at the Mayo patient registry to identify people who had MCI that subsequently developed into autopsy-proven LBD. Seven of eight such patients displayed REM sleep disorder, which preceded the MCI diagnosis by a median of 12 years (range 3-48), and the onset of cognitive symptoms by 10 years (range 2-47). Boeve hypothesized that this progression reflects an early brainstem pathology that moves to the cortex, in agreement with Braak staging of LBD pathology. View Boeve poster (for best view, enlarge your browser window), presented this past April at the Annual Meeting of the American Academy of Neurology in Seattle, Washington [.ppt] (192 KB).

Alexander Tröster of the University of North Carolina at Chapel Hill reviewed the current state of thinking about MCI in Lewy body disease. Studies report MCI in about 20-30 percent of PD cases, which most often presents as single deficits in executive/attentional domains. Another study showed that in PD patients with different subtypes of MCI, it was the patients with naMCI who had the strongest chance of progressing to dementia. No studies to date have looked at MCI progression to DLB, but it has been noted incidentally in a few studies. From this, Tröster concluded that it may be possible to distinguish with neuropsychology LBD-MCI from AD-MCI. This fits with the fact that PDD and LBD involve more impairment in visuospatial and executive/attentional function than AD. The perhaps most widely used screen for dementia, the Mini-Mental State Exam, is insensitive to early impairment seen in PD, he said, because it does not probe executive/attentional functions. For this purpose, Tröster favors the Montreal Cognitive Assessment (MoCA, Nasreddine et al., 2005), which resembles the MMSE but covers more domains. (For a recent review of the topic of MCI in LBD, see Tröster, 2008). View Tröster Presentation [.ppt] (580 KB).

Many uncertainties remain for the concept of MCI in LBD. They include defining MCI, figuring out the role of medications in producing or alleviating MCI, and understanding how an MCI diagnosis can aid treatment. Tröster pointed out that a more general PD prodrome may feature more non-cognitive changes, including deficits in olfaction, or autonomic nervous system disturbances like constipation or sleep disturbances that show up before classical motor symptoms emerge.

Session chair Douglas Galasko of the University of California, San Diego, called the talks a “nice summary of a difficult and evolving topic. The issue with cognitive changes in PD is that they are not consistent, but when they do occur, they are a major problem. The challenge will be to identify those people with PD who are at risk of dementia.” In discussion, Ross pointed out that a future goal will be to find a genetic screen for the dementia component of Lewy body diseases. One questioner asked about the role of imaging and biomarkers in PD, and the speakers replied that none of that was as advanced as in AD. There is no PIB-equivalent for imaging of synuclein deposits, and experiments looking at α-synuclein in the CSF are giving widely differing and still-controversial results (For new updates, see Alzforum DLB series Part 5, Part 6).

MCI in Vascular Dementia
Vladimir Hachinski, a renowned stroke expert at the University of Western Ontario, London, Ontario, Canada was the second keynote speaker. He treated the audience to a different perspective on dementia. Hachinski strongly urged researchers and clinicians to pay more attention to the coexistence and interactions of cerebrovascular disease and AD. He argued that Alzheimer disease may be over-diagnosed while vascular dementia is under-diagnosed. The reasons for this, he said, include the widespread use of the MMSE as a screening tool, and the resulting bias toward identifying memory problems rather than other cognitive issues. In addition, he said, a lot of dementia research comes from memory clinics, which also leads to a bias in favor of detecting and studying AD. Hachinski pointed out that community-based studies detect equal amounts of stroke and AD pathology in elderly people with late-onset dementia, in that 70 percent have AD pathology, and 78 percent show signs of stroke. The two pathologies are more than just fellow travelers, he argued. They appear to be partners in crime, each exacerbating the effect of the other. His point, Hachinski said, is that AD researchers and clinicians need to expand their horizon and start to take vascular factors more seriously in studies of dementia. Hachinski blamed stroke doctors, as well, for taking a narrow view. “They are not interested in cognition. They are too busy giving patients TPA,” he said.

In the end, the most common manifestation of cerebrovascular disease (CVD) or AD is cognitive change: memory domains fail first in AD, while executive function suffers in CVD. “Remember this and execute accordingly,” Hachinski admonished. “Dementia is dementia; let’s find it first, and then worry about etiology.”

To that end, Hachinski collaborated with U.S. and Canadian physicians, including AD specialists, to define standards for vascular cognitive impairment. The screening test they recommended was the MoCA, the same test Tröster recommended for dementia associated with PD (Hachinski et al., 2006).

It is all the more important to identify cognitive impairment due to vascular factors, Hachinksi said, “because we can do something about that now.” Many of the risk factors for stroke and dementia are shared, most are modifiable, and some are shared with AD, he added. Hachinski claimed that adopting a healthy lifestyle (optimal body mass index, exercise, moderate alcohol and healthy diet) should prevent a third of strokes in men, and one-half in women. He is now starting up a primary prevention trial in Canadian communities based on helping people make life style changes to lower the risk of stroke. That study will look at cognitive preservation as a secondary endpoint.

The keynote introduced a subsequent session devoted to vascular cognitive impairment. The first speaker, Oscar Lopez of the University of Pittsburgh, Pennsylvania, spoke about vascular risk factors for MCI based on the long-running Cardiovascular Health Study. Long-term predictors of MCI were hard to identify, partly because of mortality in the MCI group; the survivor group overall was much healthier, Lopez found. Nonetheless, progression did appear to be associated with cerebrovascular disease. Lopez concluded that long-standing vascular disease may create a vulnerable state. He proposed that measures of end-organ damage in older people might be a better predictor of MCI than mid-life risk factors. That is, instead of looking for a correlation between mid-life hypertension and MCI, it might be better to look for evidence of the effects of hypertension on the brain. Lopez and colleagues did this by measuring regional cerebral blood flow in participants by continuous arterial spin-labeled MRI (CASI). In cognitively normal people with hypertension, the scientists saw decreased blood flow in AD areas, which they hypothesize reflects a tissue vulnerable state for AD (Dai et al., 2008). View Lopez Presentation [.ppt] (682 KB).

Cerebrovascular disease has its own set of genetic risk factors. As presented by Sudha Seshadri, an investigator of the Framingham Heart Study in Boston, “stroke is the tip of the iceberg in cerebrovascular disease.” It is but one of a heterogeneous group of disorders that range from carotid atherosclerosis, intracranial stenosis, covert brain infarcts and other conditions. Likewise, genes underlying stroke and vascular cognitive impairment should range from risk genes for CVD, to genes that determine the brain’s response to ischemia and recovery. Surprisingly few genes are known to alter risk for CVD; just nine genes and two loci have been identified and together they account for a small sliver of the population stroke risk. Seshadri previewed the results of a large genomewide association study of stroke that pooled data from four large prospective studies of incident stroke covering nearly 20,000 people (subsequently published on April 15 in the New England Journal of Medicine; see Ikram et al., 2009). That study—a very large one by the standards of the neurodegenerative disease field— analyzed 550,000 genotyped single nucleotide polymorphisms (SNPs) and another 2 million imputed snps, and identified two single nucleotide polymorphisms that were highly significant for their association with ischemic stroke. Although Seshadri did not reveal the location of the snps in her talk, the published data shows that both SNPs lay near the gene for the adhesion receptor Ninjurin2, which may govern how brain cells respond to injury. Even larger studies are to come, with researchers joining up nine cohorts covering 50,000 subjects in a shared genotyping on a focused set of 2,100 genes. View Seshadri Presentation [.pdf] (1.59 MB).

Returning the discussion to pathology, Julie Schneider of Rush University Medical Center in Chicago, Illinois, looked specifically at vascular lesions in people with MCI. She presented data on 483 consecutive autopsies from the Religious Orders Study and Rush Memory and Aging Project on women who died with normal cognition, MCI or AD in roughly equal numbers. The brains were examined for AD pathology, macroscopic infarcts, and Lewy Body disease (neocortical α-synuclein deposits). Of the normal cognition group, half had one pathology, ten percent had two, and nearly 40 percent had none. More than a third of the normal group had enough AD pathology to support a pathologic diagnosis. Mixed pathologies were more evident in the MCI group, and even more common in AD. Only people in the AD group showed all three pathologies, and the presence of each pathology contributed independently and proportionately to the odds of MCI or probable AD, after controlling for age, sex, or education.

When the MCI group was broken out by domains, Schneider found that AD pathology was the most common single pathology in both aMCI and naMCI, and the most common mixed pathology was AD plus infarcts. Infarcts as a single pathology were slightly more common in non-amnestic MCI (17 percent) than amnestic (11 percent) groups. Overall, single pathologies were rare, with “pure” AD accounting for less than a third of amnestic MCI and “pure” infarct pathology accounting for less than 20 percent of non-amnestic MCI.

“The frequent coexistence of infarcts and Lewy bodies with AD is not trivial but significantly increases the likelihood of cognitive impairment,” Schneider concluded. The study supports the idea that vascular health is important for primary prevention of clinical AD. In addition, Schneider said, researchers need to be cautious in making inferences from epidemiological studies that assume that risk factors for clinical AD are the same as risk factors for AD pathology. In terms of clinical trials, the results raise the question of whether people with vascular disease should be included or excluded. Should drugs with vascular mechanisms be considered?

Schneider’s study points out the need for analysis of more vascular lesions, including microscopic infarcts, amyloid angiopathy, small vessel disease, and white matter ischemia. One problem here is that vascular lesions are difficult to quantitate. Schneider showed some data where she graded cerebral angiopathy, and tried to correlate its severity with cognitive function. She found that CAA was significantly related to perceptual speed in both demented and non-demented people. She also found that microscopic infarcts, present in a third of the subjects, almost doubled the risk of dementia. The presence of either micro or macro infarcts correlated with deficits in all cognitive domains measured, as well as with overall cognitive function.

Timo Erkinjuntti of the University of Helsinki, Finland, echoed the difficulty of quantitating vascular lesions in his talk on the neuroimaging of vascular cognitive impairment. The problem is complicated since there are many types of lesion, and their size, number or location may all be important. Erkinjuntti described the use of MRI to measure small vessel disease with a simple system that rates confluent white matter lesions (ARWMC, or age-related white matter changes) as mild, moderate or severe. Results from the multinational Leukoaraiosis and Disability Study (LADIS) showed that increased severity of white matter lesions correlates with quicker descent into disability or death, with a 30 percent rate of transition over three years in the severe group (Jokinen et al., 2009). View Erkinjuntti Presentation [.ppt] (14.55 MB).

Steve Salloway of Brown University talked about the inherited stroke disorder CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) as a genetic model of vascular cognitive impairment. The disease arises from mutation in the gene for notch3. It leads to deterioration of arterioles in the brain, white matter ischemia, lacunar strokes, and dementia in middle age. Its hallmarks include early impairment of executive function and cholinergic function. CADASIL resembles sporadic ischemic vascular disease in elderly, without the memory impairment seen in AD. There is little amyloid pathology in patients, so the disease is used as a model for pure vascular dementia. Salloway described a recent clinical trial of donepezil in mildly impaired patients that found no significant improvement in Vascular-ADAS-Cog (Dichgans et al., 2008). There was some improvement on sub-tests that measured executive function, but it was small and likely would not result in an improvement in function for the patients, Salloway said.

Final Session: Prevention
Lon Schneider of the University of California at Los Angeles reviewed recent Phase II and III studies of new therapies for Alzheimer disease, looking to explain why an entire cohort of 11 recently completed trials on a range of new treatments tested in people with mild to moderate AD all failed. One explanation offered for recent failures has been that over time, people with AD have done better. Because the placebo group do not deteriorate as much as before, treatment effects become harder to see. Schneider argues that this is not true, that placebo effects have been consistent over the past decade or more (ARF covered this topic extensively last summer; see ARF related news story). What has changed, he said, is that Phase 3 trials have gotten very large, the trajectories of individual decline show a wide variation, and many people in trials of mild AD are simply not changing over the 18-month course of study. Schneider showed data from two trials indicating that 40 percent of the individuals in the placebo group did not change at all, and so just a few patients drive any composite changes. The same problem is likely to plague 12 ongoing phase III trials with a similar design. Other possibilities to explain the string of failures could be that most of the drugs tested had anti-Aβ effects, and perhaps early to mild AD may already be too late to elicit a meaningful therapeutic effect. View Schneider Presentation [.ppt] (1.1 MB).

Frank LaFerla of the University of California, Irvine, talked about the other AD pathology, tau, as a therapeutic target in AD. He used data from mouse models to support the idea that Aβ facilitates the development of tau pathology. This could be taken to mean that targeting Aβ would be sufficient for clinical improvement, but in fact LaFerla and colleagues find that they need to reduce both Aβ and soluble tau to improve cognition in aged mice with both pathologies. The results, he said, support the idea that combination therapies may be necessary to treat people with AD.

On the topic of prevention, Steven DeKosky from the University of Virginia in Charlottesville reviewed a recent large prevention trial, the Ginkgo Evaluation of Memory (GEM) study. The trial, which was directed by DeKosky, turned up no effect of daily Ginkgo supplements on the risk of developing dementia (see ARF related news story on DeKosky et al., 2008), and did not reduce the risk of stroke, heart disease or mortality in people over 75. What the study did show, DeKosky said, is that large numbers of elderly volunteers can be kept on a research study for lengthy prevention trials. In addition, he said, researchers are building new studies on that trial, and have recruited 15 percent of the subjects for further studies using MRI, FDG and PET-PIB imaging. View DeKosky Presentation [.ppt] (806 KB).

Ingmar Skoog of the University of Gothenburg in Sweden, reviewed clinical trials of antihypertensive medication for improving dementia and MCI. Half of all older people have high blood pressure, which elevates the risk of stroke. This in turn elevates risk of dementia. Several large trials of antihypertensives with dementia or cognition as an outcome have yielded mixed and mostly negative results. Nonetheless, Skoog feels it is too early to rule out a beneficial effect. However, the chances of doing definitive placebo-controlled studies in the future are low, given the beneficial effects of anti-hypertensives on cardiovascular function. Where does that leave clinicians? Some argue against treating hypertension in the elderly, based on observations that blood pressure drops with the onset of AD. However, data suggests the drop is a consequence of AD, not a cause, and where it has been looked at, blood pressure treatment does not seem to affect cognitive function negatively. Skoog concludes that hypertension should be treated even in people with dementia to prevent new strokes and the progression of white matter lesions. View Skoog Presentation [.ppt] (5.53 MB).

Nicola Lautenschlager of the University of Western Australia in Crawley talked about a different preventive scheme involving exercise. Her group published a paper in JAMA last fall about a small, randomized trial of increased physical activity and cognitive function (see ARF related news story on Lautenschlager et al., 2008). The scientists recruited 170 people in their 50s and older who had a memory complaint, including 102 with MCI, and randomized them to a 24-week individualized intervention aimed at boosting physical activity, mainly through walking, or no intervention. People who received the intervention on average did 20 minutes more physical activity per day, and saw a statistically significant change in ADAS-Cog scores. Lautenschlager characterized the change as “modest, but remarkable,” considering the limited amount of physical activity involved. It is not clear what exactly improves cognition, but possibilities include increased blood flow, psychological benefits or other reasons. People enjoyed the program, Lautenschlager reported, and adherence approached 80 percent. View Lautenschlager Presentation [.ppt] (623 KB).

As the final session ended, participants headed out for a walk on the beach, or maybe just to find a quiet spot to start digesting the wealth of information presented. One clear conclusion is that MCI has come a long way in the decade since Petersen’s paper appeared. At the same time, researchers still have a long way to go to understand exactly what defines the prodromal stages of various dementias clinically, pathologically, and perhaps most importantly, biologically.—Pat McCaffrey.