John R. McCarten

Finding Dementia in Primary Care: The Results of a Clinical Demonstration Project

To assess the effect of screening on diagnosing cognitive impairment.

Changes in Outpatient Costs Following Screening and Diagnosis of Cognitive Impairment

restoring defective cellular metal ion homeostasis, normalizes synaptic function via an activity on various proteins and signaling cascades, including GSK3ß . We have now looked for changes in neuronal markers in APP/PS1 AD mice and also investigated the effects of PBT2 in an animal model for HD, a condition which shares pathological features with AD including evidence of glutamate excitotoxicity. Methods: Transgenic AD (APP/PS1)mice were treated with 30mg/kg PBT2 for 11 days and brain tissues assayed for levels of markers associated with neuronal function and plasticity. Separately, R6/2 HD mice were treated with PBT2 for 14 weeks and examined for alterations in behaviour, lifespan and brain anatomy. In a further in vitro experiment, we examined the effect of PBT2 upon glutamate excitotoxicity. Results: In APP/PS1 mice, levels of NMDAr, Trkb and other markers of neuronal function were restored to those seen in wild-type animals. The level of synaptophysin, markedly reduced in Tg mice, was also restored with PBT2 treatment, mirrored by large and significant increases in the density of hippocampal CA1 dendritic spines. PBT2 also prevented the excitotoxic effects of excess glutamate in primary cortical neurons. This protective effect of PBT2 was inhibited by the potent chelator diamsar demonstrating that this effect is dependent on metal delivery rather than on NMDAr inhibition. In R6/2 mice, PBT2 had significant beneficial effects on motor function, behaviour and lifespan accompanied by a marked reduction in striatal atrophy indicated by significant reduction in lateral ventricle volume compared with untreated controls. Conclusions: PBT2 has potent neurotrophic and neuroprotective effects in vitro and in vivo. The beneficial effects of PBT2 seen in R6/2 mice reflect a similar neuroprotective mechanism to that identified for AD indicating the potential of this drug for therapeutic application in both conditions.

The Case for Screening for Cognitive Impairment in Older Adults

When considering whether to pursue an evaluation for any medical problem, the basic question is: Does the benefit of knowing the diagnosis outweigh the risk of pursuing it? The latter includes the cost not only to the healthcare system, but also to the individual, family, and provider. This is particularly true when the disorder in question involves cognitive impairment. Given the unparalled importance and complexity of cognitive function, screening for impairment is a simple first step to assist in making this critical risk–benefit assessment. The alternative —to relegate the evaluation of cognition to what is obvious —is indefensible. The default assessment of mental status, “A, Ox3′′ (alert and oriented to person, place, and time), is not only inadequate, but also misleading, implying that an individual is cognitively intact. To be alert requires only the ability to keep one’s eyes open (see Terri Schiavo). Criteria for orientation vary widely, are often insensitive, and are of no localizing value neurologically. Worse, orientation often is assumed to be intact and reported as such in an individual who appears to be normal. Dementia in older adults is almost invariably the result of progressive, terminal brain disease (e.g., Alzheimer’s disease (AD)). Affected individuals are often unaware of the severity of their symptoms and appear normal in appearance, speech, and affect. Therefore, dementia, especially in its mild and moderate stages, is frequently an occult disease. Even when recognized, individuals and families may choose to believe that symptoms are part of “normal” aging and fail to report them. A provider may have little reason to suspect problems when none are reported and the individual appears to be a healthy older adult. A careful review of medications, appointments, and other individual contacts, such as telephone calls and unscheduled visits, may identify potential concerns, but the process is time consuming, and any problems identified are only indirect evidence of possible cognitive impairment. Furthermore, individuals and families, fearful of a diagnosis, may choose to wait until the provider raises concerns. It is not unreasonable that families may expect a provider to recognize symptoms and signs of a common, serious disease. A clinic visit at which the question of cognitive integrity is never addressed may be interpreted as an indication that symptoms or signs are not troubling. The effect of unrecognized cognitive impairment for someone who is mildly impaired may seem trivial. Safety concerns may be minimal, and there may be no substantial effect on overall health. Still, symptoms can be ignored only so long before cognitive impairment will become evident, and the sentinel event may be upsetting if not devastating. The likelihood of a misadventure on the job or while driving, managing medications or finances, or using tools increases as someone becomes more cognitively impaired, and early recognition and intervention has the potential to avert catastrophe. The more pernicious risks of unrecognized cognitive impairment may be the frequently attendant social isolation and poor health habits. Although such problems may not be apparent to the healthcare provider, the ever-shrinking world of the individual with dementia— particularly when unrecognized—may be a breeding ground for boredom, lack of exercise, poor diet, sleep disruption, agitation, irritability, depression, paranoia, and other undesirable outcomes. Recognizing and diagnosing cognitive disorders, particularly early in the course of terminal dementia, empowers individuals and families to address predictable needs and potentially live their lives differently, should they so choose. Failure to recognize and diagnose not only robs them of this opportunity, but may also tie them to a more-limited, unhappy existence. Brain function, and specifically cognitive function, is the most-complex and -important biological function. Unfortunately, there is a common misconception among providers that, if cognition were significantly impaired, they would recognize it. In fact, primary care providers have considerable difficulty identifying mild dementia and are generally poor at documenting dementia in the medical record. Even individuals with moderate dementia, several years into progressive dementia, may appear cognitively normal during a typical office visit. This cannot be overstated. From the Geriatric Research, Education and Clinical Center (GRECC), Minneapolis Veterans Affairs Health Care System and the Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota.When considering whether to pursue an evaluation for any medical problem, the basic question is: Does the benefit of knowing the diagnosis outweigh the risk of pursuing it? The latter includes the cost not only to the healthcare system, but also to the individual, family, and provider. This is particularly true when the disorder in question involves cognitive impairment. Given the unparalled importance and complexity of cognitive function, screening for impairment is a simple first step to assist in making this critical risk–benefit assessment. The alternative —to relegate the evaluation of cognition to what is obvious —is indefensible. The default assessment of mental status, “A, Ox3′′ (alert and oriented to person, place, and time), is not only inadequate, but also misleading, implying that an individual is cognitively intact. To be alert requires only the ability to keep one’s eyes open (see Terri Schiavo). Criteria for orientation vary widely, are often insensitive, and are of no localizing value neurologically. Worse, orientation often is assumed to be intact and reported as such in an individual who appears to be normal. Dementia in older adults is almost invariably the result of progressive, terminal brain disease (e.g., Alzheimer’s disease (AD)). Affected individuals are often unaware of the severity of their symptoms and appear normal in appearance, speech, and affect. Therefore, dementia, especially in its mild and moderate stages, is frequently an occult disease. Even when recognized, individuals and families may choose to believe that symptoms are part of “normal” aging and fail to report them. A provider may have little reason to suspect problems when none are reported and the individual appears to be a healthy older adult. A careful review of medications, appointments, and other individual contacts, such as telephone calls and unscheduled visits, may identify potential concerns, but the process is time consuming, and any problems identified are only indirect evidence of possible cognitive impairment. Furthermore, individuals and families, fearful of a diagnosis, may choose to wait until the provider raises concerns. It is not unreasonable that families may expect a provider to recognize symptoms and signs of a common, serious disease. A clinic visit at which the question of cognitive integrity is never addressed may be interpreted as an indication that symptoms or signs are not troubling. The effect of unrecognized cognitive impairment for someone who is mildly impaired may seem trivial. Safety concerns may be minimal, and there may be no substantial effect on overall health. Still, symptoms can be ignored only so long before cognitive impairment will become evident, and the sentinel event may be upsetting if not devastating. The likelihood of a misadventure on the job or while driving, managing medications or finances, or using tools increases as someone becomes more cognitively impaired, and early recognition and intervention has the potential to avert catastrophe. The more pernicious risks of unrecognized cognitive impairment may be the frequently attendant social isolation and poor health habits. Although such problems may not be apparent to the healthcare provider, the ever-shrinking world of the individual with dementia— particularly when unrecognized—may be a breeding ground for boredom, lack of exercise, poor diet, sleep disruption, agitation, irritability, depression, paranoia, and other undesirable outcomes. Recognizing and diagnosing cognitive disorders, particularly early in the course of terminal dementia, empowers individuals and families to address predictable needs and potentially live their lives differently, should they so choose. Failure to recognize and diagnose not only robs them of this opportunity, but may also tie them to a more-limited, unhappy existence. Brain function, and specifically cognitive function, is the most-complex and -important biological function. Unfortunately, there is a common misconception among providers that, if cognition were significantly impaired, they would recognize it. In fact, primary care providers have considerable difficulty identifying mild dementia and are generally poor at documenting dementia in the medical record. Even individuals with moderate dementia, several years into progressive dementia, may appear cognitively normal during a typical office visit. This cannot be overstated. From the Geriatric Research, Education and Clinical Center (GRECC), Minneapolis Veterans Affairs Health Care System and the Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota.

A case of globular glial tauopathy presenting clinically as Alzheimer disease

We report a rare case of globular glial tauopathy (GGT) in an 80-year-old man presenting clinically with Alzheimer-type dementia. The clinical phenotype was characterized by slowly progressive cognitive decline, followed by minimal parkinsonian signs, but without eye-movement abnormalities, personality changes, or neuropsychological features of frontotemporal dysfunction. Neuropathologic findings comprised abundant phospho-tau-positive globular oligodendroglial inclusions and coiled body type inclusions in white matter. There was minimal Alzheimer disease (AD) pathology; however, rare neuronal and astrocytic phosphotau-positive inclusions were present. Gallyas silver staining also highlighted glial inclusions in the section of frontal cortex examined. White matter abnormalities were prominent in most sections examined including the limbic and isocortical brain regions. In spite of prominent white matter changes, associated neurodegeneration in the frontal cortex was minimal; however, the hippocampus and adjacent structures showed moderate neuronal loss. The clinical phenotype of this patient is highly unusual for a disease process that is characterized by prominent frontal white matter involvement. Classification schemes for neurodegenerative diseases are increasingly focused on underlying pathophysiological mechanisms, specifically the type of misprocessed protein (tauopathies and synucleinopathies), rather than on clinical symptoms associated with the disease. Further categorization is based on the cell type with inclusions (glial vs. neuronal) and the anatomic distribution of the specific histopathologic markers. This can occasionally create problems when the clinical presentation is not predictive of the underlying type or distribution of pathologic changes. Tau-processing abnormalities are a key feature of many neurodegenerative diseases including AD and frontotemporal lobar degeneration with tauopathy (FTLD-tau), which includes Pick disease, corticobasal degeneration, progressive supranuclear palsy, and the more recently described entity, white matter tauopathy with GGT.1–3 Although hereditary FTLD-tau results from specific tau mutations, most tauopathies including GGT are sporadic. The clinical spectrum of GGT is broad but generally includes symptoms of frontotemporal dysfunction and associated features such as Parkinsonism and/or motor neuron disease. We report clinical and neuropathologic findings in an individual with a tauopathy characterized by the presence of globular oligodendroglial inclusions in the white matter. Clinical manifestations were most compatible with AD.

Response to Malaz Boustani.

and may lead to unintended consequences for the individuals and society. Recently, the findings of a randomized controlled trial (RCT) that evaluated the effect of screening for cognitive impairment in 424 hospitalized older adults were published. Although this trial was not conducted in a primary care setting and may not be generalizable, it offers some lessons regarding the benefits and harms of dementia screening in primary care. The rationale for the clinical trial was similar to Dr. McCarten’s argument. Approximately 40% of hospitalized older adults have cognitive impairment, and fewer than 40% of these individuals are recognized as having cognitive impairment. Individuals with cognitive impairment had higher mortality, longer hospital stays, and more hospital-acquired complications than hospitalized individuals with no cognitive impairment, but there was no difference in health outcomes between individuals with recognized and unrecognized cognitive impairment. Furthermore, the results of the RCT were negative. No positive effects of screening for cognitive impairment were found in hospitalized older adults on physician behaviors, processes of hospital care, or individual health outcomes. On the contrary, screening for cognitive impairment in the hospital setting led to the unintended consequence of more physicians’ orders for typical antipsychotics in individuals randomized into the screening arm of the trial. This experience in the hospital setting demonstrates that reducing the burden of dementia in society may start with improving recognition but requires more-comprehensive subsequent interventions; thus, screening for cognitive impairment alone is not sufficient to improve health outcomes.

Screening for cognitive impairment in an elderly veteran population

OBJECTIVES: To assess the feasibility of cognitive screening in older veterans presenting for routine primary care.

P2-244: Analyses of the equivalency of different versions of the Mini-Cog™

with dementia of the Alzheimer’s type (AD) and 57 vascular dementia patients (VaD) were interviewed individually. They were asked to report the cognitive, emotional, and physical symptoms of the patients observed in the everyday life. Results: Summarizing a pool of total 299 dementic symptoms that were reported from the family members, 33 items were finally selected as preliminary items for the KDQ. Further analyses that compared AD with VaD based on these 33 items showed that the KDQ could provide valuable information about the diagnostic differentiation and the severity of dementia. Conclusions: These results confirmed the clinical validity and usefulness of KDQ consisting of 33 items that were selected in the present study. It suggests that if normative data were provided from the following study in the healthy elderly, the KDQ can be used effectively as a screening tool for dementia as well as for the staging of dementia.

P2-222: Classification of normal elderly, MCI, and mild AD using neuropsychological tests and self-reported memory function

total tau, and p-tau 181 levels in CSF. Objective: To investigate predictors of a 1-year outcome. Subjects: Inclusion criteria were age 55 years and a new referral to a memory clinic. Exclusion criteria were dementia and disorders causing cognitive impairment. For the present analysis we selected all subjects with data on the 1-year follow-up (n 298). Subjects were at baseline on average 71 years old, scored 27.5 on the MMSE, and had 9.5 years of education. 59% of the subjects were female. Data on the APOE genotype, medial temporal lobe atrophy, and CSF values were collected in a subgroup only. Outcome measures were AD and cognitive decline at follow-up. Cognitive decline was defined as AD at follow-up, decline of at least 1 standard deviation on a memory test, or persisting memory impairment. Results: Predictors of AD were score on the delayed recall of a word list (t 2.6, p 0.01), verbal fluency (t 2.5, p 0.01), MMSE score (t 3.3, p 0.003), total tau (t 4.0, p 0.003), and p-tau 181 (t 2.5, p 0.02). Predictors of cognitive decline were age (t 4.0, p 0.001), score on the delayed recall of a word list (t 10, p 0.001), verbal fluency (t 7.9, p 0.001), score on the TMT B (t 3.1, p 0.002), MMSE score (t 5.2, p 0.001), functional impairment (chi-square 9.2, p 0.01), medial temporal lobe atrophy (chi-square 23, p 0.001), total tau (t 2.3, p 0.04), and the APOE-e4 allele (chi-square 4.4, p 0.04). Conclusions: Subjects who rapidly decline to AD are characterized by low cognitive scores and high CSF tau levels at baseline. Other predictors of AD such as age, functional impairment, medial temporal lobe atrophy, and the APOE-e4 allele may predict AD only at longer follow-up intervals. Acknowledgement: The study was funded by the European Commission (QLRT-2001-2455).

AbstractPoster presentation: Monday posterP2-125: Computer-based diagnostic algorithm for dementia: Comparison to expert opinion

3.55 for CDR 1 (52 patients); 4.10 for CDR 2 (45 patients) and 4.72 for CDR 3 (58 patients), p 0.001. Among the patients who had an IQCODE value between 3.00 and 3.12, 93.4% were classified as CDR 0 and among the patients who had an IQCODE value of 4.00 or higher, 94.8% were classified as CDR 3. Conclusions: When assessed retrospectively in a post-mortem study, the CDR and the IQCODE showed a strong correlation for the evaluation of cognitive status.