Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

Latent information in fluency lists predicts functional decline in persons at risk for Alzheimer disease.

OBJECTIVE: We constructed random forest classifiers employing either the traditional method of scoring semantic fluency word lists or new methods. These classifiers were then compared in terms of their ability to diagnose Alzheimer disease (AD) or to prognosticate among individuals along the continuum from cognitively normal (CN) through mild cognitive impairment (MCI) to AD. METHOD: Semantic fluency lists from 44 cognitively normal elderly individuals, 80 MCI patients, and 41 AD patients were transcribed into electronic text files and scored by four methods: traditional raw scores, clustering and switching scores, "generalized" versions of clustering and switching, and a method based on independent components analysis (ICA). Random forest classifiers based on raw scores were compared to "augmented" classifiers that incorporated newer scoring methods. Outcome variables included AD diagnosis at baseline, MCI conversion, increase in Clinical Dementia Rating-Sum of Boxes (CDR-SOB) score, or decrease in Financial Capacity Instrument (FCI) score. Receiver operating characteristic (ROC) curves were constructed for each classifier and the area under the curve (AUC) was calculated. We compared AUC between raw and augmented classifiers using Delong's test and assessed validity and reliability of the augmented classifier. RESULTS: Augmented classifiers outperformed classifiers based on raw scores for the outcome measures AD diagnosis (AUC .97 vs. .95), MCI conversion (AUC .91 vs. .77), CDR-SOB increase (AUC .90 vs. .79), and FCI decrease (AUC .89 vs. .72). Measures of validity and stability over time support the use of the method. CONCLUSION: Latent information in semantic fluency word lists is useful for predicting cognitive and functional decline among elderly individuals at increased risk for developing AD. Modern machine learning methods may incorporate latent information to enhance the diagnostic value of semantic fluency raw scores. These methods could yield information valuable for patient care and clinical trial design with a relatively small investment of time and money.

Realistic expectations for treatment success in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive degenerative disease that warrants active management to delay or slow progression of its symptoms. The symptoms of AD encompass behavior and daily function as well as cognition, so clinicians should take a global view in the assessment of treatment success. Because there is currently no cure for AD, one cannot expect an initial cognitive improvement observed in the first few months of therapy to be sustained indefinitely. However, one should expect that the patient who is treated early and persistently with medication for AD will show less evidence of behavioral, functional, and cognitive deterioration over a period of time than one would expect in the absence of pharmacotherapy. Thus, treatment success includes not only short-term improvement of symptoms but also less decline over the long term. Determination of treatment success therefore also requires awareness of the typical progression of untreated AD. In this article we review the natural history of AD and evidence for the effectiveness of the treatments indicated for AD: donepezil, galantamine, rivastigmine, and memantine.

DNA replication precedes neuronal cell death in Alzheimer's disease.

Alzheimer's disease (AD) is a devastating dementia of late life that is correlated with a region-specific neuronal cell loss. Despite progress in uncovering many of the factors that contribute to the etiology of the disease, the cause of the nerve cell death remains unknown. One promising theory is that the neurons degenerate because they reenter a lethal cell cycle. This theory receives support from immunocytochemical evidence for the reexpression of several cell cycle-related proteins. Direct proof for DNA replication, however, has been lacking. We report here the use of fluorescent in situ hybridization to examine the chromosomal complement of interphase neuronal nuclei in the adult human brain. We demonstrate that a significant fraction of the hippocampal pyramidal and basal forebrain neurons in AD have fully or partially replicated four separate genetic loci on three different chromosomes. Cells in unaffected regions of the AD brain or in the hippocampus of nondemented age-matched controls show no such anomalies. We conclude that the AD neurons complete a nearly full S phase, but because mitosis is not initiated, the cells remain tetraploid. Quantitative analysis indicates that the genetic imbalance persists for many months before the cells die, and we propose that this imbalance is the direct cause of the neuronal loss in Alzheimer's disease.

Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease.

BACKGROUND: Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function. OBJECTIVE: To investigate the long-term benefits of donepezil treatment in patients with AD. DESIGN: Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout). INTERVENTIONS: All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged. MEASURES: Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes. RESULTS: After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events. CONCLUSIONS: Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.

Apathy in Alzheimer's disease.

Apathy, or loss of motivation, is arguably the most common change in behavior in Alzheimer's disease (AD) but is underrecognized. Apathy represents a form of executive cognitive dysfunction. Patients with apathy suffer from decreased daily function and specific cognitive deficits and rely on families to provide more care, which results in increased stress for families. Apathy is one of the primary syndromes associated with frontal and subcortical pathology, and apathy in AD appears to have multiple neuroanatomical correlates that implicate components of frontal subcortical networks. Despite the profound effects of this common syndrome, only a few instruments have been designed to specifically assess apathy, and these instruments have not been directly compared. Assessment of apathy in AD requires clinicians to distinguish loss of motivation from loss of ability due to cognitive decline. Although apathy may be misdiagnosed as depression because of an overlap in symptoms, current research has shown apathy to be a discrete syndrome. Distinguishing apathy from depression has important treatment implications, because these disorders respond to different interventions. Further research is required to clarify the specific neuroanatomical and neuropsychological correlates of apathy and to determine how correct diagnosis and treatment of apathy may improve patient functioning and ease caregiver burden.

Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons.

Immunocytochemical studies of postmortem human tissue have shown that the neurons at risk for degeneration in Alzheimer's are marked by the ectopic expression of several cell cycle components. The current work investigates the roles that beta-amyloid activated microglia might play in leading neurons to re-express cell cycle components. Stable cultures of E16.5 mouse cortical neurons were exposed to beta-amyloid alone, microglial cells alone, or microglial cells activated by beta-amyloid. Increased cell death was found in response to each of these treatments, however, only the amyloid activated microglial treatment increased the number of neurons that were positive for cell cycle markers such as PCNA or cyclin D and incorporation of BrdU. Double labeling with BrdU and TUNEL techniques verified that the 'dividing' neurons were dying, most likely through an apoptotic mechanism. The identity of the soluble factor(s) elaborated by the microglia remains unknown, but FGF2, a suspected neuronal mitogen, was ruled out. These results further support a model in which microglial activation by beta-amyloid is a key event in the progression in Alzheimer's disease.

Three-dimensional neglect phenomena following right anterior choroidal artery infarction.

Neglect in the horizontal and vertical axes of space has been observed after acute right anterior choroidal artery (AChA) lesions. How spatial processing is affected in the radial axis during the acute period following infarction in this region is unknown. We report the case of a 69-year-old man with acute left hemineglect and deficits in 3-dimensional spatial processing following right AChA infarction. His line bisections in 4 spatial conditions, oriented in the 3 primary axes of space, were compared with 6 control participants. The patient's bisections were different from true center and from control performance in all axes. His bisections were to the right, below, and distal to the arithmetic midpoint. This patient's bisection errors show a 3-dimensional neglect pattern following right AChA infarction, supporting the view that processing of all 3 spatial dimensions may be simultaneously disturbed following unilateral right hemisphere lesions.

Age effects on random-array letter cancellation tests.

OBJECTIVE: This study was designed to determine whether young and older adults differ in the spatial pattern of omission errors on random-array letter cancellation tasks. BACKGROUND: Aging is associated with declines in the speed or efficiency of visual information processing. It is unclear whether the spatial characteristics of visual exploration also change with aging. METHOD: Thirty young adults and 30 older adults each completed 21 random-array cancellation forms. Forms were systematically varied in paper size, target-to-distractor ratio, stimulus density, and target number. RESULTS: The spatial distribution of errors was not random for older adults. Younger adults expressed a trend toward nonrandom error location, but the spatial distribution did not differ between groups. There was also a strong trend toward more errors per subject in the older group. Older subjects required more time for task completion. CONCLUSIONS: The findings are consistent with a generalized age-related decline in the speed or efficiency of visual search, but the spatial properties of directed attention do not appear to be different between young and older adults.

Spatial aspects of letter cancellation performance in Arabic readers.

Studies of visuospatial and directed attention that used subjects drawn from cultures with left-to-right reading patterns have suggested a slight performance bias toward left space. This pattern could reflect an intrinsic, organic, bias in spatial processing or the confounding effect of overlearned reading patterns. We studied the spatial distribution of errors on random array letter cancellation tasks obtained from 128 healthy Syrians who were native readers of Arabic. Fifty-eight of the 128 subjects (45.3%) made a total of 91 errors in which they omitted cancelling a target. The distribution of errors was not spatially biased. This differs from the error pattern reported for native readers of English on a similar task. The findings, consistent with results of other approaches, suggest that reading patterns influence visuospatial attention, but are not the sole cause of spatial biases observed in readers of Indo-European languages.

Clock drawing test in very mild Alzheimer's disease.

OBJECTIVES: The primary objective of this study was to determine the efficacy of the clock drawing test to predict the presence of very mild Alzheimer's disease (AD). A secondary objective was to identify elements of clock drawing that were most useful in differentiating cognitively intact older adults from those with mild Alzheimer's disease. DESIGN: Cohort based comparison of retrospective data. SETTING: Academic research center. PARTICIPANTS: Clock drawings from 41 outpatient cases of mild AD with Mini-Mental State Exam scores of 24 or higher and 39 age- and education-matched older adults were scored. MEASUREMENTS: Clock drawings were blindly and independently scored by two raters using the Clock Drawing Interpretation Scale and the scoring system reported by Rouleau et al. Predictive values for positive and negative tests were calculated using cut-off scores for total score and component subscores from each of these two systems. RESULTS: Two or more errors in the depiction of the clock hands on the Clock Drawing Interpretation Scale had a positive predictive value for AD of 100% and a negative predictive value of 51%. A score of 2 or less on the 4-point hand-placement component of the Rouleau et al. scoring system provided a positive predictive value for AD of 94% and was associated with a negative predictive value of 62%. CONCLUSION: An individual who commits two errors or more in drawing the clock hands deserves further investigation for a possible dementia. Normal hand placement on the clock drawing test does not exclude AD. However, when prevalence rates of dementia in community-dwelling older adults are considered, these results argue that normal clock hand placement indicates that dementia is unlikely.

Stimulus characteristics determine processing approach on random array letter-cancellation tasks.

Target-to-distractor ratio strongly influences performance on typical random array letter cancellation tasks, suggesting that a "controlled" processing approach is used. This study was designed to determine whether "automatic" processing could be also demonstrated in the random array cancellation paradigm by changing the perceptual characteristics of the stimuli. Thirty-two healthy subjects sequentially performed four random array cancellation tasks with 50 and 100 stimuli. The letters "I" or "O" were targets and "L" served as the distractor. Performance was measured by the number of correctly canceled targets divided by the time to completion, corrected for accuracy. There was a strong effect of the number of stimuli on forms using I targets (p < .00001), but not for O's (p = . 15) Performance scores were lower for I target forms than for O targets. These findings demonstrate that performance approximating "automatic" processing can also be elicited on clinically useful, office-based, or bedside tests such as random array cancellation.

Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain.

Alzheimer's disease (AD) is a major dementing illness characterized by regional concentrations of senile plaques, neurofibrillary tangles, and extensive neuronal cell death. Although cell and synaptic loss is most directly linked to the severity of symptoms, the mechanisms leading to the neuronal death remain unclear. Based on evidence linking neuronal death during development to unexpected reappearance of cell cycle events, we investigated the brains of 12 neuropathologically verified cases of Alzheimer's disease and eight age-matched, disease-free controls for the presence of cell cycle proteins. Aberrant expression of cyclin D, cdk4, proliferating cell nuclear antigen, and cyclin B1 were identified in the hippocampus, subiculum, locus coeruleus, and dorsal raphe nuclei, but not inferotemporal cortex or cerebellum of AD cases. With only one exception, control subjects showed no significant expression of cell cycle markers in any of the six regions. We propose that disregulation of various components of the cell cycle is a significant contributor to regionally specific neuronal death in AD.

The effect of character and array type on visual spatial search quality following traumatic brain injury.

Disorders of visuomotor function are common following traumatic brain injury (TBI), but spatially directed visual attention has received little study in this population. 'Cancellation' testing is a common bedside method for assessing directed attention, which can provide information on how task properties influence visual scanning and search following severe TBI. Groups of 20 individuals after severe TBI and 21 healthy control subjects were matched for age and education. Participants performed finger tapping tests to assess motor speed as well as four cancellation tests employing letter and geometric figure stimuli in random and structured arrays. Control and TBI groups differed significantly on measures of accuracy, task completion time, and search quality. There was no significant effect of stimulus or array type on accuracy or time. Figure targets in a higher search quality, suggesting a right hemispheric dominance effect on these tasks. The findings support a deficit in visuomotor scanning performance in TBI beyond a purely motor effect. Interactions between stimulus and array types suggest that hemispheric cooperation is required for the optimal performance of these tasks, and that interhemispheric communication may be preferentially compromised by TBI.

Treatment of functional decline in adults with Down syndrome using selective serotonin-reuptake inhibitor drugs.

Alzheimer's disease (AD) is a common cause of functional decline in Down syndrome (DS) adults. Acquired cognitive deficits may be difficult to evaluate in the context of baseline impairments. Behavioral symptoms are also common and may represent the effects of depression, AD, or both. Therefore, the objective of this study was to report a clinical case series of selected adults with DS and behavioral change who responded to treatment with selective serotonin-reuptake inhibitor (SSRI) medication. Six patients, aged 23 to 63 years, 5 women and 1 man, with the clinical diagnosis of DS presented for diagnosis and treatment of functional decline in adult life. Noncognitive symptoms were prominent and included aggression, social withdrawal, and compulsive behaviors. Memory dysfunction was reported in varying degrees. Treatment with SSRI antidepressants was instituted for depressive, apathetic, and compulsive behaviors. Treated patients showed improvement in behaviors as reported by caregivers, and on objective measures, such as workplace productivity. Noncognitive symptoms are a cardinal feature of functional decline in adults with DS and may represent either depression or AD. In some patients, the symptoms respond well to SSRI agents with concomitant improvement in daily function. Treatment trials with SSRIs may, therefore, be warranted in such cases.

Differential diagnosis of Alzheimer's disease.

Accurate diagnosis of dementia is essential to provide appropriate treatment as well as patient and family counseling. It may be difficult to differentiate dementia from delirium. In addition, several features distinguish dementia from depression, but the two can coexist and the distinction may be uncertain. Dementias can be grouped into two categories: dementia that presents without prominent motor signs and dementia that presents with prominent motor signs. Dementias without prominent motor signs include Alzheimer's disease, frontotemporal dementia, and Creutzfeld-Jakob and other prion diseases. Dementias characterized at onset by prominent motor signs include dementias with Lewy bodies, idiopathic Parkinson's disease, progressive supranuclear palsy, cortico-basal ganglionic degeneration, hydrocephalus, Huntington's disease, and vascular dementia. Routine diagnostic steps include a careful history, mental status screening, laboratory and imaging studies, and neuropsychologic testing. Genetic testing is available, but its use is controversial and raises complex ethical questions.

Enhancing recovery from ischemic stroke.

Despite the intense efforts devoted to preventing and aborting cerebral ischemia, some individuals will continue to have completed infarctions. Failure of prevention or intervention does not, however, preclude therapeutic approaches to enhance recovery. This article will review working definitions applicable to the care and rehabilitation of patients after ischemic stroke. Significant, preliminary research on how adrenergic systems may alter the recovery from cerebral damage is also reviewed. Beneficial effects of agents which promote adrenergic function, and the adverse effects of monoaminergic blockade in animals and humans are discussed. The potential role of synaptic mechanisms like long-term potentiation is reviewed in the context of motor recovery. These factors are likely to have important implications in the future acute care of patients with completed stroke.