Functional, global and cognitive decline correlates to accumulation of Alzheimer's pathology in MCI and AD.

BACKGROUND: Cognitive, global and functional instruments have been extensively investigated for correlations with neuropathological changes such as neurofibrillary tangles (NFTs), plaques, and synapse loss in the brain. OBJECTIVE: Our objective is to correlate the functional, global and cognitive decline assessed clinically with the neuropathological changes observed in a large prospectively characterized cohort of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: We examined 150 subjects (16 MCI and 134 AD) that were prospectively assessed and longitudinally followed to autopsy. MCI subjects clinically met Petersen criteria for single or multi-domain amnestic MCI. AD subjects clinically met NINCDS-ADRDA criteria for probable or possible AD. All subjects received the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and the Mini Mental State Examination (MMSE) ante-mortem. Plaque and tangle counts were gathered for hippocampus, entorhinal cortex, frontal, temporal and parietal cortices. Braak staging was performed as well. RESULTS: The GDS, FAST and MMSE correlated with plaque counts in all regions. The GDS, FAST and MMSE correlated with tangle counts in in all regions. The three instruments also correlated with the Braak score. The MMSE and GDS correlate better than the FAST in most regions. CONCLUSIONS: Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress from MCI through AD.

The wills of older people: risk factors for undue influence.

BACKGROUND: As people live longer, there is increasing potential for mental disorders to interfere with testamentary distribution and render older people more vulnerable to "undue influence" when they are making a will. Accordingly, clinicians dealing with the mental disorders of older people will be called upon increasingly to advise the courts about a person's vulnerability to undue influence. METHOD: A Subcommittee of the IPA Task Force on Testamentary Capacity and Undue Influence undertook to establish consensus on the definition of undue influence and the provision of guidelines for expert assessment of risk factors for undue influence. RESULTS: International jurisdictions differ in their approach to the notion of undue influence. Despite differences in legal systems, from a clinical perspective, the subcommittee identified some common "red flags" which might alert the expert to risk of undue influence. These include: (i) social or environmental risk factors such as dependency, isolation, family conflict and recent bereavement; (ii) psychological and physical risk factors such as physical disability, deathbed wills, sexual bargaining, personality disorders, substance abuse and mental disorders including dementia, delirium, mood and paranoid disorders; and (iii) legal risk factors such as unnatural provisions in a will, or provisions not in keeping with previous wishes of the person making the will, and the instigation or procurement of a will by a beneficiary. CONCLUSION: This review provides some guidance for experts who are requested by the courts to provide an opinion on the risk of undue influence. Whilst international jurisdictions require different thresholds of proof for a finding of undue influence, there is good international consensus on the clinical indicators for the concept.

Functional ability correlates with cognitive impairment in Parkinson's disease and Alzheimer's disease.

BACKGROUND/AIMS: Previously we have shown that functional declines in Parkinson's disease (PD) and Alzheimer's disease (AD) correlate to global measures of cognitive decline. We now determine if the correlation between cognitive impairment and functional ability in PD is similar to that in AD using individual cognitive measures. METHODS: 93 PD subjects and 124 AD/MCI subjects underwent the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and a neuropsychological battery. RESULTS: In PD subjects, the FAST and GDS correlated significantly with Rey Auditory Verbal Learning Test (AVLT), Controlled Oral Word Association (COWA), Animal Fluency, and Stroop but not with Clock Draw or Judgment Line Orientation (JLO). In AD/MCI subjects, FAST and GDS correlated with all neuropsychological components except Stroop. In the AD/MCI group, the UPDRS significantly correlated with the FAST, GDS, MMSE, and all neuropsychological parameters except the Stroop. In the PD group, the motor UPDRS significantly correlated significantly with FAST, GDS, MMSE and all neuropsychological parameters except Digit Span, Stroop, Clock Draw and JLO. CONCLUSIONS: Similar to AD, functional decline in PD correlates with multiple measures of cognitive impairment. Some differences between PD and AD may be explained by the influence of motor disability and declines in visuospatial function in PD.

[Behavioral pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD): Spanish validation]. / Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD): validación española.

INTRODUCTION: The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) is a screening instrument for the evaluation of behavioral disturbances in Alzheimer's patients. Our aim was to validate the BEHAVE-AD test in Spanish, intended for use in routine clinical practice. METHOD: We assessed the validity of the BEHAVEAD in 79 nursing-home patients with diagnosis criteria of dementia, scoring 4 or higher on the Global Deterioration Scale (GDS) scale, by developing a crossed validated form between the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and BEHAVE-AD tests. Both instruments were rated by an expert clinician. In order to study the concurrent validity of some of the BEHAVE-AD subscales, we compared the Cohen-Mansfield Agitation Inventory (CMAI) and the Hamilton Depression Rating Scale (HDRS) tests. RESULTS: The Pearson correlation index between the BEHAVE-AD test and the NPI-Q, was significant but moderate (r=0.694). Pearson's correlation between BEHAVEAD's symptoms scale and NPI-Q's severity scale was r=0.698. When comparing BEHAVE-AD's global evaluation scale (caregiver's disturbance) and NPI-Q's distress scale, the correlation index was 0.535. CONCLUSIONS: The BEHAVE-AD Spanish version offers the possibility to use a screening tool for the detection of neuropsychiatric symptoms in dementia patients, also applicable to nursing home residents, administered by an expert clinician.

Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD): validación española / Behavioral Pathology in Alzheimer's Disease Rating Sca1e (BEHAVE-AD): Spanish validation

Introducción. La Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) es un instrumento de cribado para la detección de sintomatología conductual en pacientes con demencia de tipo Alzheimer. El objetivo fue la validación española de la BEHAVE-AD para su incorporación en la práctica clínica diaria. Método. Estudio de la validez de la BEHAVE-AD en 79 pacientes con criterios diagnósticos de demencia en régimen de residencia, con puntuación de 4 o superior en la Global Deterioration Scale (GDS), mediante una validación cruzada entre el Neuropsychiatric Inventory-Questionnaire (NPI-Q) y la BEHAVE-AD. Administración de ambas escalas por parte de un clínico entrenado. Administración de las escalas Inventario de Agitación del Anciano de Cohen-Mansfield (IAACM) y Hamilton Depression Rating Scale (HDRS) para estudiar la validez convergente de dos de los dominios de la BEHAVE-AD. Resultados. índice de correlación de Pearson entre la BEHAVE-AD y el NPI-Q moderadamente significativo (r=0,694). Correlación de Pearson entre la escala de sintomatología de la BEHAVE-AD y la escala de gravedad del NPI-Q de 0,698 y entre la escala de evaluación global (perturbación en el cuidador) y la escala de estrés del NPI-Q de 0,535 puntos. Conclusiones. Esta versión en español de la BEHAVE-AD ofrece la posibilidad de aplicar un test de cribado de la sintomatología neuropsiquiátrica en pacientes con demencia, siendo también aplicable a usuarios de residencia, administrado por un clínico entrenado

Introduction. The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHA VE-AD) is a screening instrument for the evaluation of behavioral disturbances in Alzheimer's patients. Our aim was to validate the BEHA VE-AD test in Spanish, intended for use in routine clinical practice. Method. We assessed the validity of the BEHA VEAD in 79 nursing-home patients with diagnosis criteria of dementia, scoring 4 or higher on the Global Deterioration Scale (GDS) scale, by developing a crossed validated form between the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and BEHA VE-AD tests. Both instruments were rated by an expert clinician. In order to study the concurrent validity of some of the BEHA VE-AD subscales, we compared the Cohen-Mansfield Agitation Inventory (CMAI) and the Hamilton Depression Rating Scale (HDRS) tests. Results. The Pearson correlation index between the BEHA VE-AD test and the NPI-Q, was significant but moderate (r = 0.694). Pearson's correlation between BEHA VEAD's symptoms scale and NPI-Q's severity scale was r=0.698. When comparing BEHA VE-AD's global evaluation scale (caregiver's disturbance) and NPI-Q's distress scale, the correlation index was 0.535. Conclusions. The BEHA VE-AD Spanish version offers the possibility to use a screening tool for the detection of neuropsychiatric symptoms in dementia patients, also applicable to nursing home residents, administered by an expert clinician

Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment.

The diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) is limited because it is based on non-specific behavioral and neuroimaging findings. The lesions of Alzheimer's disease: amyloid beta (Abeta) deposits, tau pathology and cellular oxidative damage, affect the hippocampus in the earlier stages causing memory impairment. In a 2-year longitudinal study of MCI patients and normal controls, we examined the hypothesis that cerebrospinal fluid (CSF) markers for these pathological features improve the diagnostic accuracy over memory and magnetic resonance imaging (MRI)-hippocampal volume evaluations. Relative to control, MCI patients showed decreased memory and hippocampal volumes and elevated CSF levels of hyperphosphorylated tau and isoprostane. These two CSF measures consistently improved the diagnostic accuracy over the memory measures and the isoprostane measure incremented the accuracy of the hippocampal volume achieving overall diagnostic accuracies of about 90%. Among MCI patients, over 2 years, longitudinal hippocampal volume losses were closely associated with increasing hyperphosphorylated tau and decreasing amyloid beta-42 levels. These results demonstrate that CSF biomarkers for AD contribute to the characterization of MCI.

Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging.

An extensive literature reports changes in quantitative electroencephalogram (QEEG) with aging and a relationship between magnitude of changes and degree of clinical deterioration in progressive dementia. Longitudinal studies have demonstrated QEEG differences between mild cognitively impaired (MCI) elderly who go on to decline and those who do not. This study focuses on normal elderly with subjective cognitive complaints to assess the utility of QEEG in predicting future decline within 7 years. Forty-four normal elderly received extensive clinical, neurocognitive and QEEG examinations at baseline. All study subjects (N = 44) had only subjective complaints but no objective evidence of cognitive deficit (evaluated using the Global Deterioration Scale [GDS] score, GDS stage = 2) at baseline and were re-evaluated during 7-9 year follow-up. Baseline QEEGs of Decliners differed significantly (p < 0.0001, by MANOVA) from Non-Decliners, characterized by increases in theta power, slowing of mean frequency, and changes in covariance among regions, especially on the right hemisphere. Using logistic regression, an R2 of 0.93 (p < 0.001) was obtained between baseline QEEG features and probability of future decline, with an overall predictive accuracy of 90%. These data indicate high sensitivity and specificity for baseline QEEG as a differential predictor of future cognitive state in normal, subjectively impaired elderly.

Is the functional decline of Parkinson's disease similar to the functional decline of Alzheimer's disease?

Since many Parkinson's disease (PD) subjects develop dementia, we determined whether the correlation between functional and cognitive decline seen in Alzheimer's disease (AD) is seen in PD. Seventy-five PD subjects with and without dementia and 103 AD/MCI subjects underwent the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), the UPDRS motor portion, and the MMSE. In AD/MCI subjects, changes in FAST and GDS scores correlated with MMSE (rho=-0.814, P<0.001; rho=-0.840, P<0.001, respectively). In PD subjects, the FAST and GDS also correlated with MMSE (rho=-0.675, P<0.001; rho=-0.647, P<0.001, respectively). The UPDRS correlated with the GDS and FAST more closely in PD than in AD. Similar to AD, functional declines in PD correlates with cognitive decline and may be influenced by motor disability in PD.

Benefits of cognitive-motor intervention in MCI and mild to moderate Alzheimer disease.

OBJECTIVE: To evaluate the efficacy of a cognitive-motor program in patients with early Alzheimer disease (AD) who are treated with a cholinesterase inhibitor (ChEI). METHODS: Patients with mild cognitive impairment (MCI) (12), mild AD (48), and moderate AD (24) (Global Deterioration Scale stages 3, 4, and 5) were randomized to receive psychosocial support plus cognitive-motor intervention (experimental group) or psychosocial support alone (control group). Cognitive-motor intervention (CMI) consisted of a 1-year structured program of 103 sessions of cognitive exercises, plus social and psychomotor activities. The primary efficacy measure was the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary efficacy measures were the Mini-Mental State Examination, the Functional Activities Questionnaire, and the Geriatric Depression Scale. Evaluations were conducted at 1, 3, 6, and 12 months by blinded evaluators. RESULTS: Patients in the CMI group maintained cognitive status at month 6, whereas patients in the control group had significantly declined at that time. Cognitive response was higher in the patients with fewer years of formal education. In addition, more patients in the experimental group maintained or improved their affective status at month 12 (experimental group, 75%; control group, 47%; p = 0.017). CONCLUSIONS: A long-term CMI in ChEI-treated early Alzheimer disease patients produced additional mood and cognitive benefits.

MRI and CSF studies in the early diagnosis of Alzheimer's disease.

The main goal of our studies has been to use MRI, FDG-PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross-sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI-determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi-automated regional boundary shift analysis (BSA-R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1-42 (Abeta42). Many CSF studies of MCI and AD report elevated T-tau levels (a marker of neuronal damage) and reduced Abeta42 levels (possibly due to increased plaque sequestration). However, CSF T-tau and Abeta42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P-tau, tau hyperphosphorylated at threonine 231 (P-tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P-tau231 are accurate and specific indicators of AD-related changes in brain and cognition. In cross-section and longitudinally, our results show that evaluations of the P-tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T-tau nor P-tauX (X refers to all hyper-phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain-derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI-based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P-tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis.

Measuring cognition in advanced Alzheimer's disease for clinical trials.

Measurement of cognitive dysfunction and treatment response in the early stages of Alzheimer's disease (AD) has used such scales as the Mini-Mental State Examination (MMSE) and the AD Assessment Scale (ADAS). With the exception of clinical rating scales, however, there are only a few objective measures of cognition for tracking progression in advanced AD. Given renewed interest in potential therapies for advanced AD, objective measures of cognition are important for the adequate evaluation of change due to AD progression or therapy. Several cognitive measures for advanced AD are reviewed. One measure, the Severe Impairment Battery (SIB) is reviewed in detail. Preliminary analyses from a trial of memantine show significant change on the SIB in memory (p < 0.001) and visuospatial functions (p < 0.02) over six-months with a trend for language and praxis. Data from a donepezil trial also highlight the importance of accurate assessment in advanced AD.

Vascular fibrosis and calcification in the hippocampus in aging, Alzheimer disease, and Down syndrome.

Study of the hippocampal formation of 82 subjects, including 25 control subjects from 33 to 83 years of age, 34 subjects with Alzheimer disease (AD) from 65 to 89 years of age, and 23 subjects with Down syndrome (DS) from 33 to 72 years of age, revealed hippocampal vasculopathy with fibrosis and calcification (VFC) in 40% of control, 59% of AD, and 4% of DS subjects. VFC starts in the precapillaries/capillaries in the molecular layer of the dentate gyrus (DG) and expands to the granule cell and polymorphic cell layer of the DG, and to the stratum lacunosum/molecular in the CA1 sector. Vasculopathy spreads from the tail to the body and, in a few cases, to the head of the hippocampal formation. Light and electron microscopy reveal thickening of the vascular wall with fibrosis, calcification, and enforcement of the astrocyte interface with vessels with anchorage densities associated with hemidesmosome-like structures. In moderately and severely affected cases, fragmentation and removal of calcified and occluded vessels result in local reduction of vascular network. In two AD subjects, severe vascular calcification extending from the tail to the head of the hippocampal formation was associated with loss of almost all neurons in the CA1 sector and in the subiculum proper, corresponding to hippocampal sclerosis. The topography of affected vessels and the patterns of neuronal loss reflect the middle hippocampal artery distribution with its precapillary/capillary network. The similar prevalence of vasculopathy in the AD group and in the age-matched control group, and the presence of hippocampal VFC in only one subject in the DS cohort, 96% of which is affected by Alzheimer-type pathology, oppose the link between AD and this form of vasculopathy. However, severe VFC affects the pattern of AD pathology locally by deletion of neurofibrillary degeneration and beta-amyloidosis in the CA1 sector, subiculum proper, and the molecular layer of the dentate gyrus. Hippocampal VFC appears to be a form of vascular pathology with a unique predilection for the middle hippocampal artery and corresponding capillary network, which results in patchy neuronal loss in moderately affected subjects and in almost total neuronal loss in the area of impaired blood supply in severely affected subjects. These observations suggest an etiologic link between hippocampal VFC and hippocampal sclerosis.

Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET).

Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex. Related observations with in vivo imaging have enabled the prediction of dementia from MCI. Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change. The objective of this MRI-guided 2-[(18)F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET) study was to examine the hypothesis that among normal elderly subjects, EC METglu reductions predict decline and the involvement of the Hip and neocortex. In a 3-year longitudinal study of 48 healthy normal elderly, 12 individuals (mean age 72) demonstrated cognitive decline (11 to MCI and 1 to Alzheimer's disease). Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender. At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI. Among those who declined, the baseline EC predicted longitudinal memory and temporal neocortex metabolic reductions. At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip. Among those subjects who declined, apolipoprotein E E4 carriers showed marked longitudinal temporal neocortex reductions. In summary, these data suggest that an EC stage of brain involvement can be detected in normal elderly that predicts future cognitive and brain metabolism reductions. Progressive E4-related hypometabolism may underlie the known increased susceptibility for dementia. Further study is required to estimate individual risks and to determine the physiologic basis for METglu changes detected while cognition is normal.

The Alzheimer's disease activities of daily living international scale (ADL-IS).

BACKGROUND: Activities of daily living (ADL) deficits are integral components of dementia disorders, and ADL measures are among the most robust markers of the course of Alzheimer's disease (AD). Despite this acknowledged importance, no clearly useful ADL instrument for cross-cultural application in pharmacologic trials in the early stages of AD had been available. METHOD: An international effort was launched to develop an ADL scale for pharmacologic trials in early AD. Steps taken from 1990 to the present included: (1) international scientific working group meetings and reviews, (2) reviews of existing measures, (3) collating of existent, nonredundant items, (4) querying experts for new items, (5) interviews with informants and subjects in the USA, France, and Germany, toward the identification of potential new items, (6) identification of an item pool based upon these procedures, (7) creation of a trial instrument, (8) piloting of this instrument, and (9) refinement of the scale based upon statistical analysis of the pilot data. Final item selection was based upon: (1) relevance for > or = 80% of subjects in severity-stratified USA and German samples; (2) absence of gender and national biases; (3) significant (p <.05) discrimination between (a) normal versus mildly impaired and (b) mildly impaired versus moderately to moderately severely impaired subjects; and (4) Global Deterioration Scale (GDS) scores accounting for > or = 12% of variance in the item after controlling for age and gender. RESULTS: An ADL scale consisting of 40 items that correlate with the global and cognitive progress of AD is developed for international usage in pharmacologic trials in incipient, mild, moderate, and moderately severe AD. The scale contains 40 items falling within 13 ADL categories. The 40-item scale is shown to have .81 correlation with GDS staging, .81 with mental status assessment (Mini-Mental State Examination), and .81 with a psychometric test (the SKT) (p values < .001). CONCLUSION: This scale can be used to measure therapeutic response in AD.

Fibrillar amyloid-beta affects neurofibrillary changes but only in neurons already involved in neurofibrillary degeneration.

The aim of this study of the cerebral cortex of 8 non-demented elderly subjects and of 17 subjects in the severe stage of Alzheimer's disease (AD) (Global Deterioration Scale stage 7/Functional Assessment Staging procedure stage 7a-f) was to examine the relationships between amyloid-beta (Abeta) deposits and neurofibrillary degeneration. The study shows that neuronal processes with neurofibrillary changes are detectable in only a minority of fibrillar plaques: from 31% to 49% of fibrillar plaques within frontal, temporal, parietal, limbic, occipital, and insular cortices. The correlations observed between the numerical densities of neurons with neurofibrillary tangles (NFTs) and the densities of Thioflavin-S-positive fibrillar plaques with neurofibrillary changes (r=0.61; P<0.01) indicate that neurofibrillary pathology in neocortical plaques reflects the topography and rate of neurofibrillary changes in neocortical neurons. The accumulation of abnormally phosphorylated tau in only some plaques indicates that fibrillar Abeta enhances paired helical filament accumulation locally only in dystrophic neurites already involved in neurofibrillary degeneration. The lack of correlation between the number of neurons with neurofibrillary changes and the number of all Thioflavin-S-positive fibrillar plaques (with and without neurofibrillary changes) suggests that beta-amyloidosis does not contribute to initiation of neurofibrillary degeneration in neurons.

Addition of a frequency-weighted score to the Behavioral Pathology in Alzheimer's Disease Rating Scale: the BEHAVE-AD-FW: methodology and reliability.

The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) is a well-established instrument, designed to assess potentially remediable behavioral symptoms in Alzheimer's disease (AD) patients as well as to evaluate treatment outcome. It consists of 25 symptoms grouped into seven categories. Each symptom is scored on the basis of severity on a four-point scale. A knowledgeable caregiver is queried and items are scored on the basis of symptoms noted in the preceding two weeks. Reliability, construct validity and criterion validity data for the BEHAVE-AD have previously been published. Because of the significance of psychopathology in dementia, it is necessary to optimally describe and define the nature, magnitude and prevalence of behavioral symptomatology. Accordingly, a frequency component was added to each of the 25 items of the BEHAVE-AD scale. The objective of the present report is to describe this new Behavioral Pathology in Alzheimer's Disease Frequency-Weighted Severity Scale (BEHAVE-AD-FW) and to establish its inter-rater reliability. In this investigation the BEHAVE-AD-FW scale was administered to caregivers of 28 patients with either mildly impaired cognitive function or a dementia diagnosis. Two clinicians separately and independently rated the responses. Analyses determined that the intraclass correlation coefficients (ICCs) for the frequency component varied between 0.86 and 0.97 for each of the seven BEHAVE-AD categories (p(s) < 0.001). ICCs for the frequency-weighted scores (item severity score x item frequency score) ranged from 0.69 to 0.98 for the seven symptom categories (p(s) < 0.001). For the BEHAVE-AD-FW total scores, the ICC was 0.91 (P < 0.001). These results indicate that the frequency-weighted component is a reliable addition to the BEHAVE-AD scale.

Medical and economic benefit of a comprehensive infection control program that includes routine determination of microbial clonality.

Nosocomial infections are a major part of the problem of reemerging pathogens causing infectious diseases, affecting 5% of patients hospitalized in the United States during 1995. We assessed the medical and economic effects on the overall nosocomial infection rate of an intervention that provided an enhanced, integrated infection control program, including an in-house molecular typing laboratory capability to rapidly assess microbial clonality. Data on nosocomial infections for 24 months prior to the change in approach to infection control were compared with data from the 24 months immediately following implementation of the new program. Infections per 1,000 patient-days and percentage of hospitalized patients in whom nosocomial infection developed were assessed. Overall, nosocomial infections per 1,000 patient-days decreased more than 10% (P = .027), and percentage of patients with nosocomial infection decreased 23% during the post-intervention period compared with the previous control 24 months. This translated to a mean reduction of some 270 patients per year with nosocomial infection, and lowering of actual health care costs for our institution by $4,368,100 over the 2 years of the intervention.

Equilibrium and limb coordination in mild cognitive impairment and mild Alzheimer's disease.

OBJECTIVE: To examine changes in equilibrium and limb coordination in normal aging, mild cognitive impairment, and moderate cognitive impairment associated with early probable Alzheimer's disease (AD), by means of parametric clinical measures. DESIGN: Case series SETTING: Out-patient clinic. PARTICIPANTS: A consecutive sample of 365 community-residing ambulatory volunteers (137 men, 228 women; mean age 70.4 +/- 9.4 years; mean educational attainment 14.6 +/- 3.1 years), who were followed in an ongoing longitudinal study of aging and AD, comprising cognitively intact individuals, persons with mild cognitive impairment, and patients with mild AD. MEASUREMENTS: For general magnitude of cognitive function, the Global Deterioration Scale (GDS). For cognition, the Mini-Mental State Examination (MMSE). Equilibrium was assessed with parametric measurements of single leg stance (SLS) and tandem walking (TW). Limb coordination was assessed with parametric measurements of foot tapping (FT), alternating pronation and supination (PS), and sequential finger to thumb tapping (FTH). MAIN RESULTS: After adjustment for age, persons with mild cognitive impairment or mild AD had significantly poorer performance on parametric clinical tests of equilibrium and limb coordination compared with cognitively intact individuals (P < .05). CONCLUSIONS: Changes in equilibrium and limb coordination are clinically demonstrable in persons with mild cognitive impairment and mild AD using simple parametric tests. Such tests could potentially identify individuals with increased risk of falling. Early diagnosis and treatment of conditions that can jeopardize equilibrium and limb coordination, as well as balance and coordination training, might help cognitively impaired older people to maintain optimal function and may decrease the risk of falls and injuries.

Towards a science of Alzheimer's disease management: a model based upon current knowledge of retrogenesis.

BACKGROUND: General relationships between dotage and infancy and childhood have been acknowledged for more than two millennia. Recent findings indicate precise relationships between functional, praxic, and feeding changes in the course of the degenerative dementia of Alzheimer's disease (AD) and inverse corresponding developmental sequences. Similar inverse relationships between AD and human development can be described for cognition and language skills; for physiologic measures of electroencephalographic activity, brain glucose metabolism, and developmental neurologic reflex changes; and for the neuropathologic and neuroanatomic progression of these processes. In AD, these processes may be termed "retrogenesis." The relevance of the retrogenesis model for AD management is explored. METHOD: The functional stages of AD can be translated into developmental age equivalents that can be utilized to explicate observed changes in the disease. RESULTS: The retrogenesis-based developmental age model can usefully inform an understanding of the general care needs, emotional and behavioral changes, and activity needs of the AD patient. This model must be amended by necessary caveats regarding physical differences, variations in age-associated pathology, differences in social and societal reactions, and differences in background between AD patients and their developmental age "peers." CONCLUSIONS: Knowledge of retrogenesis and the developmental age of the AD patient can form a nidus for the development of a nascent science of disease management. Such a science must ultimately incorporate not only appropriate caveats but also relevant universal human needs, such as those for dignity, love, and movement.