Diagnosis Of Probable Alzheimer's Disease Research Articles

P3-209: Genetic variation in the alpha 7 nicotinic acetylcholine receptor is associated with delusional symptoms in Alzheimer's disease

Psychotic symptoms, such as delusions and hallucinations, are among the most common and distressing neuropsychiatric symptoms in Alzheimer's disease (AD). AD with psychosis has been proposed as a distinct endophenotype, associated with more severe cognitive deficits and faster cognitive decline. The aetiology of these symptoms is unclear but they may be attributed to genetic risk factors revealed during neurodegeneration. CHRNA7, the gene for the alpha 7 nicotinic acetylcholine receptor, has been associated with schizophrenia in linkage and association studies. Objective: To investigate genetic variation in CHRNA7 in relation to AD with psychosis. The study group consisted of 409 Northern Irish patients with a diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). Patients were assessed for the presence of psychotic symptoms using the Neuropsychiatric Inventory (NPI). Fourteen highly polymorphic intronic single nucleotide polymorphisms (SNPs) across CHRNA7 were selected and genotyped using Taqman technology and PCR-RFLP. Haploview was used to define linkage disequilibrium. Genotype and haplotype frequencies were compared using chi-squared analysis. Following correction for multiple testing, a significant association between delusions and the T allele of rs6494223 (p = 0.014, OR = 1.63, CI = 1.22–2.17) was found. Haplotype analysis revealed four blocks of high linkage disequilibrium across CHRNA7 but there were no associations between haplotypes and AD with psychosis. This novel finding suggests that the alpha 7 nicotinic acetylcholine receptor may be a suitable target in the treatment of AD with psychosis but further work in this area is required.

P3-011: Antihypertensive drug use modulates progression of Alzheimer's disease

Some antihypertensive drugs are considered to decrease the incidence of AD or slow Alzheimer's disease (AD) progression although some studies for antihypertensive drugs resulted in no effect on AD. In antihypertensive drugs, angiotensin converting enzyme inhibitors (ACE-Is) have had attention in Alzheimer's disease progression because the renin angiotensin system plays an important role in brain functions especially in cognition and learning. Our group previously presented that some brain-penetrating ACE-Is can slow the rate of cognitive decline in mild-to-moderate AD patients with hypertension (Ohrui et al. Neurology, 2004). We examined mini mental state examination (MMSE) scores every year for 2 years during exposure to one of the antihypertensive drugs to study medications. Patients with mild to moderate AD were recruited from outpatient clinics. Patients eligible for this study had a diagnosis of mild to moderate AD, were aged 64 years and older, had MMSE scores within the range of 18 to 27, and had a blood pressure of higher than 140 mmHg systolic or 90 mmHg diastolic. The diagnosis of probable AD was made according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria with no clinical or laboratory evidence of a cause other than AD for dementia. We screened 114 AD patients with hypertension taking an antihypertensive drug. All the patients examined took donepezil (5 mg/day) every day. The decrease in MMSE score was significantly smaller in groups taking angiotensin II type-2 receptor blockers (ARBs) or brain -penetrating ACE-Is than in groups taking non-brain penetrating ACE-I or calcium channel blockers. We concluded that the use of ARBs and brain-penetrating ACE-Is could be beneficial to manage AD patients with hypertension to slow the progression of dementia. Therefore physicians should be more careful in choosing antihypertensive drug for AD patients with hypertension.

Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh Compound-B.

There is increasing evidence for an empiric link between late-life depression and Alzheimer disease (AD). The neuropathology of AD, previously only confirmed at autopsy, may now be detectable in vivo using selective imaging ligands for beta-amyloid. Positron emission tomography (PET) with [11C] 6-OH-BTA-1 [Pittsburgh Compound-B (PiB)] has shown high tracer retention in cortical areas in patients with clinical diagnoses of probable AD and low retention in age-matched controls. We also previously reported variable PiB retention in patients with mild cognitive impairment (MCI). In this study, we used PiB-PET to evaluate whether amyloid is present in elders with treated major depression, many of whom have persistent cognitive impairment. We evaluated 9 subjects with remitted major depression [3M: 6F, mean (SD) age=71.8(5.7) y]. Seven of the 9 depressed subjects also met criteria for the diagnosis of MCI. PiB-PET data from healthy elders [n=8; mean (SD) age=71.5(3.0) y] were used for comparison. PET was acquired with arterial sampling and PiB retention was quantified using magnetic resonance imaging-guided cortical regions and graphical analysis of time-activity data; arterial line failure led to exclusion of 1 depressed subject. The data demonstrated variably elevated PiB retention. PiB retention in the 2 depressed subjects with normal cognitive ability was in the range of nondepressed cognitively normal subjects. PiB retention in 3 of the 6 depressed subjects with MCI fell in the range of subjects with AD. PiB retention in the remaining 3 depressed subjects with cooccurring MCI was variable and generally was intermediate to the other subjects. Our findings are consistent with and supportive of the hypothesis that depression may herald the development of AD in some individuals.

Neuronal gene expression in non-demented individuals with intermediate Alzheimer's Disease neuropathology

While the clinical and neuropathological characterization of Alzheimer's Disease (AD) is well defined, our understanding of the progression of pathologic mechanisms in AD remains unclear. Post-mortem brains from individuals who did not fulfill clinical criteria for AD may still demonstrate measurable levels of AD pathologies to suggest that they may have presented with clinical symptoms had they lived longer or are able to stave off disease progression. Comparison between such individuals and those clinically diagnosed and pathologically confirmed to have AD will be key in delineating AD pathogenesis and neuroprotection. In this study, we expression profiled laser capture microdissected non-tangle bearing neurons in 6 post-mortem brain regions that are differentially affected in the AD brain from 10 non-demented individuals demonstrating intermediate AD neuropathologies (NDAD; Braak stage of II through IV and CERAD rating of moderate to frequent) and evaluated this data against that from individuals who have been diagnosed with late onset AD as well as healthy elderly controls. We identified common statistically significant expression changes in both NDAD and AD brains that may establish a degenerative link between the two cohorts, in addition to NDAD specific transcriptomic changes. These findings pinpoint novel targets for developing earlier diagnostics and preventative therapies for AD prior to diagnosis of probable AD. We also provide this high-quality, low post-mortem interval (PMI), cell-specific, and region-specific NDAD/AD reference data set to the community as a public resource.

Progranulin gene mutation with an unusual clinical and neuropathologic presentation

Progranulin gene (PGRN) mutations cause frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Patients usually present with a frontotemporal dementia syndrome and have prominent atrophy and neuronal loss in frontal and temporal cortices and the striatum, with neuronal intranuclear and cytoplasmic inclusions. Clinical, neuropathological, and genetic studies are reported on an individual with PGRN mutation and her family members. We describe a patient with a PGRN c.26C>A mutation who presented with progressive stuttering dysarthria, oculomotor abnormalities, choreic buccolingual movements, and mild parkinsonism. Two other family members were affected, one with a behavioral variant frontotemporal dementia syndrome, the other with a diagnosis of probable Alzheimer's disease. At autopsy there was no neuronal loss in the cortex or medial temporal lobe structures, but there was striatal gliosis. Immunohistochemistry for ubiquitin and TDP-43 revealed neuronal cytoplasmic and intranuclear inclusions as well as neurites. This study further expands the clinical and pathological spectrum of PGRN mutations, and suggests the diagnosis could be missed in some individuals with atypical presentations.

Association Analysis of Bace1 C786g and Apolipoprotein E Polymorphisms in Alzheimer's Disease

Amyloid β peptide (Aβ) is one of the hallmarks of Alzheimer's disease (AD). Aβ is a major constituent of extracellular plaques and is derived from the proteolytic processing of the β-amyloid precursor protein (APP). The β -site APP cleaving enzyme (BACE1) is a candidate risk factor for AD because of its involvement in generating Aβ. Its gene is located on chromosome 11q23.3.The aim of this study was to investigate the BACE1 exon5 C786G polymorphism in AD and healthy control subjects and correlate it with the apolipoprotein E (ApoE) 4 allele status.Blood was collected from 180 patients with AD and 102 healthy control subjects. The diagnosis of probable AD was based on NINCDS-ADRDA criteria. DNA was extracted by Roche kit. The ApoE and BACE1 polymorphisms were genotyped by RFLP-PCR. The results were analyzed by SPSS program.There was a higher frequency of ApoE 3/4 genotype and ApoE 4 allele occurrence in AD patients (33%) than in the controls (10%). Regarding BACE1 C786G polymorphism there were no statistically significant differences between the investigated groups in the genotype and allele frequencies. In the presence of ApoE 4 allele the BACE1 GG and CG genotypes occurred in higher frequency in AD (10.2% and 22.2%) than in the control (2.0% and 5.1%) group.These results suggest that BACE1 gene polymorphism itself is not associated with AD, but in the presence of ApoE 4 allele the GG and CG genotypes might be risk factors in the development of AD.Supported by:ETT19804/2006, OTKA T046152/2004, K60589/2006.

QEEG spectral peak in Alzheimer's disease: A possible tool for treatment follow-up.

qEEG spectral analysis has been considered highly sensitive to cortical functional changes and agrees strongly with the clinical diagnosis of AD. The sensitivity of spectral analysis has ranged from 71% to 81% in several studies.1-3.ObjectiveThe aim of this study was to retrospectively evaluate whether alpha qEEG spectral peak can supplement clinical examination by constituting an independent tool to monitor treatment and follow-up of dementia progression in Alzheimer’s disease (AD). In addition, we examined the demographic data and alpha power spectra distribution of patients and elderly normal controls.MethodsqEEGs were selected from 2 groups of patients: normal controls (n=30), and patients who fulfilled criteria for mild probable AD diagnosis (n=41). The alpha qEEG spectral analysis and MMSE were performed once or twice a year.ResultsIn our groups, MMSE scores and qEEG alpha spectral peak were unchanged (no statistical differences) after anticholinesterase use where qEEG spectral peak was never lower than 8 Hz in the control group.ConclusionThis study supports two important concepts. First, 8 Hz alpha appears to be the lowest awake spectral peak compatible with normality. And finally, in a clinical context, qEEG is a valuable diagnostic tool that could prove useful for Dementia follow-up.

Distribución factorial de la carga en cuidadores de pacientes con enfermedad de Alzheimer

Care of patients with Alzheimer's disease (AD) is so demanding that it can trigger states of physical, emotional and psychological distress among caregivers. The aims of this study were to determine the factorial structure of the Zarit Burden Scale (BS), to establish the differences among the factors according to the characteristics of patients and caregivers, and to determine the effect of the course of the disease on the factors on the BS over a period of two years.We conducted a prospective, longitudinal study on non-professional caregivers of patients with AD. The study involved 463 patients with a diagnosis of probable AD. The mean age was 75.2 years. All the subjects were administered the study protocol on a six-monthly basis over a period of 24 months. The patient's cognitive and functional capacity and the presence of psychological and behavioural symptoms were evaluated. The main caregiver was asked to complete the Zarit BS.The 21 items on the BS were distributed into five factors that accounted for 59.7% of the total variance of the score. A multivariate analysis identified aggressiveness, apathy, irritability, the caregiver's age and his or her relation to the family as the main causes of distress.This study confirms the multidimensional structure of the BS and offers information about the effect exerted on burden by the different clinical variables of the patients and the sociodemographic variables of the caregivers.

Safety and Tolerability of Donepezil at Doses up to 20 mg/day

Donepezil is licensed for the treatment of mild-to-moderate Alzheimer's disease (AD) at doses of 5-10 mg/day and has recently been approved in the US for severe AD. Multiple studies have suggested that donepezil 10 mg/day provides additional cognitive and functional benefits over the 5 mg/day dose. Higher doses of donepezil, if safe and well tolerated, might provide further benefits for patients with AD. To evaluate the safety and tolerability of donepezil at doses of 15 and 20 mg/day. A 24-week, randomized, double-blind, placebo-controlled, pilot study conducted at two investigational sites in the US. Enrolled patients (male and female; aged 50-86 years) had a diagnosis of probable AD at the mild-to-moderate stage (Mini-Mental State Examination [MMSE] score 10-26). All patients had been treated with donepezil 10 mg/day for 12-30 months prior to enrolment. Patients (n = 31) were randomized 1 : 1 to receive either a standard dose of donepezil (donepezil 10 mg/day plus placebo 5 mg/day for weeks 1-12; donepezil 10 mg/day plus placebo 10 mg/day for weeks 13-24) or a higher dose of donepezil (donepezil 15 mg/day for weeks 1-12; donepezil 20 mg/day for weeks 13-24). Primary outcome measures were tolerability (as determined by monitoring of discontinuations, dose modifications and adverse events) and safety (as determined by adverse event monitoring, physical examinations, clinical laboratory tests and ECGs). Psychometric measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-cog], MMSE and Clinician's Interview-Based Impression of Change with caregiver information [CIBIC+]) and pharmacokinetic/pharmacodynamic parameters were secondary outcomes. No patients withdrew from the study and there were no serious adverse events or deaths. By week 24, 15 of 16 patients in the higher-dose group tolerated the maximum 20 mg/day dose; one patient had a permanent dose reduction to donepezil 15 mg/day. In the standard-dose group, 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study; one patient had a permanent dose reduction to donepezil 10 mg/day plus placebo 5 mg/day. Temporary dose reductions occurred in two patients (one from each group). Adverse events reported were as expected for donepezil and were all mild to moderate in intensity. Adverse events considered to be possibly or probably related to treatment were reported for three patients in the standard-dose group and six patients in the higher-dose group. One patient in the higher-dose group had weight loss reported as possibly or probably treatment related. Mean changes on ECGs were not clinically significant in either group, and the incidence of bradycardia was comparable. No treatment difference on any of the psychometric measures was observed between the groups. Pharmacokinetic analyses showed that an increased donepezil dose was associated with an increase in donepezil plasma concentrations from baseline. In this small pilot study of patients with mild-to-moderate AD already stabilized on donepezil 10 mg/day, doses of 15 and 20 mg/day of donepezil appeared safe and well tolerated. These results justify initiation of larger clinical trials designed to investigate the efficacy and safety of doses of donepezil higher than 10 mg/day in patients with AD.

Amyloid Beta Protein as a Marker or Risk Factor of Alzheimers Disease

Alzheimer disease (AD) is a neurodegenerative disease that affects cognition, behavior and function. The etiology of the disease is unknown, however, the Primary Risk Factors for AD are aging, and family history. Neurofibrillary tangles (NFT) and amyloid-bearing neuritic plaques in the limbic and cerebral cortices are the characteristic neuropathologic lesions in brains of patients with AD. The NFT is mainly composed of hyprephosphorylated tau, whereas the major component of the neuritic plaques is the amyloid beta (Abeta) protein. The clinical diagnosis of probable AD is based on history, physical examination, neuropsychological testing, laboratory studies and neuroimaging techniques. However, there is no specific laboratory marker to support the diagnosis of definite AD or monitoring the progression of the disease. Several biochemical markers related to neuropathology have been identified in cerebrospinal fluid (CSF). We describe the studies of CSF or blood levels of amyloid beta protein in patients with AD and age-matched nondemented controls. Due to the heterogeneity and complex nature of the disease, it is highly unlikely that that a single marker specific for AD will be found.

VOXEL-BASED INVESTIGATIONS OF REGIONAL CEREBRAL BLOOD FLOW ABNORMALITIES IN ALZHEIMERS DISEASE USING A SINGLE-DETECTOR SPECT SYSTEM

To evaluate the feasibility of using the Statistical Parametric Mapping (SPM) program for an automated, voxel-by-voxel assessment of regional cerebral blood flow (rCBF) deficits in Alzheimer's disease (AD) subjects relative to age-matched controls studied with a conventional, single-detector SPECT system. We used a databank of 99mTc-HMPAO images of 19 patients with a diagnosis of probable AD and 15 elderly healthy volunteers; data were acquired using an Orbiter-Siemens single-detector SPECT system. Using SPM, images were transformed spatially, smoothed (12mm), and the data were compared on a voxel-by-voxel basis with t-tests. There were significant rCBF reductions in AD patients relative to controls involving regions predicted a priori to be affected in AD, namely the left temporal and parietal neocortices, and the right posterior cingulate gyrus (p<0.05, corrected for multiple comparisons). The location of rCBF reductions in AD subjects in our study is consistent with the deficits detected in previous functional imaging studies of AD using higher-resolution devices. This suggests the potential usefulness of using SPM for the analysis of data acquired with single-detector SPECT systems, despite the limited sensitivity and spatial resolution of such equipment.

CHOLINESTERASE INHIBITOR TREATMENT AND URINARY INCONTINENCE IN ALZHEIMER'S DISEASE

To the Editor: Dementia and urinary incontinence are common, often coexisting, problems in older people. Muscarinic receptors are important for detrusor contraction,1 and anticholinergic drugs are used to treat detrusor instability. Conversely, cholinesterase inhibitors, used to treat Alzheimer's disease (AD), have been reported to cause urinary incontinence.2 A retrospective population-based study of patients with dementia found that those prescribed cholinesterase inhibitors were significantly more likely to be subsequently prescribed an anticholinergic drug for urinary incontinence.3 Of the cholinesterase inhibitors currently prescribed for AD, only donepezil lists urinary incontinence as a potential adverse effect; rivastigmine and galantamine just mention the possibility of urinary obstruction.4 The potential to worsen urinary continence is an important consideration when starting cholinesterase treatment in AD. Urinary symptom data were collected from 216 (55 male, 161 female) consecutive patients attending a memory treatment center (mean age 76.7, range 49–94).5 Patients were eligible if they had a diagnosis of probable AD, were treated with a cholinesterase inhibitor, and had continence and cognitive assessments at baseline and after 26 weeks of treatment. Mean Mini-Mental State Examination (MMSE) score was 19.3 (n=213) at baseline and 18.8 (n=185) at 26 weeks. One hundred forty-two (65.7%) were treated with donepezil and 74 (34.3%) with rivastigmine. Urinary continence was scored as an item from the Physical Self-Maintenance Scale6 as fully continent, occasionally incontinent (no more than once a week), frequently incontinent, or always incontinent. Behavioral and psychological symptoms of dementia (BPSDs) were scored using the Neuropsychiatric Inventory (NPI).7 Cognitive testing comprised the MMSE, the Hopkins Verbal Learning Test,8 Verbal Fluency Categorical and Lexical forms,9 and for a proportion of patients, Paired Associate Learning and Delayed Matching to Sample subtests from the Cambridge Neuropsychological Test Automated Battery visual and working memory battery.10 Premorbid intelligence was estimated using the National Adult Reading Test (see 6). At baseline, 197 patients were fully continent, 12 had infrequent incontinence, one had frequent incontinence, and six were always incontinent. At 26 weeks, 184 were fully continent (a decrease of 6.6%), 18 had infrequent incontinence, three had frequent incontinence, and 11 were always incontinent. The change toward greater incontinence was significant (P=.03). Worsening continence was not associated with sex (chi-square=0.04, P=.85) or drug prescribed (chi-square=2.29, P=.13) on univariate analysis. A logistic regression model comprising age, sex, and drug prescribed with stepwise conditional forward entry at P<.05 found that rivastigmine significantly increased the risk of worse continence (odds ratio (OR)=2.91, 95% confidence interval (CI)=1.06–7.99). Adding baseline MMSE and NPI scores to the model (n=207) identified NPI as the only significant predictor (OR=1.05, 95% CI=1.01–1.09 per point higher). Including the other cognitive test scores in addition failed to improve the model significantly. To examine whether worse continence was associated with change in cognition or behavioral symptoms, the differences in MMSE and NPI scores between baseline and Week 26 were calculated. Entering these into the logistic regression model together with age, sex, and drug prescribed (n=179) identified poorer MMSE (OR=1.17, 95% CI=1.03–1.34 per point decline) and poorer NPI (OR=1.09, 95% CI=1.04–1.18 per point worse) as the only significant dependent variables. Cholinesterase inhibitor treatment was associated with significantly worse urinary continence in this sample. There was no significant difference between rivastigmine and donepezil once baseline characteristics were adjusted for. Patients with worse BPSDs were more likely to experience deterioration in continence; age, sex, and cognitive status were not significant predictors. When the course of cognitive and behavioral change was examined, significant associations between worse continence and cognitive and behavioral decline were found. This implies that improved cognition and behavior in patients who respond to cholinesterase inhibitors offsets the potential for worse continence. The incontinence rates for patients taking donepezil in this sample were the same as those found in a Japanese sample.2 They are higher than the proxy rate of anticholinergic prescriptions of 4% found in the Ontario dementia cohort.3 The proxy measure probably underestimates incontinence rates, because not all patients with incontinence receive anticholinergic treatments. Ideally, changes in continence should be assessed in future clinical trials of cholinesterase inhibitors. Until such trial data become available, clinicians should advise patients with AD considering cholinesterase inhibitor treatment that there is an approximately 7% risk of precipitating urinary incontinence and that any current incontinence may be significantly worsened. Risk is highest in those with more-severe BPSD, although should the patient respond well to treatment cognitively or behaviorally, the risk is substantially lower. Financial Disclosure: Grant support: Health Foundation, Leading Practice Through Research award, October 2003 through September 2005, to assess physical health status in older adults with learning disability. Author Contributions: JMS proposed the hypotheses, analyzed the data, and wrote the letter. Sponsor's Role: NHS Lothian Health Board approved and resourced the collection of all data as part of the evaluation of local dementia services.

Premorbid Personality and Behavioral and Psychological Symptoms in Probable Alzheimer Disease

Previous research investigating the influence of premorbid personality on behavioral and psychological symptoms in dementia (BPSD) has produced mixed findings. Addressing some limitations of previous studies, the authors aimed to investigate whether some of the common individual symptoms of BPSD (depression, anxiety, irritability, and aggression) were associated with key aspects of previous personality (neuroticism and agreeableness); and also to perform an exploratory investigation into the broader influence of personality factors on behavioral and psychological syndromes. Two hundred eight patients with a diagnosis of probable Alzheimer disease were assessed for the presence of BPSD over the disease course using the caregiver-rated Neuropsychiatric Inventory (NPI). One or two knowledgeable informants rated patients' midlife personalities using a retrospective version of the NEO-FFI questionnaire. Premorbid neuroticism was correlated with anxiety and total NPI score, although not with depression. Premorbid agreeableness was negatively correlated with agitation and irritability. Principal components analysis of the 10 NPI behavioral domains identified three syndromes: "agitation/apathy," "psychosis," and "affect." In stepwise linear regression analyses, including personality domains from the Five-Factor Model and a range of potential confounders as independent variables; the only significant personality predictor of a behavioral syndrome was "agitation/apathy," predicted by lower premorbid agreeableness. Lower premorbid agreeableness is associated with agitation and irritability symptoms in Alzheimer disease and also predicts an "agitation/apathy" syndrome. The relationship between premorbid neuroticism and BPSD is less straightforward, and premorbid neuroticism does not appear to be associated with depression in Alzheimer disease or predict an "affect" syndrome.

Use of the Brief Smell Identification Test for olfactory deficit in a Norwegian population with Alzheimer's disease

Several studies have shown that Alzheimer's disease (AD) is associated with hyposmia. Olfactory identification may be a cheap and simple additional test in the assessment of early cognitive changes. The sense of smell is influenced by factors such as experience and culture and the aim of the present study was to assess the validity of the Brief Smell Identification Test (B-SIT) in distinguishing patients with AD from healthy gender and age-matched controls in a Norwegian population. The study included 39 patients with a diagnosis of probable AD, and 52 gender and age-matched controls. Olfactory function was assessed with B-SIT, and a non-standardized olfactory identification task (freshly ground coffee). The difference in olfactory performance between patients and controls was highly significant, both for the whole AD patient group and the subgroup of patients with MMSE >or= 24. Receiver operating curve (ROC) analyses indicated that B-SIT distinguished patients from controls with high sensitivity and specificity. All the odours in B-SIT with the exception of turpentine showed highly significant differences between patients and controls. AD-associated memory impairment did not seem to affect the answers given for B-SIT in this population. For patients with AD, the Brief Smell Identification Test (B-SIT) appears to be well-suited for detecting a deficit in olfactory identification in a Norwegian population.

Practice Effects on Motor Control in Healthy Seniors and Patients with Mild Cognitive Impairment and Alzheimer's Disease

ABSTRACT This research was designed to test the hypothesis that motor practice can enhance the capabilities of motor control in healthy controls (NC) and patients with a diagnosis of probable Alzheimer's disease (AD) and mild cognitive impairment (MCI), and consequently results in better motor performance. Approximately half of the subjects in the NC (n = 31), AD (n = 28), and MCI (n = 29) either received or did not receive practice on a task of fast and accurate arm movement with a digitizer. Changes in movement time (MT), movement smoothness (jerk), and percentage of primary submovement (PPS) were recorded and compared among the three groups across six blocks of trials (baseline and five training sessions). For all subjects, practice improved motor functions as reflected by faster and smoother motor execution, as well as a greater proportion of programming control. Compared to unaffected matched controls, AD and MCI subjects exhibited a greater reduction in movement jerk due to practice. Movement time and PPS data revealed that motor practice appeared to reduce the use of “on-line” correction adopted by the AD or MCI patients while performing the aiming movements. Evidently, their arm movements were quicker, smoother, and temporally more consistent than their untrained peers. The findings of this study shed light on how MCI and AD may affect motor control mechanisms, and suggest possible therapeutic interventions aimed at improving motor functioning in these impaired individuals.

Automated cortical thickness measurements from MRI can accurately separate Alzheimer's patients from normal elderly controls

We investigated the potential of fully automated measurements of cortical thickness to reproduce the clinical diagnosis in Alzheimer's Disease (AD) using 19 patients and 17 healthy controls. Thickness maps were analyzed using three different discriminant techniques to separate patients from controls. All analyses were performed using leave-one-out cross-validation to avoid overtraining of the discriminants. The results show regionally variant patterns of discrimination ability, with over 90% accuracy obtained in the medial temporal lobes and other limbic structures. Multivariate discriminant analysis produced 100% accuracy with six different combinations, all involving the parahippocampal gyrus. We therefore propose automated measurements of cortical thickness as a tool to improve the clinical diagnosis of probable AD, as well as a research method to gain unique insight into the etiology of cortical pathology in the disease.

The effects of commonly prescribed drugs in patients with Alzheimer’s disease on the rate of deterioration

Background: Prescribed drugs in patients with Alzheimer’s disease may affect the symptomatic progression of their disease, both positively and negatively. Aim: To examine the effects of drugs on the progression...

Facing reality: The cost of Alzheimer dementia—Who will pay?

The Baby Boomers are “coming of age.” They are living longer, on average, than any generation before. With this increased life span comes some real challenges. One is the expected increase in Alzheimer disease (AD) and other dementias (see About dementia predictions). As people live longer, the chances of developing AD increase markedly. At age 60, less than 0.1% of people have dementia. By age 85, 30 to 40% have the disease. Scientists are racing against the clock to find a cure or at least a way to slow the process. In the meantime, the costs for the person with AD, the family, and society are mounting. The cost of AD cannot be measured in terms of the emotional impact on the victim and his or her family. The fear of losing one’s ability to think clearly is frightening. Many just hope “it won’t happen to me” and click to a “more pleasant” topic. However, this is a reality that our society must face if we are to avoid putting the United States into bankruptcy. What exactly are the costs in dollars of having dementia? In the current issue of Neurology , Zhu and others discuss this important topic (Zhu CW, Scarmeas N, Torgan R, et al. Longitudinal study of the effects of patient characteristics on direct costs in Alzheimer disease. Neurology 2006; 67: 998–1005). The study looked at people with probable AD in the early stages. These people were seen in three different Alzheimer clinics: in New York, Baltimore, and Boston. About 200 people were followed for 2 to 7 years. At the start of the study, the 200 people each had a full battery of tests. These included tests to make the diagnosis of probable AD. Other tests looked at each person’s ability to perform activities of daily …

P4-408: Early real-world clinical experience with memantine treatment for Alzheimer’s disease in the United States

Memantine HCl, available in the U.S. only since 2004, has been shown in randomized, double–blinded, placebo–controlled clinical trials to modestly slow symptomatic progression of cognitive and functional decline in moderate to severe Alzheimer's disease (AD). However, clinical trials involve highly selected populations and rigorous compliance; the “real–world” clinical effectiveness of memantine is unknown. To perform a preliminary assessment of the clinical use and effects of memantine treatment in a U.S. memory disorders clinic. Longitudinal analysis of clinical data from the Massachusetts Alzheimer's Disease Research Center Patient Registry using linear mixed fixed and random effects modeling. 518 patients underwent serial clinical evaluations for dementia at the Massachusetts General Hospital Memory Disorders Unit: 117 were treated with memantine (± cholinesterase–inhibitor, ChEI), 160 treated with ChEI only, and 241 not treated with memantine or ChEI. At baseline subjects had/were (mean ± S.E.): age 74.6 ± 0.4 years, education 13.4 ± 0.2 years, 54% female, 95% Probable AD diagnosis, age at onset of symptoms 71.6 ± 0.4 years, Blessed Dementia–IMC score (BDS) 12.0 ± 0.3 errors, Activities of Daily Living score (ADL) 33.9 ± 0.9% dependent. Patients received memantine for a mean of 1.5 years and were followed for a mean of 2.4 years. As a group, patients not treated with memantine or ChEI deteriorated by 4.0 errors/year and 12.0% dependent/year, those taking ChEI–only deteriorated by 3.0 errors/year and 12.5% dependent/year, and those taking memantine (± ChEI) deteriorated by 2.2 errors/years and 8.5% dependent/year, on BDS and ADLs, respectively (p < 0.001 all between–group rate comparisons, except nonsignificant for ADL in no–treatment versus ChEI). Memantine was used mostly in mild to moderate AD in combination with a ChEI. Treatment with memantine and ChEI was associated with statistically significant decreases in the rates of cognitive and functional decline in the early years after treatment, beyond the benefit associated with ChEI treatment alone. This limited and preliminary analysis supports efficacy data from short–term clinical trials, but more expansive analysis of longer term data is required before reaching more definitive conclusions regarding the real–world clinical effectiveness of memantine treatment in AD.

Verbal Learning and Everyday Functioning in Dementia: An Application of Latent Variable Growth Curve Modeling

This study used latent variable growth curve modeling to identify predictors and correlates of verbal learning over trials on a list-learning task in patients with dementia. Data from 116 patients evaluated at the Detroit satellite of the Michigan Alzheimer's Disease Research Center were incorporated in the present analyses. Patients were administered the Fuld Object Memory Evaluation, examined independently by a geriatrician, and, if appropriate, given a diagnosis of probable Alzheimer's disease according to criteria from the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association. The presence of dementia significantly predicted both the intercept (i.e., level of performance) and the slope (i.e., learning over trials), with dementia patients demonstrating lower overall levels of performance and less verbal learning over trials. Rate of verbal learning over trials was a significant predictor of everyday functioning (instrumental activities of daily living) above and beyond general cognitive impairment and demographics.