Dual Task Performance Is Associated with Amyloidosis in Cognitively Healthy Adults.

BACKGROUND: Preclinical Alzheimer's disease (AD) provides an opportunity for the study and implementation of interventions and strategies aimed at delaying, mitigating, and preventing AD. While this preclinical state is an ideal target, it is difficult to identify efficiently and cost-effectively. Recent findings have suggested that cognitive-motor dual task paradigms may provide additional inference. OBJECTIVES: Investigate the relationship between dual task performance and amyloidosis, suggestive of preclinical Alzheimer's disease and whether dual task performance provides additional information beyond a cognitive composite, to help in the identification of amyloidosis. DESIGN: Cross-sectional. SETTING: Outpatient specialty brain health clinical research institution in the United States. PARTICIPANTS: 52 cognitively healthy adults. MEASUREMENTS: The data included demographics, amyloid standardized uptake value ratio obtained via florbetapir-PET, neuropsychological testing, apolipoprotien E genotype, and dual task performance measures. Data were analyzed via hierarchal multiple linear regression or logistic regression, controlling for age, education, and apolipoprotien E genotype. Receiver operating characteristic curves were plotted, and sensitivity and specificity calculated via 2x2 contingency tables. RESULTS: There was a moderate relationship (rs>.30) between motor and cognitive dual task effects and amyloid standardized uptake value ratio (ps<.042). A strong relationship (r=.58) was found between combined dual task effect, a measure of automaticity derived from dual task performance, and amyloid standardized uptake value ratio (p<.001). Additionally, combined dual task effect showed promise in its unique contributions to amyloid standardized uptake value ratio, accounting for 7.8% of amyloid standardized uptake value ratio variance beyond cognitive composite scores (p=.018). Additionally, when incorporated into the cognitive composite, combined dual task effect resulted in improved diagnostic accuracy for determining elevated amyloid standardized uptake value ratio, and increased the sensitivity and specificity of the cognitive composite. CONCLUSSION: Dual task performance using the combined dual task effect, a measure of automaticity, was a moderate predictor of cerebral amyloidosis, which suggests that it has utility in the screening and diagnosis of individuals for preclinical AD. Additionally, when combined with the cognitive composite, the combined dual task effect improves diagnostic accuracy. Further research is warranted.

Recruitment into the Alzheimer Prevention Trials (APT) Webstudy for a Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's Disease (TRC-PAD).

BACKGROUND: The Alzheimer Prevention Trials (APT) Webstudy is the first stage in establishing a Trial-ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD). This paper describes recruitment approaches for the APT Webstudy. OBJECTIVES: To remotely enroll a cohort of individuals into a web-based longitudinal observational study. Participants are followed quarterly with brief cognitive and functional assessments, and referred to Sites for in-clinic testing and biomarker confirmation prior to enrolling in the Trial-ready Cohort (TRC). DESIGN: Participants are referred to the APT Webstudy from existing registries of individuals interested in brain health and Alzheimer's disease research, as well as through central and site recruitment efforts. The study team utilizes Urchin Tracking Modules (UTM) codes to better understand the impact of electronic recruitment methods. SETTING: A remotely enrolled online study. PARTICIPANTS: Volunteers who are at least 50 years old and interested in Alzheimer's research. MEASUREMENTS: Demographics and recruitment source of participant where measured by UTM. RESULTS: 30,650 participants consented to the APT Webstudy as of April 2020, with 69.7% resulting from referrals from online registries. Emails sent by the registry to participants were the most effective means of recruitment. Participants are distributed across the US, and the demographics of the APT Webstudy reflect the referral registries, with 73.1% female, 85.0% highly educated, and 92.5% Caucasian. CONCLUSIONS: We have demonstrated the feasibility of enrolling a remote web-based study utilizing existing registries as a primary referral source. The next priority of the study team is to engage in recruitment initiatives that will improve the diversity of the cohort, towards the goal of clinical trials that better represent the US population.

TRC-PAD: Accelerating Recruitment of AD Clinical Trials through Innovative Information Technology.

BACKGROUND: The Trial-Ready Cohort for Preclinical/Prodromal Alzheimer's Disease (TRC-PAD) Informatics Platform (TRC-PAD IP) was developed to facilitate the efficient selection, recruitment, and assessment of study participants in support of the TRC-PAD program. OBJECTIVES: Describe the innovative architecture, workflows, and components of the TRC-PAD IP. DESIGN: The TRC-PAD IP was conceived as a secure, scalable, multi-tiered information management platform designed to facilitate high-throughput, cost-effective selection, recruitment, and assessment of TRC-PAD study participants and to develop a learning algorithm to select amyloid-bearing participants to participate in trials of early-stage Alzheimer's disease. SETTING: TRC-PAD participants were evaluated using both web-based and in-person assessments to predict their risk of amyloid biomarker abnormalities and eligibility for preclinical and prodromal clinical trials. Participant data were integrated across multiple stages to inform the prediction of amyloid biomarker elevation. PARTICIPANTS: TRC-PAD participants were age 50 and above, with an interest in participating in Alzheimer's research. MEASUREMENTS: TRC-PAD participants' cognitive performance and subjective memory concerns were remotely assessed on a longitudinal basis to predict participant risk of biomarker abnormalities. Those participants determined to be at the highest risk were invited to an in-clinic screening visit for a full battery of clinical and cognitive assessments and amyloid biomarker confirmation using positron emission tomography (PET) or lumbar puncture (LP). RESULTS: The TRC-PAD IP supported growth in recruitment, screening, and enrollment of TRC-PAD participants by leveraging a secure, scalable, cost-effective cloud-based information technology architecture. CONCLUSIONS: The TRC-PAD program and its underlying information management infrastructure, TRC-PAD IP, have demonstrated feasibility concerning the program aims. The flexible and modular design of the TRC-PAD IP will accommodate the introduction of emerging diagnostic technologies.

The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's Disease (TRC-PAD): Experience from the First 3 Years.

BACKGROUND: The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD) aims to accelerate enrollment for Alzheimer's disease (AD) clinical trials by remotely identifying and tracking individuals who are at high risk for developing symptoms of AD, and referring these individuals to in-person cognitive and biomarker evaluation with the purpose of engaging them in clinical trials. A risk algorithm using statistical modeling to predict brain amyloidosis will be refined as TRC-PAD advances with a maturing data set. OBJECTIVES: To provide a summary of the steps taken to build this Trial-Ready cohort (TRC) and share results of the first 3 years of enrollment into the program. DESIGN: Participants are remotely enrolled in the Alzheimer Prevention Trials (APT) Webstudy with quarterly assessments, and through an algorithm identified as potentially at high risk, referred to clinical sites for biomarker confirmation, and enrolled into the TRC. SETTING: Both an online study and in-clinic non-interventional cohort study. PARTICIPANTS: APT Webstudy participants are aged 50 or older, with an interest in participation in AD therapeutic trials. TRC participants must have a study partner, stable medical condition, and elevated brain amyloid, as measured by amyloid positron emission tomography or cerebrospinal fluid analysis. Additional risk assessments include apolipoprotein E genotyping. MEASUREMENTS: In the APT Webstudy, participants complete the Cognitive Function Index and Cogstate Brief Battery. The TRC includes the Preclinical Alzheimer's Cognitive Composite, comprised of the Free and Cued Selective Reminding Test, the Delayed Paragraph Recall score on the Logical Memory IIa test from the Wechsler Memory Scale, the Digit-Symbol Substitution test from the Wechsler Adult Intelligence Scale-Revised, and the Mini Mental State Examination total score (1). RESULTS: During the first 3 years of this program, the APT Webstudy has 30,650 consented participants, with 23 sites approved for in person screening, 112 participants have been referred for in-clinic screening visits with eighteen enrolled to the TRC. The majority of participants consented to APT Webstudy have a family history of AD (62%), identify as Caucasian (92.5%), have over twelve years of formal education (85%), and are women (73%). Follow up rates for the first quarterly assessment were 38.2% with 29.5% completing the follow up Cogstate Battery. CONCLUSIONS: After successfully designing and implementing this program, the study team's priority is to improve diversity of participants both in the APT Webstudy and TRC, to continue enrollment into the TRC to our target of 2,000, and to improve longitudinal retention, while beginning the process of referring TRC participants into clinical trials.

Skin reactions at the application site of rivastigmine patch (4.6 mg/24 h, 9.5 mg/24 h or 13.3 mg/24 h): a qualitative analysis of clinical studies in patients with Alzheimer's disease.

BACKGROUND AND OBJECTIVES: Rivastigmine patch is approved for the treatment of all stages of Alzheimer's disease (AD). Application site reactions may be a concern to clinicians and we used two large clinical trial databases to investigate the incidence of skin reactions in patients receiving rivastigmine patch. METHODS: Data from a 24-week, randomised, double-blind (DB) evaluation of 13.3 vs. 4.6 mg/24 h rivastigmine patch in severe AD (ACTION) and a 72- to 96-week study comprising an initial open-label (IOL) phase followed by a 48-week randomised, DB phase (13.3 vs. 9.5 mg/24 h rivastigmine patch) in declining patients with mild-to-moderate AD (OPTIMA) were analyzed. The incidence, frequency, severity, management and predictors of application site reactions were assessed. RESULTS: Application site reactions were mostly mild or moderate in severity and reported by similar proportions in each treatment group ( ACTION: 13.3 mg/24 h, 24.5% and 4.6 mg/24 h, 24.2%; OPTIMA: IOL 9.5 mg/24 h, 22.9%; DB 13.3 mg/24 h, 11.4% and 9.5 mg/24 h, 12.0%); none were rated serious. In both studies, <9% of patients required treatment for application site reactions. Application site reactions led to discontinuation of 1.7% and 2.5% of the 13.3 mg/24 h and 4.6 mg/24 h groups, respectively, in ACTION, 8.7% in OPTIMA IOL and 1.8% and 3.5% of the 13.3 mg/24 h and 9.5 mg/24 h groups, respectively, in OPTIMA DB. CONCLUSIONS: Application site reactions were experienced by <25% of patients in both studies, with no notable effect of dose. No reactions qualified as serious and skin reactions were uncommon as a reason for study discontinuation.

Activation of innate anti-viral immune response genes in symptomatic benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is the most common urologic disease in men over age 50. Symptoms include acute urinary retention, urgency to urinate and nocturia. For patients with severe symptoms, surgical treatment is used to remove the affected tissue. Interestingly, the presence of histologic BPH does not always correlate with symptoms. The molecular basis of symptomatic BPH and how it differs from asymptomatic BPH is unknown. Investigation into the molecular players involved in symptomatic BPH will likely give insight into novel therapeutic, and potentially preventative, targets. We determined the expression of genes involved in the innate anti-viral immune response in tissues from patients undergoing surgery to alleviate the symptoms of BPH, and compared the results with prostate tissue with histologic BPH, but from patients with few urinary issues (asymptomatic BPH). We found that expression of complement factor I, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like protein 3G, oligoadenylate synthetase 2 and interferon-induced tetratricopeptide 1, four genes whose protein products are involved in the innate anti-viral immune response, was significantly transcriptionally upregulated in symptomatic BPH. Additionally, we observe hypomethylation and concomitant expression of ancient retroviral-like sequences, the long interspersed nuclear element 1 retrotransposons, in symptomatic BPH when compared with normal prostate tissue. These findings merit further investigation into the anti-viral immune response in symptomatic BPH.

Chronic divalproex sodium use and brain atrophy in Alzheimer disease.

OBJECTIVE: We evaluated the effect of the divalproex sodium formulation of valproic acid on brain volumes using MRI in people with mild to moderate Alzheimer disease (AD) and assessed for changes associated with behavioral and cognitive effects. METHODS: Eighty-nine of 313 participants randomized to divalproex or placebo in a 24-month, parallel-group trial received MRI scans at baseline and 12 months. Interval MRI annual percent changes in whole brain, ventricular, and hippocampal volumes were the primary outcomes of interest. Change from baseline in clinical outcomes was assessed at 6-month intervals. RESULTS: There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ε4 carrier status. The group treated with divalproex showed a greater rate of decline in left and right hippocampal and brain volumes (-10.9% and -12.4% vs -5.6% and -6.3%, and -3.5% vs -1.4%, respectively), and a greater rate of ventricular expansion (24.5% vs 9.9%) (p < 0.001). Mini-Mental State Examination scores showed a more rapid decline with divalproex through month 12 (placebo = -2.0 ± 4.3, divalproex = -3.9 ± 4.0) (p = 0.037), although there were no changes on other cognitive, behavioral, or functional ratings at 12 and 24 months. CONCLUSIONS: Divalproex treatment was associated with accelerated brain volume loss over 1 year and perhaps with greater cognitive impairment. The long-term clinical effects of these changes are not known.

Donepezil delays progression to AD in MCI subjects with depressive symptoms.

OBJECTIVE: To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship. METHODS: The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD. RESULTS: Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score > or =10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants. CONCLUSIONS: Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.

Biochemical markers in persons with preclinical familial Alzheimer disease.

BACKGROUND: Persons at risk for familial Alzheimer disease (FAD) provide a model in which biomarkers can be studied in presymptomatic disease. METHODS: Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (Abeta(40), Abeta(42), F(2)-isoprostanes) and CSF (F(2)-isoprostanes, t-tau, p-tau(181), Abeta(40), Abeta(42), and Abeta(42)/Abeta(40) ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs). RESULTS: Plasma Abeta(42) levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Abeta(42)/Abeta(40) (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma Abeta(42) levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Abeta(42) to Abeta(40) was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau(181) levels were elevated in presymptomatic FAD MCs. CSF levels of F(2)-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031). CONCLUSIONS: Our data indicate that Abeta(42) is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of Abeta(42) to Abeta(40) was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau(181) are sensitive indicators of presymptomatic disease. Our finding of elevated F(2)-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.

Neuropsychiatric symptoms in patients with Parkinson's disease and dementia: frequency, profile and associated care giver stress.

OBJECTIVE: To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson's disease (PDD). METHODS: 537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables were analysed. RESULTS: 89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and 64% had at least one symptom with a score > or = 4. The most common symptoms were depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced Parkinson's disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy (24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson's Disease Rating Scale and care giver distress scores. CONCLUSION: Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified. These subgroups may be associated with distinct neurobiological changes, which should be explored in future studies.

[Neuropsychiatric Inventory-Nursing Home version (NPI-NH): Spanish validation]. / Neuropsychiatric Inventory-Nursing Home version (NPI-NH): validación española.

INTRODUCTION: The Neuropsychiatric Inventory-Nursing Home version (NPI-NH) is a screening instrument to be used by the nursing staff to evaluate neuropsychiatric symptoms in dementia patients in the nursing home setting. The aim of the present study was to validate the NPI-NH in Spanish. METHODS: We assessed the validity of the NPI-NH in 80 patients who were also nursing home residents, comparing the responses of nursing home staff on the NPI-NH with that filled out by the external observer. We developed a crossed validated form between the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and both NPI-NH. We determined the concurrent validity of the domains "depression" and "agitation/aggression" of the NPI-NH with the Cohen-Mansfield Agitation Inventory (IAACM, Spanish version) and the Hamilton Depression Rating Scale (HDRS). RESULTS: Among the totals of the NPI-NH of the nursing staff and the NPI-Q, the convergent validity was r = 0.536 and r = 0.669 for the occupational disruptiveness scale (distress in NPI-Q). The Pearson correlation index between the NPI-Q and NPI-NH of the observations was r = 0.342. The convergent validity between the NPINH of the nursing home staff and NPI-NH of the observers with the Pearson correlation index was r = 0.274. CONCLUSIONS: The NPI-NH Spanish version offers the possibility to use a screening tool for detecting neuropsychiatric symptoms in dementia patients in the nursing home setting. It should be administered by adequately trained staff to avoid limitations in the evolutive control of behavioral changes.

Neuropsychiatric Inventory-Nursing Home version (NPI-NH): validación española / Neuropsychiatric Inventory - Nursing Horne version (NPI-NH): Spanish validation

Introducción. El Neuropsychiatric Inventory-Nursing Home version (NPI-NH) es un instrumento de cribado para evaluar por el personal de enfermería o auxiliar la sintomatología neuropsiquiátrica en pacientes con demencia ingresados en residencia. El objetivo del presente estudio fue validar la versión española del NPI-NH. Métodos. Estudio de la validez del NPI-NH en 80 pacientes con demencia ingresados en residencia mediante la comparación entre la escala contestada por el auxiliar y la cumplimentada por el observador externo. Validación cruzada entre el Neuropsychiatric Inventory-Questionnaire (NPI-Q) y ambos NPI-NH. Estudio de la validez convergente de los dominios «depresión» y «agitación/agresividad» del NPI-NH con las escalas Inventario de Agitación del Anciano Cohen-Mansfield (lAACM) y Hamilton Depression Rating Scale (HDRS). Resultados. Entre los totales del NPI-NH auxiliares y el NPI-Q la validez convergente fue de r = 0,536 Y de r = 0,669 para la escala de interrupción ocupacional (estrés en NPI-Q). Entre el NPI-Q y el NPI-NH de las observaciones el índice de correlación de Pearson fue de r = 0,342. La validez convergente entre el NPI-NH de los auxiliares y NPI-NH de los observadores mediante el índice de correlación de Pearson fue de r = 0,273. Conclusiones. La versión española del NPI-NH ofrece la posibilidad de aplicar un test de cribado de sintomatología neuropsiquiátrica en pacientes con demencia alojados en una residencia geriátrica. Debe ser administrado por personal debidamente entrenado para evitar limitaciones en el control evolutivo de los cambios de conducta

Introduction. The Neuropsychiatric Inventory-Nursing Horne version (NPI-NH) is a screening instrument to be used by the nursing staff to evaluate neuropsychiatric symptoms in dementia patients in the nursing home setting. The aim of the present study was to validate the NPI-NH in Spanish. Methods. We assessed the validity of the NPI-NH in 80 patients who were also nursing home residents, comparing the responses of nursing home staff on the NPI-NH with that filled out by the external observer. We developed a crossed validated form between the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and both NPI-NH. We determined the concurrent validity of the domains «depression» and «agitation/aggression» of the NPI-NH with the Cohen-Mansfield Agitation Inventory (IAACM, Spanish version) and the Hamilton Depression Rating Scale (HDRS). Results. Among the totals of the NPI-NH of the nursing staff and the NPI-Q, the convergent validity was r = 0.536 and r = 0.669 for the occupational disruptiveness scale (distress in NPI-Q). The Pearson correlation index between the NPI-Q and NPI-NH of the observations was r = 0.342. The convergent validity between the NPINH of the nursing home staff and NPI-NH of the observers with the Pearson correlation index was r = 0.274. Conclusions. The NPI-NH Spanish version offers the possibility to use a screening tool for detecting neuropsychiatric symptorns in dementia patients in the nursing home setting. It should be administered by adequately trained staff to avoid limitations in the evolutive control of behavioral changes

Neuropsychiatric profiles in patients with Alzheimer's disease and vascular dementia.

OBJECTIVE: To explore the neuropsychiatric manifestations in patients with Alzheimer's disease (AD) and cortical and subcortical vascular dementia (VaD). METHODS: We investigated consecutive patients with dementia. All the participants received brain computed tomography. The diagnosis of dementia was confirmed by clinical criteria and the imaging findings. Only patients with probable AD, and subcortical and cortical VaD were included. The Mini Mental State Examination (MMSE) was used to evaluate global cognitive function, and the Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. RESULTS: Of the 536 participants with dementia, 320 (59.7%) had AD, 161 (30%) had subcortical VaD, 35 (6.4%) had cortical VaD, and 16 (2.9%) had mixed cortical and subcortical VaD. Cortical VaD patients had the highest mean composite NPI scores in all domains and AD patients had the lowest composite scores in most domains. The mean composite scores of the apathy and sleep disturbance domains in patients with cortical VaD were significantly higher than those in the patients with AD after controlling for years of education and MMSE score (p < 0.01). CONCLUSIONS: There were few differences among the patients with AD, subcortical VaD and cortical VaD. The most consistent differences were the high sleep disturbance scores in those with cortical VaD.

Agitation in Alzheimer's disease is a manifestation of frontal lobe dysfunction.

OBJECTIVES: (1) To investigate the prevalence and characteristics of agitation in patients with Alzheimer's disease (AD) and other forms of dementia; (2) to explore the association between agitation and other clinical variables, including disease severity, functional impairment and other neuropsychiatric symptoms, and (3) to determine the predictors of agitation. METHODS: Data for 427 men and women with dementia from outpatient clinics of the University of California, Los Angeles Alzheimer's Disease Center were analyzed. There were 277 patients with AD, 43 with vascular dementia, 47 with mixed dementia, 45 with frontotemporal dementia and 15 with dementia with Lewy bodies. Patients were evaluated with the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Functional Activities Questionnaire (FAQ), neuropsychological tests and the Caregiver Appraisal instrument. SPSS10 was utilized for statistical analysis. RESULTS: There was no difference in agitation subscale scores among patients with dementia of various etiologies. In patients with AD, there was increased prevalence of agitation with increasing dementia severity. Agitation contributed substantially to caregiver burden and impact. There was a significant correlation between the FAQ and the NPI agitation subscale score after adjusting for MMSE scores. Delusion, disinhibition and irritability subscale scores in AD patients were correlated with agitation across disease severity. Subscale scores of frontally mediated behaviors including irritability, delusions and disinhibition predicted most of the variance in agitation levels. CONCLUSION: Agitation is common in AD and other dementias and has a marked impact on caregivers. It is related to dementia severity and to specific types of associated psychopathology implicating frontal lobe dysfunction. The present study is the largest and most comprehensive assessment of agitation reported. The data suggest that agitation in AD is a frontal lobe syndrome. Frontal lobe dysfunction may predispose AD patients to agitation by exaggerating behavioral responses to many types of coexisting psychopathology or environmental provocations.

Possible association of the tau H1/H1 genotype with primary progressive aphasia.

The authors screened for tau gene mutations and polymorphisms to determine whether genetic variation at or near the tau locus contributes to the development of primary progressive aphasia (PPA). No mutations were detected in 25 patients with PPA. However, a significant overrepresentation of the tau H1/H1 genotype, also found in progressive supranuclear palsy and corticobasal degeneration, was found in the PPA group. Whether tau haplotypes have a primary causal role or whether they affect the topology of neurodegeneration remains to be determined.

Telomere shortening in T cells correlates with Alzheimer's disease status.

Telomeres, the repeated sequences that cap chromosome ends, undergo shortening with each cell division, and therefore serve as markers of a cell's replicative history. In vivo, clonal expansion of T cells during immune responses to both foreign and autoantigens is associated with telomere shortening. To investigate possible immune alterations in Alzheimer's disease (AD) that might impact current vaccine-based therapeutic strategies, we analyzed telomere lengths in immune cell populations from AD patients. Our data show a significant telomere shortening in PBMC from AD versus controls (P=0.04). Importantly, telomere length of T cells, but not of B cells or monocytes, correlated with AD disease status, measured by Mini Mental Status Exam (MMSE) scores (P=0.025). T cell telomere length also inversely correlated with serum levels of the proinflammatory cytokine TNFalpha (a clinical marker of disease status), with the proportion of CD8+ T cells lacking expression of the CD28 costimulatory molecule, and with apoptosis. These findings suggest an immune involvement in AD pathogenesis.

A transcultural study of agitation in dementia.

Agitation is one of the most troublesome behaviors in demented patients. It is etiologically heterogeneous and has varied associated behaviors. To explore the transcultural differences in the manifestation of agitation, we evaluated 50 consecutive Alzheimer's disease (AD) patients in three countries (Taiwan, Italy, and the United States) using the Neuropsychiatric Inventory (NPI) and the Mini-Mental State Examination (MMSE). In a focused analysis, only patients with composite NPI scores > 2 for agitation were selected, with similar levels of disease severity as measured by the MMSE, from the three groups (n = 15 per group) to evaluate culturally specific correlates of agitation. Agitated Taiwanese had significantly more hallucinations than either Italian or American patients. Agitated Italian patients had significantly more apathy than both Taiwanese and American patients. Cultural factors may influence the manifestation of agitation more than a common underlying neuropathology. Management strategies targeting unique behavioral instigators of agitation may be specific for different ethnic groups.