Muscle strength, quantity and quality and muscle fat quantity and their association with oxidative stress in patients with facioscapulohumeral muscular dystrophy: Effect of antioxidant supplementation.

The purpose of this study was to identify causes of quadriceps muscle weakness in facioscapulohumeral muscular dystrophy (FSHD). To this aim, we evaluated quadriceps muscle and fat volumes by magnetic resonance imaging and their relationships with muscle strength and oxidative stress markers in adult patients with FSHD (n = 32) and healthy controls (n = 7), and the effect of antioxidant supplementation in 20 of the 32 patients with FSHD (n = 10 supplementation and n = 10 placebo) (NCT01596803). Compared with healthy controls, the dominant quadriceps strength and quality (muscle strength per unit of muscle volume) were decreased in patients with FSHD. In addition, fat volume was increased, without changes in total muscle volume. Moreover, in patients with FSHD, the lower strength of the non-dominant quadriceps was associated with lower muscle quality compared with the dominant muscle. Antioxidant supplementation significantly changed muscle and fat volumes in the non-dominant quadriceps, and muscle quality in the dominant quadriceps. This was associated with improved muscle strength (both quadriceps) and antioxidant response. These findings suggest that quadriceps muscle strength decline may not be simply explained by atrophy and may be influenced also by the muscle intrinsic characteristics. As FSHD is associated with increased oxidative stress, supplementation might reduce oxidative stress and increase antioxidant defenses, promoting changes in muscle function.

Cystatin C for kidney function assessment in patients with facioscapulohumeral muscular dystrophy.

BACKGROUND AND AIMS: Muscle mass (MM) impairment observed in facioscapulohumeral muscular dystrophy (FSHD) may bias estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcreat). eGFR based on cystatin C (eGFRcys), produced by all nucleated cells, should be an interesting alternative. Main objectives were to compare eGFRcreat and eGRFcys for chronic kidney disease (CKD) staging and for annual eGFR evolution. Secondary objective was to analyse creatinine, cystatin C with measured MM. MATERIAL AND METHODS: During 4 years, 159 FSHD patients having one or more creatinine and cystatin C measurements (total samples: n = 379), with MM determination by bio-impedancemetry during their follow-up were included. eGFR were determined with CKD-Epi and EKFC equations. RESULTS: On first examination samples, mean eGFRcys was significantly lower than mean eGFRcreat of 25.5 and 17.9 ml/min/1.73 m2 using CKD-Epi and EKFC equations, respectively. 53.5% (CKD-Epi) and 59.1% (EKFC) of agreement were obtained when using eGFRcys instead of eGFRcreat with reclassifications occurring mainly towards more severe stages. Age was correlated with cystatin C but not with creatinine, MM was correlated with creatinine but not with cystatin C. eGFR decreases > 1 ml/min/1.73 m2 were more important when using eGFRcys instead of eGFRcreat (CKD-Epi: 37.5 vs 15.4%, p < 0.001; EKFC: 34.6 vs 20.2%, p < 0.01). CONCLUSION: Cystatin C which is independent of MM appears as a promising candidate biomarker for CKD diagnosis and follow-up in FSHD patient.

Evaluation of CSF1R-related adult onset leukoencephalopathy with axonal spheroids and pigmented glia diagnostic criteria.

BACKGROUND AND PURPOSE: Diagnostic criteria for adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation have recently been proposed. Our objective was to assess their accuracy in an independent multicenter cohort. METHODS: We evaluated the sensitivity and specificity of the diagnostic criteria for ALSP (including the "probable" and "possible" definitions) in a national cohort of 22 patients with CSF1R mutation, and 59 patients with an alternative diagnosis of adult onset inherited leukoencephalopathy. RESULTS: Overall, the sensitivity of the diagnostic criteria for ALSP was 82%, including nine of 22 patients diagnosed as probable and nine of 22 diagnosed as possible. Twenty of the 59 CSF1R mutation-negative leukoencephalopathies fulfilled the diagnostic criteria, leading to a specificity of 66%. CONCLUSIONS: Diagnostic criteria for ALSP have an overall limited sensitivity along with a modest specificity. We suggest that in patients suspected of genetic leukoencephalopathy, a comprehensive magnetic resonance imaging pattern-based approach is warranted, together with white matter gene panel or whole exome sequencing.

Mean arterial pressure change associated with cerebral blood flow in healthy older adults.

We investigate over a 12-year period the association between regional cerebral blood flow (CBF) and cardiovascular risk factors in a prospective cohort of healthy older adults (81.96 ± 3.82 year-old) from the Cognitive REServe and Clinical ENDOphenotype (CRESCENDO) study. Cardiovascular risk factors were measured over 12 years, and gray matter CBF was measured at the end of the study from high-resolution magnetic resonance imaging using arterial spin labeling. The association between cardiovascular risk factors, their long-term change, and CBF was assessed using multivariate linear regression models. Women were observed to have higher CBF than men (p < 0.05). Increased mean arterial pressure (MAP) over the 12-year period was correlated with a low cerebral blood flow (p < 0.05, R(2) = 0.21), whereas no association was detected between CBF and MAP at the time of imaging. High levels of glycemia tended to be associated with low cerebral blood flow values (p < 0.05). Age, alcohol consumption, smoking status, body mass index, history of cardiovascular disease, and hypertension were not associated with CBF. Our main result suggests that change in MAP is the most significant predictor of future CBF in older adults.

Working memory performance is related to intrinsic resting state functional connectivity changes in community-dwelling elderly cohort.

Characterization of normal age-related changes in resting state brain networks associated with working memory performance is a major prerequisite for studying neurodegenerative diseases. The aim of this study was to investigate the relationship between performing a working memory task (under MRI) and resting-state brain networks in a large cohort of healthy elderly subjects (n=337). Functional connectivity and interactions between networks were assessed within the default mode (DMN), salience (SN), and right and left central executive (CEN) networks in two groups of subjects classed by their performance (low and high). The low performance group showed lower functional connectivity in both the DMN and SN, and higher functional connectivity in the right and left CEN compared to the high performance group. Overall the functional connectivity within the DMN and the CEN were correlated. The lower functional connectivity within the DMN and SN in the low performance group is suggestive of altered attentional and memory processes and/or altered motivation. The higher functional connectivity within the CEN could be related to compensatory mechanisms, without which the subjects would have even lower performances. The correlation between the DMN and CEN suggests a modulation between the lower functional connectivity within the DMN and the higher functional connectivity within the CEN when performance is reduced. Finally, this study suggests that performance modifications in healthy elderly subjects are associated with reorganization of functional connectivity within the DMN, SN, and CEN.

Working memory activation of neural networks in the elderly as a function of information processing phase and task complexity.

Changes in working memory are sensitive indicators of both normal and pathological brain aging and associated disability. The present study aims to further understanding of working memory in normal aging using a large cohort of healthy elderly in order to examine three separate phases of information processing in relation to changes in task load activation. Using covariance analysis, increasing and decreasing neural activation was observed on fMRI in response to a delayed item recognition task in 337 cognitively healthy elderly persons as part of the CRESCENDO (Cognitive REServe and Clinical ENDOphenotypes) study. During three phases of the task (stimulation, retention, probe), increased activation was observed with increasing task load in bilateral regions of the prefrontal cortex, parietal lobule, cingulate gyrus, insula and in deep gray matter nuclei, suggesting an involvement of central executive and salience networks. Decreased activation associated with increasing task load was observed during the stimulation phase, in bilateral temporal cortex, parietal lobule, cingulate gyrus and prefrontal cortex. This spatial distribution of decreased activation is suggestive of the default mode network. These findings support the hypothesis of an increased activation in salience and central executive networks and a decreased activation in default mode network concomitant to increasing task load.

APOE ε4 and risk for Alzheimer's disease: do regionally distributed white matter hyperintensities play a role?

BACKGROUND: We previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase the risk for Alzheimer's disease (AD). Here, we examined whether individuals with apolipoprotein E gene (APOE ε4) have increased parietal WMH volume. METHODS: Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n = 694, 47 with dementia) in northern Manhattan and the Etude Santé Psychologique Prévalence Risques et Traitement study (ESPRIT; n = 539, 8 with dementia) in Montpellier. The association between regional WMH and APOE ε4 was examined separately in each group and then in a combined analysis. RESULTS: In WHICAP, ε4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, ε4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, ε4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE ε4 status; those with the ε4 were more likely to have dementia if they also had increased parietal WMH. CONCLUSIONS: APOE ε4 is associated with increased parietal lobe WMH.

Education modulates the impact of white matter lesions on the risk of mild cognitive impairment and dementia.

OBJECTIVES: Conflicting results have been reported regarding the association between white matter lesions (WML) and cognitive impairment. We hypothesized that education, a marker of cognitive reserve (CR), could modulate the effects of WML on the risk of mild cognitive impairment (MCI) or dementia. METHODS: We followed 500 healthy subjects from a cohort of community-dwelling persons aged 65 years and over (ESPRIT Project). At baseline, WML volume was measured using a semi-automatic method on T2-weighted MRI. Standardized cognitive and neurological evaluations were repeated after 2, 4, and 7 years. The sample was dichotomized according to education level into low (≤8 years) and high (>8 years) education groups. Cox proportional hazard models were constructed to study the association between WML and risk of MCI/dementia. RESULTS: The interaction between education level and WML volume reached significance (p = 0.017). After adjustment for potential confounders, the association between severe WML and increased MCI/dementia risk was significant in the low education group (≤8 years) (p = 0.02, hazard ratio [HR]: 3.77 [1.29-10.99]), but not in the high education group (>8 years) (p = 0.82, HR: 1.07 [0.61-1.87]). CONCLUSIONS: Severe WML significantly increases the risk of developing MCI/dementia over a 7-year period in low educated participants. Subjects with higher education levels were seen to be more likely to be resilient to the deleterious effects of severe WML. The CR hypothesis suggests several avenues for dementia prevention.

Spatial distribution of cerebral white matter lesions predicts progression to mild cognitive impairment and dementia.

CONTEXT: White matter lesions (WML) increase the risk of dementia. The relevance of WML location is less clear. We sought to determine whether a particular WML profile, based on the density and location of lesions, could be associated with an increased risk of mild cognitive impairment (MCI) or dementia over the following 7 years. METHODS: In 426 healthy subjects from a cohort of community-dwelling people aged 65 years and over (ESPRIT Project), standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. Patterns of WML were computed with a supervised data mining approach (decision trees) using the regional WML volumes (frontal, parietal, temporal, and occipital regions) and the total WML volume estimated at baseline. Cox proportional hazard models were then constructed to study the association between WML patterns and risk of MCI/dementia. RESULTS: Total WML volume and percentage of WML in the temporal region proved to be the best predictors of progression to MCI and dementia. Specifically, severe total WML load with a high proportion of lesions in the temporal region was significantly associated with the risk of developing MCI or dementia. CONCLUSIONS: Above a certain threshold of damage, a pattern of WML clustering in the temporal region identifies individuals at increased risk of MCI or dementia. As this WML pattern is observed before the onset of clinical symptoms, it may facilitate the detection of patients at risk of MCI/dementia.

Metabolic syndrome and localization of white matter hyperintensities in the elderly population.

BACKGROUND: Metabolic syndrome (MetS) is defined as a clustering of metabolic disorders: abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Although specific components of MetS have been associated with white matter hyperintensities (WMH), less is known about the association between MetS as a whole and WMH, especially in normal aging. We aimed to: (1) investigate this association in a cohort of healthy elderly individuals, and (2) examine the relationship between MetS and the regional distribution of WMH, to further understanding of the relationship between MetS and structural brain changes. METHODS: Analyses were carried out on 308 participants (48.1% men, age: 71.0 ± 3.9 years) from the French longitudinal ESPRIT (Enquête de Santé Psychologique--Risques, Incidence et Traitement) study, who were free of cerebrovascular disease cognitive and functional impairment. Logistic regression models were used to examine the cross-sectional association between MetS (defined using the National Cholesterol Education Program-Adult Treatment Panel III criteria) and (1) WMH volumes, and (2) WMH volumes according to their localization in insulofrontal and temporoparietal regions. RESULTS: After adjusting for potential confounders, participants with MetS had a twofold increased chance of presenting with high levels of WMH volume compared with those without (odds ratio [OR] = 2.74, 95% confidence interval [CI]: 1.25-6.03). MetS was specifically associated with an increase of temporoparietal WMH volumes, but no association was found between MetS and WMH localized in the insulofrontal region. CONCLUSION: Our findings suggest that effective management of MetS may reduce WMH accumulation in brain areas already vulnerable to the aging process.

Depression in elderly persons subject to childhood maltreatment is not modulated by corpus callosum and hippocampal loss.

Childhood adversity has been observed to engender structural changes in the hippocampus and corpus callosum associated with increased risk for depression in childhood and early adulthood. This study investigated this association in the elderly. Corpus callosum area and hippocampal volume were measured from structural MRI in 427 community dwelling elderly. Information on childhood adversity was obtained in the course of a clinical examination using a questionnaire covering multiple aspects of abuse. Multivariate analyses found a significant increase in corpus callosum area and hippocampal volume in subjects exposed to mental disorder in parents and poverty, respectively. No association was found with childhood sexual and physical abuse.

An international perspective on advanced neuroimaging: cometh the hour or ivory tower?

Over the past five to ten years, neuroimaging capability for neurodegenerative diseases has made remarkable progress. However, debate remains as to the true clinical utility of these advanced and costly investigations. Not only is the place of these tests in diagnostic algorithms unclear, but the access to them varies both within and between countries. We sought to gather informed opinion from recognized leaders in the field who can combine both an academic and a clinical perspective on the use of neuroimaging in their own countries. Opinion is presented from Scotland, Argentina, the Czech Republic, France, the USA and Australia. The emerging consensus was one of ongoing caution. While in most countries there was a sense that the use of more advanced imaging techniques was growing, their hour has not yet cometh. However, these techniques, rather than falling from the Ivory Tower, should descend slowly step by step onto fertile and receptive clinics from where better clinical guidelines will emerge.

Public financial support receipt and non-medical resource utilization in Alzheimer's disease results from the PLASA study.

A major health policy objective is to encourage and sustain informal caregiving networks for people with Alzheimer's disease (AD). This goal can be reached by providing financial assistance to patients facing difficulties in the accomplishment of activities of daily living, in order to encourage utilization of professional service and therefore alleviate informal caregiver burden. The main issue is to understand if and how financial assistance is correlated with the distribution between informal and professional care. We used a cross-sectional sample of 1131 French elderly patients (≥65) with mild to moderate AD. Informal and professional service resource use was measured in hours per month using a validated instrument, the Resource Use in Dementia questionnaire. Our results confirmed the utter dominance of informal care, which represented more than 80% of total care even among patients receiving public financial support. However financial support receipt was associated with differences in care utilization: higher use of total non-medical care (formal and informal) and lower proportion of informal care in total non-medical care. Our results suggested the presence of a threshold effect that would influence non-medical care demand decisions. Even if on average the use of informal care in total was 13.3% lower among patients receiving public financial support, informal care use represented more than 80% of total non-medical care use. Providing robust evidence of these associations is crucial to further identify the right dosage between professional service demand and informal care utilization that could be associated with a lower burden and therefore a lower probability of institutionalization.

Brain perfusion SPECT with an automated quantitative tool can identify prodromal Alzheimer's disease among patients with mild cognitive impairment.

OBJECTIVE: To improve diagnosis of early Alzheimer's disease (AD), i.e., prodromal AD, by an automated quantitative tool combining brain perfusion single-photon emission computed tomography (SPECT) images and memory tests scores in order to be applied in clinical practice. PATIENTS AND METHODS: In this prospective, longitudinal, multi-centric study, a baseline (99m)Tc-ECD perfusion SPECT was performed in 83 patients with memory complaint and mild cognitive impairment (MCI). After a 3-year follow-up, 11 patients progressed to Alzheimer's disease (MCI-AD group), and 72 patients remained stable (MCI-S group), including 1 patient who developed mild vascular cognitive impairment. After comparison between the MCI-S and MCI-AD groups with a voxel-based approach, region masks were extracted from the statistically significant clusters and used alone or in combination with Free and Cued Selective Reminding Test (FCSRT) scores for the subject's categorization using linear discriminant analysis. Results were validated using the leave-one-out cross-validation method. RESULTS: Right parietal and hippocampal perfusion was significantly (p<0.05, corrected) decreased in the MCI-AD group as compared to the MCI-S group. The patients' classification in the MCI group using the mean activity in right and left parietal cortex and hippocampus yielded a sensitivity, specificity, and accuracy of 82%, 90%, and 89%, respectively. Combination of SPECT results and FCSRT free recall scores increased specificity to 93%. CONCLUSION: The combination of an automated quantitative tool for brain perfusion SPECT images and memory test scores was able to distinguish, in a group of amnestic MCI, patients at an early stage of AD from patients with stable MCI.

Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population.

We performed a three-stage genome-wide association study (GWAS) to identify common Parkinson's disease (PD) risk variants in the European population. The initial genome-wide scan was conducted in a French sample of 1039 cases and 1984 controls, using almost 500 000 single nucleotide polymorphisms (SNPs). Two SNPs at SNCA were found to be associated with PD at the genome-wide significance level (P < 3 × 10(-8)). An additional set of promising and new association signals was identified and submitted for immediate replication in two independent case-control studies of subjects of European descent. We first carried out an in silico replication study using GWAS data from the WTCCC2 PD study sample (1705 cases, 5200 WTCCC controls). Nominally replicated SNPs were further genotyped in a third sample of 1527 cases and 1864 controls from France and Australia. We found converging evidence of association with PD on 12q24 (rs4964469, combined P = 2.4 × 10(-7)) and confirmed the association on 4p15/BST1 (rs4698412, combined P = 1.8 × 10(-6)), previously reported in Japanese data. The 12q24 locus includes RFX4, an isoform of which, named RFX4_v3, encodes brain-specific transcription factors that regulate many genes involved in brain morphogenesis and intracellular calcium homeostasis.

Caffeine, cognitive functioning, and white matter lesions in the elderly: establishing causality from epidemiological evidence.

The present study examines the epidemiological evidence for a causal relationship between caffeine consumption and cognitive deterioration in the elderly. Using a population of 641 elderly persons, we examined cognitive functioning, caffeine consumption, magnetic resonance imaging volumetrics, and other factors known to affect cognitive performance. Our findings demonstrate the association between caffeine consumption and lower cognitive change over time to be statistically significant for women only, taking into account multiple confounders, to be dose-dependent and temporarily related (caffeine consumption precedes cognitive change). Mean log transformed white matter lesion/cranial volume ratios were found to be significantly lower in women consuming more than 3 units of caffeine per day after adjustment for age (-1.23 SD=0.06) than in women consuming 2-3 units (-1.04 SD=0.04) or one unit or less (-1.04 SD=0.07, -35% in cm3 compared to low drinkers). This observation is coherent with biological assumptions that caffeine through adenosine is linked to amyloid accumulation and subsequently white matter lesion formation. The significant relationship observed between caffeine intake in women and lower cognitive decline is highly likely to be a true causal relationship and not a spurious association.

Retrospective identification and characterization of mild cognitive impairment from a prospective population cohort.

OBJECTIVES: Mild cognitive impairment (MCI) case-finding criteria have low specificity in general population studies. This study retrospectively identifies cases of MCI and determines baseline criteria giving the highest discriminability. The ability of these criteria to increase current case detection specificity is estimated. DESIGN: A population-based cohort was recruited from electoral rolls from three French cities. Clinical and environmental characteristics were evaluated at baseline and at 2- and 4-year follow-up. The clinical characteristics of incident cases of dementia were examined retrospectively. PARTICIPANTS: Eight thousand nine hundred nineteen persons aged 65 years and older without dementia (60.8% women) were included in this study. The mean age (SD) of the participants was 74.2 (5.6) years for men and 74.4 (5.6) years for women. RESULTS: Three hundred twenty persons (3.6%) were retrospectively classified as MCI at baseline. This MCI group had poorer performance on all cognitive tests compared with the rest of the cohort, and a subsample undergoing MRI were found to have more white matter hyperintensities. The group were also characterized by the presence of an ApoE ε4 genotype (odds ratio [OR]: 2.17, confidence interval [CI]: 1.44-3.29 for men; OR: 2.27, CI: 1.59-3.24 for women) and instrumental activities of daily living loss (OR: 1.72, CI: 1.01-3.0 for men; OR: 1.49; CI: 0.97-2.3 for women). Women with MCI also had high depressive symptomatology (OR: 1.96; CI: 1.34-2.87), anticholinergic drug use (OR: 1.59; CI: 1.05-2.28), and low body mass index (OR: 1.54, CI: 1.05-2.28) and for men a history of stroke (OR: 2.17, CI: 1.16-4.05) and glycemia (OR: 1.72, CI: 1.13-2.71). Addition of these characteristics to conventional MCI definitions increases their specificity. CONCLUSIONS: This general population study using a retrospective method for classifying persons with MCI identified gender-specific noncognitive clinical variables that may increase specificity.

Neurological signs and late-life depressive symptoms in a community population: the ESPRIT study.

OBJECTIVE: Depression in the elderly is common and often resistant to treatment. It has been suggested that late-life depression may be related to underlying neurobiological changes. However, these observations are derived from diverse clinical samples and as yet have not been confirmed in a more representative population study. Our aim was to investigate associations between neurological signs as markers of underlying brain dysfunction and caseness for depression in an elderly community sample, controlling for physical health and comorbid/past neurological disorders. METHOD: A cross-sectional analysis of 2102 older people without dementia from the ESPRIT project. Depressive symptomatology was ascertained using the CES-D and abnormal neurological signs/comorbidity from a full neurological examination according to ICD-10 criteria. RESULTS: Pyramidal, extrapyramidal, cranial nerve and sensory deficit signs were significantly associated with case-level depressive symptoms. However, all odds ratios were close to null values in participants who did not have previous neurological disorder. CONCLUSIONS: We confirmed previous findings of an association between neurological signs and case-level depressive symptoms in late life. However, this association may simply reflect the impact of more severe comorbid neurological disorder.

Olive oil and cognition: results from the three-city study.

BACKGROUND: Olive oil is a major component of the Mediterranean diet suggested to be beneficial to counteract Alzheimer's disease. AIM OF THE STUDY: Our objective was to examine the association between olive oil use, cognitive deficit and cognitive decline in a large elderly population. METHODS: We followed 6,947 subjects with a brief baseline food frequency questionnaire and repeated cognitive tests. Olive oil intake was categorized as none (22.7%), moderate (use for cooking or dressing, 39.9%) and intensive (use for both cooking and dressing, 37.4%). Associations between olive oil and cognitive outcomes were examined taking into account socio-economic factors, health behaviors, health measures and other dietary intakes. RESULTS: Participants with moderate or intensive use of olive oil compared to those who never used olive oil showed lower odds of cognitive deficit for verbal fluency and visual memory. For cognitive decline during the 4-year follow-up, the association with intensive use was significant for visual memory (adjusted OR = 0.83, 95% CI: 0.69-0.99) but not for verbal fluency (OR = 0.85, 95% CI: 0.70-1.03) in multivariate analysis. CONCLUSIONS: This olive oil-cognition association needs to be confirmed by further studies. However, our findings already shed light on the potential importance of olive oil in the Mediterranean diet and on its beneficial effects on health.

Extrapyramidal signs before and after diagnosis of incident Alzheimer disease in a prospective population study.

BACKGROUND: Extrapyramidal signs (EPSs) are commonly accepted as a feature of Alzheimer disease (AD) and may influence both the profile of impairment and prognosis. OBJECTIVE: To examine rates of occurrence and risk factors for all types of EPSs and to describe the impact of EPSs over time on the clinical course of AD. DESIGN: Longitudinal study. SETTING: The Washington Heights Hamilton Heights Inwood Columbia Aging Project. Patients A total of 388 patients with incident AD (mean age, 79 years; 71.4% female). MAIN OUTCOME MEASURES: Extrapyramidal signs rated by means of a standardized portion of the Unified Parkinson's Disease Rating Scale; prevalence and incidence rates and cumulative risk for non-drug-induced EPSs; and rates of change in EPSs over time, taking into account potential covariates. RESULTS: Extrapyramidal signs were detected in 12.3% of patients at first evaluation and 22.6% at last evaluation. In a multivariate-adjusted generalized estimating equation model of change, total EPS score increased at an annual rate of 1.3%. Women (relative risk [RR], 1.57; P = .03), older patients (RR, 1.03; P = .02), and those with EPSs at baseline (RR, 2.07; P = .001) had greater rates of cognitive decline. CONCLUSIONS: Extrapyramidal signs occur frequently and progress significantly in AD. Patients with incident AD and concomitant EPSs have a greater rate of cognitive decline than do patients with incident AD but without EPSs.