Effect of long-term physical exercise and multidomain interventions on cognitive function and the risk of mild cognitive impairment and dementia in older adults: A systematic review with meta-analysis.

INTRODUCTION: Recent studies have suggested that sustained multidomain interventions, including physical exercise, may be beneficial in preventing cognitive decline. This review aims to assess the impact of prolonged physical exercise and multidomain strategies on overall cognitive faculties and dementia risk among community-dwelling older adults without dementia. METHODS: We systematically searched PubMed, Web of Science, PsychInfo, and CINHAL databases from inception until April 1, 2024, for randomized controlled trials that investigated the effects of long-term (≥ 12 months) physical exercise or multidomain interventions on non-demented, community-dwelling older adults. The primary outcomes assessed were changes in global cognition and the risk of mild cognitive impairment (MCI) or dementia. Standardized mean differences (SMD) and risk ratios (RR) with 95 % confidence intervals were computed using a random-effects inverse-variance method with the Hartung-Knapp-Sidik-Jonkman adjustment for effect size calculation. The Cochrane Risk-of-Bias-2 tool (RoB-2) was used for bias assessment, and the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was applied to evaluate the certainty of evidence. RESULTS: Sixteen trials, including 11,402 participants (mean age 73.2 [±5.5] years; 62.3 % female) were examined. The risk of bias was low. Moderate-certainty evidence indicated that physical exercise interventions had modest to no effect on cognitive function (k= 9, SMD: 0.05; 95 % CI: -0.04-0.13; p = 0.25), whereas multidomain interventions were significantly impactful (k=7, SMD: 0.09; 95 % CI: 0.04-0.15; p < 0.01). Physical exercise interventions did not alter MCI risk (k= 4, RR: 0.98; 95 % CI: 0.73-1.31; p = 0.79) or dementia onset (k= 4, RR: 0.61; 95 % CI: 0.25-1.52; p = 0.19), with very low-to low-certainty evidence, respectively. CONCLUSIONS: Integrative multidomain strategies incorporating physical exercise may benefit the global cognitive function of older adults. However, long-term physical exercise alone did not yield any cognitive gains. The effectiveness of such exercise interventions to mitigate the overall risk of incident MCI and dementia warrants further research.

Brief cognitive tests as a decision-making tool in primary care. A population and validation study.

INTRODUCTION AND OBJECTIVES: Brief cognitive tests (BCT) are used in primary care (PC) for the detection of cognitive impairment (CI). Still, there are little data on their diagnostic utility (DU) in a community setting. This work evaluates the DU at the population level of Fototest, T@M, AD8 questionnaire and MMSE. It provides new cut-off points (CoP) validated in a CI early detection program. MATERIAL AND METHODS: In the population and validation samples, the evaluation was carried out in two phases, a first of screening and administration of BCT and a second of clinical diagnosis, blinded to the results of the BCT, applying the current NIA-AA criteria. The DU of BCT in the population sample was evaluated with the area under the ROC curve (aROC). Youden index and the CoP with the best specificity that ensured a sensitivity of 80% were used to decide on the most appropriate CoP. The sensitivity, specificity, and predictive values for these CoP were calculated in the validation sample. RESULTS: 260 participants (23.1% with CI) from the population sample and 177 (42.4% with CI) from the validation sample were included. The Fototest has the best UD at the population level (aROC 0.851), which improves with the combination of Fototest and AD8 (aROC 0.875). The proposed CoP are AD8 ≥ 1, Fototest ≤ 35, T@M ≤ 40, and MMSE ≤ 26. CONCLUSION: BCT are helpful in detecting CI in PC. This work supports the use of more demanding PoC.

Validity of a computerised population registry of dementia based on clinical databases.

INTRODUCTION: The handling of information through digital media allows innovative approaches for identifying cases of dementia through computerised searches within the clinical databases that include systems for coding diagnoses. The aim of this study was to analyse the validity of a dementia registry in Gipuzkoa based on the administrative and clinical databases existing in the Basque Health Service. METHODS: This is a descriptive study based on the evaluation of available data sources. First, through review of medical records, the diagnostic validity was evaluated in two samples of cases identified and not identified as dementia. The sensitivity, specificity and positive and negative predictive value of the diagnosis of dementia were measured. Subsequently, the cases of living dementia in December 31, 2016 were searched in the entire Gipuzkoa population to collect sociodemographic and clinical variables. RESULTS: The validation samples included 986 cases and 327 no cases. The calculated sensitivity was 80.2% and the specificity was 99.9%. The negative predictive value was 99.4% and positive value was 95.1%. The cases in Gipuzkoa were 10 551, representing 65% of the cases predicted according to the literature. Antipsychotic medication were taken by a 40% and a 25% of the cases were institutionalised. CONCLUSIONS: A registry of dementias based on clinical and administrative databases is valid and feasible. Its main contribution is to show the dimension of dementia in the health system.

Plasma Aß42/40 Ratio Detects Early Stages of Alzheimer's Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study.

BACKGROUND: Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer's disease (AD) in large population screening strategies. OBJECTIVES: This study evaluated the potential of plasma ß-amyloid (Aß) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years. DESIGN: Total plasma Aß42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern. RESULTS: Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF). CONCLUSIONS: TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.

Obesity parameters, physical activity, and physical fitness are correlated with serum dipeptidyl peptidase IV activity in a healthy population.

OBJECTIVE: To determine whether obesity, physical fitness, and physical activity parameters are associated with the enzymatic activity of serum dipeptidyl peptidase IV (sDPPIV) in a sample of healthy women and men. DESIGN AND METHODS: We have correlated parameters of obesity, physical fitness, and physical activity with sDPPIV activity in 374 healthy subjects (age: 60.7 ± 6.9 years, body mass index: 26.1 ± 4.1 kg/m2). Enzymatic activity was analyzed using spectrofluorimetry, body composition was assessed by impedanciometry, physical fitness data were obtained using the Senior Fitness Test, and physical activity data were collected by accelerometer. Pearson's partial correlation analysis was applied to determine the relationship between DPPIV activity and the rest of parameters and significantly correlated variables were introduced into linear regression models to predict DPPIV. RESULTS: Serum DPPIV activity was negatively associated with obesity parameters such as body mass (r = -0.112), body mass index (BMI) (r = -0.147), waist circumference (r = -0.164), waist-to-hip ratio (-0.104), and percentage of fat mass (r = -0.185). Serum DPPIV activity was positively associated with cardiovascular fitness (r = 0.138), total amount of physical activity (r = 0.153), and time spent doing light exercise (r = 0.184). Regression models revealed sex differences in enzyme activity with overall activity higher in women than in men (ß = 0.437, p < 0.001). Further, percent fat mass was an independent negative predictor of DPPIV activity (ß = -0.184, p = 0.001). Serum DPPIV activity was positively predicted based on the amount of time spent doing light physical activity (ß = 0.167, p = 0.001). CONCLUSION: Our results demonstrate that sDPPIV activity is positively associated with healthier parameters regarding fatness, fitness and physical activity.

Sex differences in the aging pattern of renin-angiotensin system serum peptidases.

BACKGROUND: Serum peptidases, such as angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (ACE2), neutral endopeptidase (NEP), aminopeptidase N (APN), and aminopeptidase A (APA), are important elements of the renin-angiotensin system (RAS). Dysregulation of these enzymes has been associated with hypertension and cardiovascular risk. In the present study, serum activities of RAS peptidases were analyzed to evaluate the existence of sexual differences, with a possible different pattern in pre- and post-andropausal/post-menopausal participants. METHODS: One hundred and eighteen healthy men and women between 41 and 70 years of age (58 women and 60 men) were recruited to participate in the study. Serum RAS-regulating enzymes were measured by spectrofluorimetry. Enzymatic activity was recorded as units of enzyme per milliliter of serum (U/mL). RESULTS: Significantly lower serum APA activity was observed in men with respect to women; no sex differences were detected for ACE, ACE2, NEP, or APN. Significantly lower APA and ACE serum activity were observed in older men compared to older women. In contrast, younger (<55 years) men had significantly higher values of NEP serum activity than younger women. Significantly lower ACE serum activity was detected in older men compared to younger men. In women, significantly higher ACE2 serum activity was observed in older women compared to younger women. CONCLUSIONS: These results suggest a differential effect of aging on the activity of RAS enzymes in men and women, especially with respect to the breakpoint of andropausia/menopausia, on the critical serum enzymatic activities of the RAS, which could correlate with sexual differences in cardiovascular risk.

Automated analysis of FDG PET as a tool for single-subject probabilistic prediction and detection of Alzheimer's disease dementia.

PURPOSE: To introduce, evaluate and validate a voxel-based analysis method of ¹8F-FDG PET imaging for determining the probability of Alzheimer's disease (AD) in a particular individual. METHODS: The subject groups for model derivation comprised 80 healthy subjects (HS), 36 patients with mild cognitive impairment (MCI) who converted to AD dementia within 18 months, 85 non-converter MCI patients who did not convert within 24 months, and 67 AD dementia patients with baseline FDG PET scan were recruited from the AD Neuroimaging Initiative (ADNI) database. Additionally, baseline FDG PET scans from 20 HS, 27 MCI and 21 AD dementia patients from our institutional cohort were included for model validation. The analysis technique was designed on the basis of the AD-related hypometabolic convergence index adapted for our laboratory-specific context (AD-PET index), and combined in a multivariable model with age and gender for AD dementia detection (AD score). A logistic regression analysis of different cortical PET indexes and clinical variables was applied to search for relevant predictive factors to include in the multivariable model for the prediction of MCI conversion to AD dementia (AD-Conv score). The resultant scores were stratified into sixtiles for probabilistic diagnosis. RESULTS: The area under the receiver operating characteristic curve (AUC) for the AD score detecting AD dementia in the ADNI database was 0.879, and the observed probability of AD dementia in the six defined groups ranged from 8% to 100% in a monotonic trend. For predicting MCI conversion to AD dementia, only the posterior cingulate index, Mini-Mental State Examination (MMSE) score and apolipoprotein E4 genotype (ApoE4) exhibited significant independent effects in the univariable and multivariable models. When only the latter two clinical variables were included in the model, the AUC was 0.742 (95% CI 0.646 - 0.838), but this increased to 0.804 (95% CI 0.714 - 0.894, bootstrap p=0.027) with the addition of the posterior cingulate index (AD-Conv score). Baseline clinical diagnosis of MCI showed 29.7% of converters after 18 months. The observed probability of conversion in relation to baseline AD-Conv score was 75% in the high probability group (sixtile 6), 34% in the medium probability group (merged sixtiles 4 and 5), 20% in the low probability group (sixtile 3) and 7.5% in the very low probability group (merged sixtiles 1 and 2). In the validation population, the AD score reached an AUC of 0.948 (95% CI 0.625 - 0.969) and the AD-Conv score reached 0.968 (95% CI 0.908 - 1.000), with AD patients and MCI converters included in the highest probability categories. CONCLUSION: Posterior cingulate hypometabolism, when combined in a multivariable model with age and gender as well as MMSE score and ApoE4 data, improved the determination of the likelihood of patients with MCI converting to AD dementia compared with clinical variables alone. The probabilistic model described here provides a new tool that may aid in the clinical diagnosis of AD and MCI conversion.

Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease.

Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.

Progression of Alzheimer disease in Europe: data from the European ICTUS study.

The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North, South, West) and investigated with biannual follow-up over 2 years. Primary outcomes were cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Participant cognitive function declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances (NPI scale) was linear. Neither scale showed regional differences, and progression of the disease was similar across Europe despite different health care systems. Functional decline (ADL, IADL) tended to progress more rapidly in Southern Europe (p=0.09), while progression of caregiver burden (Zarit Burden Interview) was most rapid in Northern Europe (5.6 pts/y, p=0.04). Incidences of hospital admission (10.44, 95%CI: 8.13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe. In general cognitive and functional decline was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden.

The impact of silent vascular brain burden in cognitive impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) detected by magnetic resonance imaging (MRI) of the brain are associated with dementia and cognitive impairment in the general population and in Alzheimer's disease. Their effect in cognitive decline and dementia associated with Parkinson's disease (PD) is still unclear. METHODS: We studied the relationship between WMHs and cognitive state in 111 patients with PD classified as cognitively normal (n = 39), with a mild cognitive impairment (MCI) (n = 46) or dementia (n = 26), in a cross-sectional and follow-up study. Cognitive state was evaluated with a comprehensive neuropsychological battery, and WMHs were identified in FLAIR and T2-weighted MRI. The burden of WMHs was rated using the Scheltens scale. RESULTS: No differences in WMHs were found between the three groups in the cross-sectional study. A negative correlation was observed between semantic fluency and the subscore for WMHs in the frontal lobe. Of the 36 non-demented patients re-evaluated after a mean follow-up of 30 months, three patients converted into MCI and 5 into dementia. Progression of periventricular WMHs was associated with an increased conversion to dementia. A marginal association between the increase in total WMHs burden and worsening in the Mini Mental State Examination was encountered. CONCLUSIONS: White matter hyperintensities do not influence the cognitive status of patients with PD. Frontal WMHs have a negative impact on semantic fluency. Brain vascular burden may have an effect on cognitive impairment in patients with PD as WMHs increase overtime might increase the risk of conversion to dementia. This finding needs further confirmation in larger prospective studies.

Somatic mosaicism in a case of apparently sporadic Creutzfeldt-Jakob disease carrying a de novo D178N mutation in the PRNP gene.

Transmissible spongiform encephalopathies (TSEs) are a group of rare fatal neurodegenerative disorders. Creutzfeldt-Jakob disease (CJD) represents the most common form of TSE and can be classified into sporadic, genetic, iatrogenic and variant forms. Genetic cases are related to prion protein gene mutations but they only account for 10-20% of cases. Here we report an apparently sporadic CJD case with negative family history carrying a mutation at codon 178 of prion protein gene. This mutation is a de novo mutation as the parents of the case do not show it. Furthermore the presence of three different alleles (wild type 129M-178D and 129V-178D and mutated 129V-178N), confirmed by different methods, indicates that this de novo mutation is a post-zygotic mutation that produces somatic mosaicism. The proportion of mutated cells in peripheral blood cells and in brain tissue was similar and was estimated at approximately 97%, suggesting that the mutation occurred at an early stage of embryogenesis. Neuropathological examination disclosed spongiform change mainly involving the caudate and putamen, and the cerebral cortex, together with proteinase K-resistant PrP globular deposits in the cerebrum and cerebellum. PrP typing was characterized by a lower band of 21 kDa. This is the first case of mosaicism described in prion diseases and illustrates a potential etiology for apparently sporadic neurodegenerative diseases. In light of this case, genetic counseling for inherited and sporadic forms of transmissible encephalopathies should take into account this possibility for genetic screening procedures.

Assessing physician attitudes and perceptions of Alzheimer's disease across Europe.

Given the important role that physicians play in clinical care, disease advocacy, national health policy making and clinical research, the IMPACT survey sought to assess the attitudes and perceptions of physicians in 3 general categories: diagnosis and treatment of Alzheimer's disease (AD); caregivers and families of patients with AD; and the role of government in dealing with this disease and its consequences. Survey respondents comprised a total of 250 generalists and 250 specialists (neurologists, geriatricians, neuro-psychiatrists, psychiatrists and psychogeriatricians) from France, Germany, Italy, Spain and the United Kingdom. Physicians were aged 25 to 69 years, in practice for between 5 and 30 years and currently spending more than 50% of their time in direct patient care. Results showed that a sizable majority of physicians throughout Europe, specialists and generalists alike, agree that: 1) AD is underdiagnosed and undertreated; 2) patients and families are not prepared to recognise the early symptoms of the disease; 3) early treatment can help to slow the progression of the disease; and 4) more effective treatments are needed. Attitudes were statistically significantly different between some groups of physicians regarding disclosure of the diagnosis of AD, the benefits of lifestyle modification, and the value of AD-specific medication in patients whose symptoms are worsening. Differences in attitudes and perceptions of AD between specialists and generalists were limited; differences between countries were more common and of greater magnitude, particularly with respect to barriers to the use of prescription medications.

Turning principles into practice in Alzheimer's disease.

The prevalence of dementia is reaching epidemic proportions globally, but there remain a number of issues that prevent people with dementia, their families and caregivers, from taking control of their condition. In 2008, Alzheimer's Disease International (ADI) launched a Global Alzheimer's Disease Charter, which comprises six principles that underscore the urgency for a more ambitious approach to diagnosis, treatment and care. This review highlights some of the most important aspects and challenges of dementia diagnosis and treatment. These issues are reviewed in light of the six principles of the recent ADI Charter: promoting dementia awareness and understanding; respecting human rights; recognizing the key role of families and caregivers; providing access to health and social care; stressing the importance of optimal diagnosis and treatment; and preventing dementia through improvements in public health. The authors continue to hope that, one day, a cure for Alzheimer's disease will be found. Meanwhile, healthcare professionals need to unite in rising to the challenge of managing all cases of dementia, using the tools available to us now to work toward improved patient care.

GAB2 gene does not modify the risk of Alzheimer's disease in Spanish APOE 4 carriers.

OBJECTIVES: The genetic basis of Alzheimer's disease (AD) is being analyzed in multiple whole genome association studies (WGAS). The GAB2 gene has been proposed as a modifying factor of APOE epsilon 4 allele in a recent case-control WGAS conducted in the US. Given the potential application of these novel results in AD diagnostics, we decided to make an independent replication to examine the GAB2 gene effect in our series. DESIGN: We are conducting a multicenter population-based study of AD in Spain. PARTICIPANTS: We analyzed a total of 1116 Spanish individuals. Specifically, 521 AD patients, 475 controls from the general population and 120 neurologically-normal elderly controls (NNE controls). METHODS: We have genotyped GAB2 (rs2373115 G/T) and APOE rs429358 (SNP112)/rs7412 (SNP158) polymorphisms using real time-PCR technologies. RESULTS: As previously reported in Spain, APOE epsilon 4 allele was strongly associated with AD in our series (OR=2.88 [95% C.I. 2.16- 3.84], p=7.38E-11). Moreover, a large effect for epsilone 4/epsilone 4 genotype was also observed (OR=14.45 [95% C.I., 3.34-125.2], p=1.8E-6). No difference between the general population and the NNE controls series were observed for APOE genotypes (P > 0.61). Next, we explored GAB2 rs2373115 SNP singlelocus association using different genetic models and comparing AD versus controls or NNE controls. No evidence of association with AD was observed for this GAB2 marker (p > 0.17). To evaluate GAB2-APOE genegene interactions, we stratified our series according to APOE genotype and case-control status, in accordance with the original studies. Again, no evidence of genetic association with AD was observed in any strata of GAB2-APOE loci pair (p > 0.34). CONCLUSION: GAB2 rs2373115 marker does not modify the risk of Alzheimer's disease in Spanish APOE epsilon 4 carriers.

Genes related to iron metabolism and susceptibility to Alzheimer's disease in Basque population.

Alzheimer's disease (AD) is the most common dementing disorder and presents with a progressive and irreversible cognitive decline of gradual onset. To date, several reports have involved iron in AD physiopathology. In this study, we have analysed TFC2 variant and HFE mutations (H63D and C282Y) in 211 AD patients and 167 controls recruited from an area of the Basque Country. Furthermore, we have studied APOE genotype as it is a well-known risk factor for AD. APOE epsilon 4 allele was associated with an increased risk of AD and an earlier age at onset, whereas no association was found between TFC2 or HFE C282Y mutation and disease susceptibility. The frequency of H63D mutation was higher in control population (29.9%) than in AD patients (18%), suggesting a protective role of this allele on AD either due to the presence of the mutation itself or through the effect of other related genes in the ancestral haplotype in which it is included.

[Values of GERMCIDE neuropsychological protocol in a sample of normal subjects]. / Valores del protocolo neuropsicológico GERMCIDE en una muestra de sujetos normales.

INTRODUCTION: The diagnosis of patients with cognitive deterioration or dementia requires a global approach in which the neuropsychological examination is a key piece. As part of the GERMCIDE study (Group for the Study and Multicenter Registry of Incident Cases of Dementia in Spain), a protocol was designed that included an assessment of the different cognitive functions that are most frequently altered in dementias (memory, orientation, speech, praxis, abstraction capacity and executive function). METHODS: In order to obtain data in normal subjects, this neuropsychological protocol was applied to a group of persons over 50 years without cognitive deterioration or dementia. RESULTS: A total of 103 subjects whose ages ranged from 50 to 95 years (mean: 73.5; SD: 9.3 years); 39 (37.9%) men and 64 (62.1%) women were studied. The mean score on the Mini-Mental State Examination (MMSE) was 27/30 (SD: 2.0). In the speech and praxis tests, 90% of the subjects obtained the maximum value, while performances were more unequal in memory, reasoning and programming. Mean score, standard deviation and distribution in percentages for each subtest are presented. CONCLUSIONS: The values obtained in this sample of normal subjects and their distribution in percentages may be very helpful to facilitate the interpretation of the findings of the neuropsychological examination with the GERMCIDE protocol in the general neurology clinic visits and also in the specialized visits in dementia.

The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia.

OBJECTIVE: To provide evidence for the hypothesis that the corticobasal degeneration syndrome (CBDs) overlaps significantly with primary progressive aphasia and frontotemporal dementia, and that CBDs is part of the Pick complex. BACKGROUND: Corticobasal degeneration has been mainly described as a movement disorder, but cognitive impairment is also increasingly noted. METHODS: Thirty-five cases of clinically diagnosed CBDs were followed-up with clinical, neuropsychological, and neuroimaging investigations. Twenty-nine patients were seen prospectively in movement disorder and cognitive neurology clinics; five of these came to autopsy. Six other autopsied cases that fulfilled the clinical criteria of CBDs were added with retrospective review of records. RESULTS: All 15 patients presenting with movement disorders developed behavioral, cognitive, or language deficits shortly after onset or after several years. Patients presenting with cognitive problems (n = 20), progressive aphasia (n = 13), or frontotemporal dementia (n = 7) developed the movement disorder subsequently. Eleven cases with autopsy had CBD or other forms of the Pick complex. CONCLUSIONS: There is a clinical overlap between CBD, frontotemporal dementia, and primary progressive aphasia. There is also a pathologic overlap between these clinical syndromes. The recognition of this overlap will facilitate the diagnosis and avoid consideration of CBD as "heterogenous."