Long-Term Cognitive Decline After Stroke: An Individual Participant Data Meta-Analysis.

BACKGROUND: Poststroke cognitive impairment is common, but the trajectory and magnitude of cognitive decline after stroke is unclear. We examined the course and determinants of cognitive change after stroke using individual participant data from the Stroke and Cognition Consortium. METHODS: Nine longitudinal hospital-based cohorts from 7 countries were included. Neuropsychological test scores and normative data were used to calculate standardized scores for global cognition and 5 cognitive domains. One-step individual participant data meta-analysis was used to examine the rate of change in cognitive function and risk factors for cognitive decline after stroke. Stroke-free controls were included to examine rate differences. Based on the literature and our own data that showed short-term improvement in cognitive function after stroke, key analyses were restricted to the period beginning 1-year poststroke to focus on its long-term effects. RESULTS: A total of 1488 patients (mean age, 66.3 years; SD, 11.1; 98% ischemic stroke) were followed for a median of 2.68 years (25th-75th percentile: 1.21-4.14 years). After an initial period of improvement through up to 1-year poststroke, decline was seen in global cognition and all domains except executive function after adjusting for age, sex, education, vascular risk factors, and stroke characteristics (-0.053 SD/year [95% CI, -0.073 to -0.033]; P<0.001 for global cognition). Recurrent stroke and older age were associated with faster decline. Decline was significantly faster in patients with stroke compared with controls (difference=-0.078 SD/year [95% CI, -0.11 to -0.045]; P<0.001 for global cognition in a subgroup analysis). CONCLUSIONS: Patients with stroke experience cognitive decline that is faster than that of stroke-free controls from 1 to 3 years after onset. An increased rate of decline is associated with older age and recurrent stroke.

The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey.

We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aß42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Hyperammonemia as a Possible Cause of Dementia Not Classified as Alzheimer's Disease or Frontotemporal Dementia.

The genetic bases of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia due to hyperammonemia caused by mutations in urea cycle genes. The analysis was performed by pooled whole-exome sequencing (WES) of 90 patients and by searching for rare pathogenic variants in autosomal genes for enzymes or transporters of the urea cycle pathway. The survey returned two rare pathogenic coding mutations leading to citrullinemia type I: rs148918985, p.Arg265Cys, C>T; and rs121908641, p.Gly390Arg, G>A in the argininosuccinate synthase 1 (ASS1) gene. The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. These variants found in simple or compound heterozygosity can lead to the late-onset form of citrullinemia type I, associated with high ammonia levels, which can lead to cerebral dysfunction and thus to the development of dementia. The presence of urea cycle disorder-causing mutations can be used for the early initiation of antihyperammonemia therapy in order to prevent the neurotoxic effects.

Short-term Trajectories of Poststroke Cognitive Function: A STROKOG Collaboration Study.

BACKGROUND AND OBJECTIVES: Past studies on poststroke cognitive function have focused on the average performance or change over time, but few have investigated patterns of cognitive trajectories after stroke. This project used latent class growth analysis (LCGA) to identify clusters of patients with similar patterns of cognition scores over the first-year poststroke and the extent to which long-term cognitive outcome is predicted by the clusters ("trajectory groups"). METHODS: Data were sought from the Stroke and Cognition consortium. LCGA was used to identify clusters of trajectories based on standardized global cognition scores at baseline (T1) and at the 1-year follow-up (T2). One-step individual participant data meta-analysis was used to examine risk factors for trajectory groups and association of trajectory groups with cognition at the long-term follow-up (T3). RESULTS: Nine hospital-based stroke cohorts with 1,149 patients (63% male; mean age 66.4 years [SD 11.0]) were included. The median time assessed at T1 was 3.6 months poststroke, 1.0 year at T2, and 3.2 years at T3. LCGA identified 3 trajectory groups, which were characterized by different mean levels of cognition scores at T1 (low-performance, -3.27 SD [0.94], 17%; medium-performance, -1.23 SD [0.68], 48%; and high-performance, 0.71 SD [0.77], 35%). There was significant improvement in cognition for the high-performance group (0.22 SD per year, 95% CI 0.07-0.36), but changes for the low-performance and medium-performance groups were not significant (-0.10 SD per year, 95% CI -0.33 to 0.13; 0.11 SD per year, 95% CI -0.08 to 0.24, respectively). Factors associated with the low- (vs high-) performance group include age (relative risk ratio [RRR] 1.18, 95% CI 1.14-1.23), years of education (RRR 0.61, 95% CI 0.56-0.67), diabetes (RRR 3.78, 95% CI 2.08-6.88), large artery vs small vessel strokes (RRR 2.77, 95% CI 1.32-5.83), and moderate/severe strokes (RRR 3.17, 95% CI 1.42-7.08). Trajectory groups were predictive of global cognition at T3, but its predictive power was comparable with scores at T1. DISCUSSION: The trajectory of cognitive function over the first-year poststroke is heterogenous. Baseline cognitive function ∼3.6 months poststroke is a good predictor of long-term cognitive outcome. Older age, lower levels of education, diabetes, large artery strokes, and greater stroke severity are risk factors for lower cognitive performance over the first year.

Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries.

Importance: Diagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches. Objective: To assess the incidence of FTLD across Europe. Design, Setting, and Participants: The Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021. Main Outcomes and Measures: Random-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity. Results: Based on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057. Conclusions and Relevance: The findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.

Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease.

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

Neurosyphilis with dementia and bilateral hippocampal atrophy on brain magnetic resonance imaging.

BACKGROUND: This article reports a rare case of active neurosyphilis in a man with mild to moderate dementia and marked hippocampal atrophy, mimicking early onset Alzheimer's disease. Few cases have so far described bilateral hippocampal atrophy mimicking Alzheimer's disease in neurosyphilis. CASE PRESENTATION: The patient presented here is a 33 year old Bulgarian male, whose clinical features include progressive cognitive decline and behavioral changes over the last 18 months. Neuropsychological examination revealed mild to moderate dementia (Mini Mental State Examination score was 16/30) with impaired memory and attention, and executive dysfunction. Pyramidal, and extrapyramidal signs, as well as dysarthria and impairment in coordination, were documented. Brain magnetic resonance imaging showed cortical atrophy with noticeable bilateral hippocampal atrophy. The diagnosis of active neurosyphilis was based on positive results of the Venereal Disease Research Laboratory test/Treponema pallidum hemagglutination reactions in blood and cerebrospinal fluid samples. In addition, cerebrospinal fluid analysis showed pleocytosis and elevated protein levels. High-dose intravenous penicillin therapy was administered. At 6 month follow up, improvements were noted clinically, on neuropsychological examinations, and in cerebrospinal fluid samples. CONCLUSION: This case underlines the importance of early diagnosis of neurosyphilis. The results suggest that neurosyphilis should be considered when magnetic resonance imaging results indicate mesiotemporal abnormalities and hippocampal atrophy. Neurosyphilis is a treatable condition which requires early aggressive antibiotic therapy.

Effect of Aromatherapy Massage on Depression and Anxiety of Elderly Adults: a Randomized Controlled Trial.

Introduction: This study investigated the effect of aromatherapy massage with lavender, chamomile, and rosemary oils on the depression and anxiety of elderly adults living in nursing homes. Methods: This randomized controlled trail was conducted on elderly adults living in nursing homes in Kerman, Iran. Through convenience sampling, 38 elderly adults were recruited and assessed using demographic questionnaire and Hospital Anxiety Depression Scale (HADS), respectively. Then, elderly adults were randomly allocated to either a control (19) or an intervention (19) group through block randomization. Elderly adults in the intervention group received aromatherapy massage using lavender, chamomile, and rosemary. Each massage session lasted 20 min and was performed three times per week for two three-week periods with an intervening one-week break, while their counterparts in the control group solely received routine nursing homes care services. HADS Scale completed with repeated measurements before the intervention, at the end of the third week, at the beginning of the fifth week and at the end of the seventh week. Results: According to the results, mean anxiety in the intervention group went from 11.9 ± 4 to 6.26 ± 3.38 (p <.0001), and the mean depression went from 9.94 ± 3.2 to 4.15 ± 2.14, indicating that anxiety and depression were significantly reduced compared with before intervention (p <.0001). Conclusion: Aromatherapy massage with lavender, chamomile, and rosemary oils is effective in significantly reducing anxiety and depression of elderly adults living in the nursing homes.

Dementia care in the Danube Region. A multi-national expert survey.

BACKGROUND: Dementia is a particularly severe societal challenge in several countries of the Danube Region due to higher-than-average increment in population longevity, disproportionate increase of the old-age dependency ratio, and selective outward migration of health care professionals. A survey was conducted among dementia experts to obtain a deeper understanding of the dementia care structures and services in this geographical area, and to identify the educational needs of health care professionals, and the availability of assistive technology. SUBJECTS AND METHODS: A standardized questionnaire was sent out to 15 leading dementia experts/clinicians in 10 Danube Region countries inquiring about professional groups involved in dementia care, availability and reimbursement of services, inclusion of dementia in professional education and training, acceptability of Internet-based education, and availability of assistive technology. The authors are the survey respondents. RESULTS: The majority of individuals with dementia receive care in the community rather than in institutions. The roles of medical specialties are disparate. General practitioners usually identify dementia symptoms while specialists contribute most to clinical diagnosis and treatment. Health care professionals, particularly those who work closely with patients and carers, have limited access to dementia-specific education and training. The greatest need for dementia-specific education is seen for general practitioners and nurses. An Internet-based education and skill-building program is considered to be equivalent to traditional face-to-face but offer advantages in terms of convenience of access. Assistive technology is available in countries of the Danube Region but is significantly underused. CONCLUSION: Dementia care in the Danube Region can be improved by an educational and skill-building program for health care professionals who work in the frontline of dementia care. Such a program should also attempt to enhance interdisciplinary and intersectorial collaboration, to intensify the interaction between primary care and specialists, and to promote the implementation of assistive technology.

Phenotypic variability and neuropsychological findings associated with C9orf72 repeat expansions in a Bulgarian dementia cohort.

BACKGROUND: The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in several European populations. The objective of this study was to determine the frequency of C9orf72 repeat expansions in a Bulgarian dementia cohort and to delineate the associated clinical features. METHODS AND FINDINGS: PCR-based assessments of the C9orf72 hexanucleotide repeat expansion in all study samples (including 82 FTD, 37 Alzheimer's disease (AD), and 16 other neurodegenerative/dementia disorder cases) were performed. We report the clinical, neuropsychological, and neuroimaging findings obtained for the C9orf72 repeat expansion carriers. Of the 135 cases screened, 3/82 (3.7%) of all FTD cases and 1/37 (2.7%) of all clinical AD cases had a C9orf72 repeat expansion. In this cohort, the C9orf72 pathological expansion was found in clinical diagnoses bridging the FTD, parkinsonism, ALS and AD spectrum. Interestingly, we showed early writing errors without aphasia in two subjects with C9orf72 expansions. CONCLUSIONS: This study represents the first genetic screening for C9orf72 repeat expansions in a Bulgarian dementia cohort. The C9orf72 repeat expansion does not appear to be a common cause of FTD and related disorders. This report confirms the notion that C9orf72 repeat expansions underlie a broad spectrum of neurodegenerative phenotypes. Relatively isolated agraphia in two cases with C9orf72 repeat expansions is a strong motivation to provide detailed and sophisticated oral and written language assessments that can be used to more precisely characterize early cognitive deficits in these heterogeneous conditions.

Apolipoprotein E epsilon4 allele frequency in elderly depressed patients with and without cerebrovascular disease.

Late-onset depression (LOD) could be a very early manifestation of Alzheimer's disease (AD), although contradictory results have been reported. Cerebrovascular disease (CVD) may favor the development of LOD, and that the particular forms of vascular depression should be individualized. The Apolipoprotein E (ApoE) epsilon4 allele was shown to be a risk factor for AD. Its role in LOD is controversial, while it is still unknown in vascular depression. Our objective was to clarify the relationship between ApoE epsilon4 allele and LOD in patients with and without CVD. We examined the ApoE phenotypes in a sample of 311 subjects: 50 with vascular LOD, 24 with LOD without CVD, 115 with AD and 122 normal controls (NC). The study of the ApoE epsilon4 allele frequency showed significant differences between: AD group and the vascular LOD and NC groups; LOD group without CVD compared with NC group (p<0.05 to 0.001). The frequency of the epsilon4 allele in the LOD group without CVD did not differ significantly from the AD group, similarly the frequency of the epsilon4 allele in the vascular LOD group was not different from that in NC. The study suggests an association between the ApoE epsilon4 allele and the LOD without CVD. These patients could be at risk of developing AD by an epsilon4-dependent pathway. In contrast, the results show no association between the presence of ApoE epsilon4 allele and vascular depression and provide further evidence in support of the concept that ApoE epsilon4 allele is not associated with clinical CVD.

Investigation of neuropsychological characteristics of very mild and mild dementia with Lewy bodies.

INTRODUCTION: The study aimed to compare the profile of very mild and mild dementia with Lewy bodies (DLB) patients with disease duration up to 5 years in order to find markers for faster progression in this early stage. METHOD: We investigated 45 DLB patients with disease duration up to 5 years and 22 normal controls. DLB patients were divided into two subgroups on the basis of the Mini-Mental State Examination (MMSE): very mild and mild. RESULTS: Compared to normal controls, very mild DLB patients show significant deficits on tests for attention/executive functions, language, visuospatial/constructional abilities, and retrieval of the episodic memory. In addition, mild DLB (mDLB) patients show a significantly lower score on recall and recognition of the Free and Cued Selective Reminding Test (FCSRT), Trail Making Test Part B (TMT-B), Stroop test, verbal fluency, and Clock Drawing Test than did very mild DLB (vmDLB) patients. Patients with mDLB also have more visual hallucinations, but not significant motor differences compared to vmDLB. CONCLUSIONS: In the present work we found that faster progression to the mild DLB stage in the first few years of the disease is mainly related to deterioration of memory, attention/executive functions, and visuospatial abilities, as well as an increased frequency of visual hallucinations.

Familial early-onset dementia with complex neuropathologic phenotype and genomic background.

Despite significant progress in our understanding of hereditary neurodegenerative diseases, the list of genes associated with early-onset dementia is not yet complete. In the present study, we describe a familial neurodegenerative disorder characterized clinically as the behavioral and/or dysexecutive variant of Alzheimer's disease with neuroradiologic features of Alzheimer's disease, however, lacking amyloid-ß deposits in the brain. Instead, we observed a complex, 4 repeat predominant, tauopathy, together with a TAR DNA-binding protein of 43 kDa proteinopathy. Whole-exome sequencing on 2 affected siblings and 1 unaffected aunt uncovered a large number of candidate genes, including LRRK2 and SYNE2. In addition, DDI1, KRBA1, and TOR1A genes possessed novel stop-gain mutations only in the patients. Pathway, gene ontology, and network interaction analysis indicated the involvement of pathways related to neurodegeneration but revealed novel aspects also. This condition does not fit into any well-characterized category of neurodegenerative disorders. Exome sequencing did not disclose a single disease-specific gene mutation suggesting that a set of genes working together in different pathways may contribute to the etiology of the complex phenotype.

Neuropsychological and neuroimaging markers in prediction of cognitive impairment after ischemic stroke: a prospective follow-up study.

BACKGROUND: There are few longitudinal studies with controversial results examining delayed changes in cognition after ischemic stroke and predictive values of neuropsychological and neuroimaging markers. OBJECTIVE: The objectives of this study were to evaluate the delayed changes in cognition in poststroke patients and their relationship to the neuropsychological and neuroimaging markers measured during the acute poststroke phase. METHODS: Eighty-five first-ever stroke inpatients (mean age 65.6±5.6 years) without previous cognitive complaints were prospectively evaluated with a comprehensive neuropsychological battery at the 5th day and the 1st, 6th, and 12th months. A wide range of clinical, radiological, and neuropsychological variables were examined. RESULTS: Our results showed significantly poorer performance on mini-mental state examination, memory, attention/executive functions, and processing speed in patients with stroke in comparison with stroke-free cognitively intact controls. Multiple regression analysis revealed that hippocampal atrophy is the strongest predictor of delayed cognitive impairment. Secondary divided subgroups according to Isaacs Set Test (IST) score showed that patients with IST score ≤28 had different patterns of cognitive and neurological impairment after 1 year. Baseline impairments in attention/executive functions and memory were associated with development of dementia in poststroke patients. CONCLUSION: Executive functioning deficit appears to have a predictive power for cognitive impairment progression. The study suggests that IST as a screening test has a potential to be a reliable and quick tool for poststroke cognitive impairment evaluation and delayed cognitive and neurological outcome. Hippocampal atrophy was the strongest predictor for cognitive impairment outcome, even in poststroke cognitive impairment. The findings may set the stage for better poststroke management.

The perceptions of cognitively impaired patients and their caregivers of a home telecare system.

Assistive and telecare technologies have been developed to support older adults with cognitive impairments, as well as their caregivers, from their homes. The way potential users perceive telecare and smart home systems plays a key role in their acceptance of this new technology. We evaluate the acceptance of home telecare technologies among patients suffering from cognitive impairment and their caregivers. Prototypes of telecare devices were developed to demonstrate their features and capabilities and to train patients, families, and health care professionals in their use. We conducted semistructured interviews to elicit the perceptions of 30 patients with mild cognitive impairment, 32 patients with Alzheimer's disease, and 30 caregivers, regarding the risks and advantages of home telecare and smart houses. Survey results reflected participants' largely positive reactions to these technologies. Regarding home telecare, the cognitive stimulation program earned the highest proportion of positive responses, followed by the devices' care of emergencies. The participants generally agreed that home telecare and smart houses could significantly improve their quality of life. However, some technical and ethical concerns, such as the way of provision, installation, and monitoring of the systems, were reported to be in need of addressing before implementation of this system.

Cerebrospinal fluid biomarkers for Alzheimer's disease: the role of apolipoprotein E genotype, age, and sex.

INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers improve the diagnostic accuracy for Alzheimer's disease (AD), even at the predementia stage of the disease. The ε4-allele of apolipoprotein E (ApoE ε4), female sex, and older age are well-known risk factors for AD. It is unclear how these risk factors affect the CSF biomarkers in patients with AD. AIM: The objective of this study was to investigate the associations of ApoE ε4, sex, and age with CSF biomarker levels in a unicenter sample of patients with AD that includes a high proportion of patients with early-onset AD (EOAD). METHODS: The CSF levels of amyloid-ß 1-42 (Aß1-42) and total-tau of 117 subjects with mild to moderate AD (55 late-onset AD and 62 EOAD) were assessed. All subjects underwent ApoE genotyping, clinical evaluation, comprehensive neuropsychological assessments, and neuroimaging. Associations between CSF biomarker levels, ApoE ε4 allele frequency, age, and sex were evaluated. RESULTS: In the whole patient sample and in the late-onset AD subgroup ε4 homozygous subjects had significantly lower CSF Aß1-42 levels compared with ε4 heterozygous subjects and ε4 noncarriers. This association was not detected in the EOAD group. Age group, sex, and severity of cognitive decline did not have a significant impact on CSF Aß1-42 levels. No significant associations were found between ApoE ε4 allele frequency and CSF total-tau levels. CONCLUSION: ApoE ε4 allele is associated with a reduction of CSF Aß1-42 levels. This result is consistent with the findings of several previous studies. In the subgroup of patients with EOAD this association was not replicated. Larger studies are necessary to further investigate associations between ApoE ε4 allele frequency and CSF biomarker levels in patients with EOAD.

Cognitive, neuropsychiatric, and motor features associated with apolipoprotein E ε4 allele in a sample of Bulgarian patients with late-onset Parkinson's disease.

OBJECTIVE: To evaluate the role of apolipoprotein E (APOE) ε4 allele on cognitive, neuropsychiatric, and motor features in a sample of Bulgarian patients with late-onset Parkinson's disease (LOPD, age at onset > 55 years). METHODS: A total of 16 patients with LOPD having APOE ε3/ε4 genotype were compared to 30 patients with LOPD having APOE ε3/ε3 genotype and 20 healthy control individuals. Detailed cognitive assessment and evaluation of neuropsychiatric and motor symptoms were performed. RESULTS: The patients with LOPD had significantly lower scores in all cognitive domains compared to controls. The patients with LOPD carrying an ε4 allele showed some significant differences in their cognitive, motor, and neuropsychiatric features. CONCLUSIONS: The data suggest a role of the APOE genotype as a disease-modifying factor.

Cognitive dysfunction profile and arterial stiffness in type 2 diabetes.

BACKGROUND: The causative mechanisms of type 2 diabetes (T2D) on cognitive dysfunction are still undergoing development. AIM: To explore the cognitive dysfunction profile and its relation to the potential role of arterial stiffness in later middle age T2D patients. METHODS: We studied 37 patients with T2D (age range 45-65 years) and 22 normal controls. All participants underwent comprehensive neuropsychological assessment. The carotid-femoral pulse wave velocity (CF-PWV) measurements were taken with the PulsePen device. RESULTS: Our results showed significantly poorer performance on all tests assessing attention/executive functions and processing speed in patients with T2D. In addition to cognitive slowing T2D patients demonstrated significant deficits in almost all measures of verbal episodic memory after adjustment for age, education and blood pressure (BP) levels (p<0.05). Carotid-femoral pulse wave velocity (CF-PWV) appeared significantly higher in T2D subjects than in normal controls after adjustment for age and BP level (p<0.001). Significant relationship was observed between CF-PWV and cognitive status. CONCLUSION: We revealed that arterial stiffness was increased and associated with cognitive impairment in T2D. The cognitive profile indicates hippocampal amnestic type mild cognitive impairment associated with a pronounced dysexecutive syndrome suggesting that diabetes may affect cognition through both vascular and neurodegenerative processes. However, neurodegenerative cognitive profile caused by hippocampal atrophy in a pure vascular process could not be excluded.

Relationship between orthostatic hypotension and cognitive impairment in the elderly.

BACKGROUND AND PURPOSE: To determine the relationship between orthostatic hypotension (OH) and cognitive function in elderly subjects with memory complaints. METHODS: We studied the association between cognitive function and OH in 495 consecutive elderly outpatients attending a memory centre. Blood pressure (BP) was measured in a sitting and standing position. We examined cognitive function using a validated comprehensive battery of neuropsychological tests, the cognitive efficiency profile (CEP) assessing the main cognitive areas. Subjects were classified into 4 categories according to their cognitive status: normal cognitive function, mild cognitive impairment (MCI), Alzheimer's disease (AD) or vascular dementia (VaD). RESULTS: In this population, 76±8 years of age (women 72%), 18% had normal cognitive function, 28% had MCI, 47% AD, and 7% VaD. Hypertension was observed in 74% of patients. OH was present in 14% of subjects (n=69). After adjustment for age, education level, systolic BP, diastolic BP, weight, and antihypertensive drugs, subjects with OH had worse cognitive function than those without OH (CEP score 50±24 vs 56±22, p<0.05). Moreover, a significant relationship was observed between OH and cognitive status (normal cognitive function, MCI, AD, or VaD). OH was present in 22% in VaD subjects, 15% in AD subjects, 12% in MCI subjects and 4% in normal control subjects (p<0.01 for overall test). CONCLUSION: Our results showed an association between OH and cognitive impairment and emphasize the need for longitudinal studies designed to evaluate the nature of the relationship between OH and cognitive decline.

Effects of antihypertensive therapy on cognitive decline in Alzheimer's disease.

BACKGROUND: Therapeutic trials concerning the effect of antihypertensive therapy on cognition have produced controversial findings. Our objective was to evaluate the impact of antihypertensive therapy on the cognitive function in subjects already diagnosed with Alzheimer's disease (AD). METHODS: We conducted an observational study in a memory clinic assessing outpatients suffering from AD. A total of 321 patients were included. Cognitive function was assessed yearly by the Mini-Mental State Examination (MMSE; score/30). RESULTS: The mean age of patients was 78.1 +/- 6 years, 54% of them received antihypertensive therapy and the mean MMSE scores were similar in both groups (patients taking antihypertensive therapy and patient without antihypertensive therapy). The mean follow-up was 34.1 +/- 6 months. MMSE means were significantly higher among patients using antihypertensive therapy compared to those without antihypertensive therapy (MMSE scores = 21.9 +/- 4.9 vs. 21.2 +/- 5.1 at 1 year (P = 0.001); 20.8 +/- 5.5 vs. 19.4 +/- 5.7 at 2 years (P < 0.001); 19.0 +/- 6.7 vs. 17.5 +/- 6.4 at 3 years (P < 0.001)), after adjustment for age, gender, education level, systolic blood pressure (SBP), and diastolic blood pressure (DBP) at baseline, MMSE at baseline, coronary heart disease, statins, and antiplatelet agents' consumption. Furthermore, the use of antihypertensive therapy was associated with a lower estimated risk of cognitive decline (as defined by a decrease of at least one point in MMSE score over time) (hazard ratio = 0.61; 95% confidence interval = 0.45-0.81) after adjustment for the same factors. CONCLUSIONS: These results suggest an association between antihypertensive therapy, a lower decrease in mean MMSE and a lower cognitive decline over time in AD.