Intracranial volume in mild cognitive impairment,Alzheimer's disease and vascular dementia: evidence for brain reserve?

OBJECTIVE: The possibility of brain volume reserve effects was examined in a sample of geriatric outpatients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD). The total intracranial volume (ICV) served as an estimate of the maximum attained brain volume in life. METHODS: Subjects (n = 181, mean age 60.7) were consecutive referrals to a geriatric outpatients clinic (n = 96) and a group of age-matched healthy control subjects (n = 85). ICV and brain volume were attained from T1-weighted magnetic resonance images using a stereological method. Hippocampal atrophy was assessed with a visual rating scale. RESULTS: ICV was significantly smaller in patients with AD and VaD than in control subjects, but effect size was small. After adjusting for age and gender, having ICV in the smallest quartile significantly increased the risk of cognitive impairment (either MCI or dementia). In patients with dementia, but not in MCI, severity of cognitive impairment and ICV were moderately correlated. The effect of ICV on cognition was not mediated by hippocampal atrophy. CONCLUSIONS: These findings are compatible with volume reserve effects that modify the clinical expression of symptoms in both AD and VaD. They may have implications for the design of neuroimaging studies that use ICV for normalization procedures.     

Screening for mild cognitive impairment (MCI) utilizing combined mini-mental-cognitive capacity examinations for identifying dementia prodromes

OBJECTIVE: To test correctness of results when combining Mini-Mental State Examination (MMSE) and Cognitive Capacity Screening Examination (CCSE) for identifying mild cognitive impairment (MCI) among non-demented elderly subjects at risk for developing dementia. METHODS: A retrospective study was conducted among consecutively referred volunteers with memory complaints to a research out-patient clinic. Two cognitive screening tests (MMSE and CCSE) were performed according to established protocol. Resulting combined screening test (termed by acronym as CMC) combined the non-overlapping test items derived from both MMSE and CCSE. Conversion to dementia at follow-up served as the 'gold-standard' for evaluating correctness of CMC for identifying MCI. RESULTS: Of 351 subjects completing cognitive assessments and meeting requirements for study protocol, 84 (23.9%) developed dementia of different types within 3-6 years (3.89 +/- 2.17) of follow-up. Among these, 47 met criteria for probable Alzheimer disease (AD), 22 for probable vascular dementia (VaD), 12 for mixed AD/VaD and three for probable frontotemporal dementia. When final diagnosis of AD was used as the 'gold standard' for testing correctness of MCI identified by cognitive screening tests, sensitivities of MMSE, CCSE and CMC for identifying MCI were relatively 61.0%, 74.3% and 83.1% with minimum specificity set at 80%. When diagnosis of all types of dementia was used as the standard for testing predictive correctness of MCI, CCSE emerged as an optimal MCI screening test. CONCLUSION: Combining the CCSE and MMSE screening tests resulted in higher sensitivity than was achieved by MMSE alone and maintained specificity at comparable levels for identifying MCI. The results confirmed that CMC has optimal correctness and utility as a brief cognitive test for screening MCI as a prodrome for dementia among non-demented elderly populations.     

Rate of progression of mild cognitive impairment to dementia – meta‐analysis of 41 robust inception cohort studies

Objective: To quantify the risk of developing dementia in those with mild cognitive impairment (MCI). Method: Meta‐analysis of inception cohort studies. Results: Forty‐one robust cohort studies were identified. To avoid heterogeneity clinical studies, population studies and clinical trials were analysed separately. Using Mayo defined MCI at baseline and adjusting for sample size, the cumulative proportion who progressed to dementia, to Alzheimer’s disease (AD) and to vascular dementia (VaD) was 39.2%, 33.6% and 6.2%, respectively in specialist settings and 21.9%, 28.9% and 5.2%, respectively in population studies. The adjusted annual conversion rate (ACR) from Mayo defined MCI to dementia, AD and VaD was 9.6%, 8.1% and 1.9%, respectively in specialist clinical settings and 4.9%, 6.8% and 1.6% in community studies. Figures from non‐Mayo defined MCI and clinical trials are also reported. Conclusion: The ACR is approximately 5–10% and most people with MCI will not progress to dementia even after 10 years of follow‐up.     

Mild cognitive impairment in a population-based epidemiological study

Background: It would be of considerable importance to be able to estimate the rate at which subjects with mild cognitive impairment (MCI) progress to dementia in a cohort of a population‐based epidemiological study and to establish simple diagnostic methods for the identification of people at high‐risk of dementia. Subjects in a community based elderly cohort of MCI were followed longitudinally. Methods: Subjects were selected from participants in the first epidemiological study conducted on all persons aged 65 years and older residing at home in Nakayama, Japan, using the Mini‐Mental State Examination (MMSE). Mild cognitive impairment was defined as memory deficit with objective memory assessment, without dementia, impairment of general cognitive function or disability in activities of daily living. The conversion rate was calculated using the person–year method. Results: At baseline, the sample consisted of 104 subjects selected from 1162 community dwellers aged over 65 years of age. During the 5‐year follow up, 11 subjects (10.6%) were diagnosed with Alzheimer's disease (AD), five (4.8%) were diagnosed with vascular dementia (VaD) and six (5.8%) were diagnosed with dementia of other etiology. In this survey, the annual conversion rate of MCI to AD was calculated as 8.5% per 100 person–years and shifted to dementia at a rate of 16.1% per 100 person–years. The proportion of subjects with MCI who progressed to develop dementia was the same as in previous reports. However, nearly 40% of subjects returned to normal. Conclusion: The MCI concept, as currently defined, is an unstable and heterogeneous group.     

Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia

Vascular cognitive impairment (VCI) was proposed as an umbrella term to include subjects affected with any degree of cognitive impairment resulting from cerebrovascular disease (CVD), ranging from mild cognitive impairment (MCI) to vascular dementia. VCI may or may not exclude the host of "focal" circumscribed impairments of specialized functions such as language (aphasia), intentional gesture (apraxia), or categorical recognition (agnosia), among others, that may result from a stroke. Therefore, there are no universally accepted diagnostic criteria for VCI. We conclude that this concept could be more useful if it were to be limited to cases of vascular MCI without dementia, by analogy with the concept of amnestic MCI, currently considered the earliest clinically diagnosable stage of Alzheimer disease (AD). In agreement with our view,the Canadian Study on Health and Aging successfully implemented a restricted definition of VCI, excluding cases of dementia (i.e., vascular cognitive impairment no dementia, VCI-ND). The Canadian definition and diagnostic criteria could be utilized for future studies of VCI. This definition excludes isolated impairments of specialized cognitive functions.Vascular dementia (VaD): The main problem of this diagnostic category stems from the currently accepted definition of dementia that requires memory loss as the sine qua non for the diagnosis. This may result in over-sampling of patients with AD worsened by stroke (AD+CVD). This problem was minimized in controlled clinical trials of VaD by excluding patients with a prior diagnosis of AD, those with pre-existing memory loss before the index stroke, and those with amnestic MCI. We propose a definition of dementia in VaD based on presence of abnormal executive control function, severe enough to interfere with social or occupational functioning. Vascular cognitive disorder (VCD): This term, proposed by Sachdev [P. Sachdev, Vascular cognitive disorder. Int J Geriat Psychiatry 14 (1999)402-403.] would become the global diagnostic category for cognitive impairment of vascular origin, ranging from VCI to VaD. It would include specific disease entities such as post-stroke VCI, post-stroke VaD, CADASIL, Binswanger disease, and AD plus CVD. This category explicitly excludes isolated cognitive dysfunctions such as those mentioned above.     

Is there any relation between insulin resistance and cognitive function in the elderly?

BACKGROUND: Vascular risk factors are blamed as being involved in the pathogenesis of cognitive dysfunction in the elderly. Alzheimer's disease or vascular-type dementia could be part of a metabolic syndrome. The aim of this study was to evaluate whether there is any relation between insulin resistance and cognitive status of the elderly regarding normal, mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia.METHODS: 267 elderly patients admitted to an outpatient geriatrics clinic were evaluated medically and cognitively in this study. The patients were diagnosed using ARDRA and DSM-IV criteria for AD; NINDS-AIREN and DSM-IV criteria for VaD; and Petersen criteria for MCI. Insulin resistance was calculated using both the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) formulas.RESULTS: The mean values of HOMA and QUICKI scores were 2.79 (SD+/-3.56) and 0.346 (SD+/-0.036) for the normal group, 2.81 (SD+/-3.06) and 0.354 (SD+/-0.047) for AD group, 2.20 (SD+/-1.82) and 0.360 (SD+/-0.048) for VaD group, 2.87 (SD+/-1.81) and 0.339 (SD+/-0.038) for mixed dementia group, 2.79 (SD+/-2.81) and 0,349 (SD+/-0.042) for MCI group, respectively. There were no statistically significant differences between HOMA and QUICKI scores of all the groups.CONCLUSION: This is the first study of the possible relation between insulin resistance and cognitive function in people categorized according to five forms of cognitive status. Unfortunately the results do not allow generalizations. Further prospective cohort studies that follow a normal cognitive group and MCI patients with and without insulin resistance are necessary.     

Evaluation of CSF biomarkers as predictors of Alzheimer's disease: a clinical follow-up study of 4.7 years

In this study, we determined the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers to predict development of Alzheimer's disease (AD) within five years in patients with mild cognitive impairment (MCI). To do so, the levels of tau, phosphorylated tau, Aβ42, Aβ40, Aβ38, sAβPPα, and sAβPPβ were analyzed in 327 CSF samples obtained at baseline from patients with AD (n = 94), MCI (n = 166), depressive disorder (n = 29), and cognitively healthy controls (n = 38). In the cohort with MCI at baseline, 33% subsequently developed AD and 16% developed other types of dementia; however, 51% were still cognitively stable after a followup of 4.7 years (range 3.0-7.2). Optimal cutoffs for each biomarker or combinations of biomarkers were defined in the AD, control, and depressive disorder groups. Several combinations resulted in sensitivity and specificity levels > 85% for differentiation of AD from controls and depressive disorder. Using the previously established cutoffs, a combination of Aβ42 and tau could predict future development of AD in MCI patients with a sensitivity of 88%, specificity 82%, positive predictive value 71%, and negative predictive value 94%. MCI patients with both low Aβ42 and high tau levels had a substantially increased risk of developing AD (OR 20; 95% CI 6-58), even after adjustment for confounding factors. Ultimately, CSF biomarkers can stratify MCI patients into those with very low or high risk for future development of AD. However, the specificities and positive predictive values are still too low to be able to diagnose AD before the patients fulfill the clinical criteria.     

Correlation of entorhinal amyloid with memory in Alzheimer's and vascular but not Lewy body dementia

OBJECTIVE: To examine the relationship of the anatomic distribution of amyloid deposition to focal and global cognitive dysfunction in different subtypes of dementia. METHODS: We quantified AB40 and AB42 in the temporal lobe and entorhinal cortex and examined their relationship to cognitive functions in Alzheimer's disease (AD), vascular dementia (VaD) and dementia with Lewy bodies (DLB). RESULTS: We found a correlation between memory impairment, but not global cognitive impairment, and amyloid load in these areas in AD and VaD but not in DLB. This relationship was stronger for AB42 and in the entorhinal cortex. CONCLUSION: The anatomic location of amyloid deposition is an important factor-specific factor in memory impairment in AD and VaD.     

Neuropathological profile of mild cognitive impairment from a population perspective

Whether the neuropathological profile of mild cognitive impairment (MCI) reflects an intermediate state between normal aging and dementia is not clear. Identifying which phenomena initiate disease and which occur secondary to the neuropathological process is important for targeted disease prevention. Current definitions of MCI include amnestic (aMCI), nonamnestic (nMCI), and multidomain (mMCI) subtypes. In an unbiased population-based cohort of brain donors, we have determined how many individuals fulfill these criteria in the period leading up to death [n=10 (5 multidomain MCI, 4 amnestic MCI, 1 nonamnestic MCI)]. All MCI cases were collapsed into 1 group and we tested whether their pathologic profile, including markers of Alzheimer disease (AD) and vascular disease (VD), is intermediate to individuals (matched for age, sex, and education) without cognitive impairment (n=20) or dementia (n=20). The main findings are of a significant linear trend in the odds of neuritic plaques (entorhinal/hippocampus), atrophy (hippocampal and cortical), infarcts, and small vessel disease (SVD) with increased cognitive impairment. Neuropathologically, MCI is complex, with 10% of MCI brains classified as normal, 10% as VD, 10% as AD, and 40% as mixed AD/VD, with the remaining showing other pathologies. Rather than pure pathologic changes, several different factors seem to contribute to the impairment of MCI. In MCI, both AD and non-AD pathology should be considered as possible intervention targets.     

Effectiveness of the Takeda Three Colors Combination Test as a screening test for dementia

Background:  The aged population is increasing worldwide and it is expected that dementia, for which aging is a risk factor, will increase as well. A critical issue then becomes a community's capacity for the early detection of dementia among its senior citizens. In the present paper, we report on the development and potential use of a screening test for dementia that can be administered and assessed easily in a short period of time by non-specialist clinicians and represents no burden for those undergoing the screening.
Methods:  Three hundred and sixty senior citizens, over 60 years of age, participated in the study. Of these, 126 had Alzheimer's disease (AD), 60 had vascular dementia (VaD), 41 had mild cognitive impairment (MCI), and 133 were healthy volunteers (control group). A screening test for dementia, which consisted of a colored cards configuration memory task (the Takeda Three Colors Combination Test; TTCC) was examined for sensitivity, specificity, reliability and criterion-related validity.
Results:  Sufficient sensitivity and specificity were demonstrated for each clinical group (AD, VaD) and the control group. The sensitivity of the TTCC was 0.94, 0.82, and 0.71 for the AD, VaD, and MCI groups, respectively; specificity was 0.83. In addition, sufficient reliability and validity were established. Administration of the TTCCand assessment procedures required only 1 or 2 min.
Conclusion:  Satisfactory sensitivity and specificity were indicated for both the AD and VaD groups, with sufficient reliability and validity also indicated. Thus, the TTCC is an effective dementia screening test.     

Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease

Controversy exists regarding the apolipoprotein E (ApoE) epsilon4 allele association with vascular dementia (VaD), ranging from increased epsilon4 frequency, similar to that found for Alzheimer's disease (AD), to no association between the epsilon4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE epsilon4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE epsilon4 allele-bearing individuals had greater risk of having late-onset AD (OR = 8.8; 95% CI 3.7-21.0), or non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0).     

Clustering and switching during a semantic verbal fluency test contribute to differential diagnosis of cognitive impairment

The verbal fluency test (VFT) can be dissociated into "clustering" (generating words within subcategories) and "switching" (shifting between clusters), which may be valuable in differential diagnosis. In the current study, we investigated the validity of VFT in the differential diagnosis of Alzheimer’s disease (AD, n = 65), vascular dementia (VaD, n = 65), mild cognitive impairment (MCI, n = 92), and vascular cognitive impairment without dementia (VCIND, n = 76) relative to cognitively normal senior controls (NC, n = 374). We found that in the NC group, the total correct score was significantly correlated with age and education; males generated more subcategories; cluster size increased with education, and subcategory and switching decreased with age. A significantly progressive advantage was observed in VFT scores in the sequence NC > MCI/VCIND > AD/VaD, and this significantly discriminated dementia patients from the other groups. AD patients performed better in all four VFT scores than VaD patients. Subcategory and switching scores significantly distinguished AD from VaD patients (AD > VaD; mean difference, 0.50 for subcategory, P <0.05; 0.71 for switching, P <0.05). MCI patients scored higher than VCIND patients, but the difference did not reach statistical significance. These results suggest that semantic VFT is useful for the detection of MCI and VCIND, and in the differential diagnosis of cognitive impairment.     

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.     

A longitudinal study regarding conversion from mild memory impairment to dementia in a Japanese community

OBJECTIVE: To estimate the rate that subjects with Mild Memory Impairment /Not Dementia (MMI/ND) shifted to dementia in a population-based cohort and to establish simple diagnostic methods for identification of high-risk persons for dementia. METHODS: Subjects in a community-based elderly cohort of MMI/ND were followed longitudinally. Subjects were selected from the participants in the first Nakayama study. MMI/ND was defined as memory deficit with objective memory assessment, without dementia, impairment of general cognitive function, or disability in activities of daily living. The conversion rate was calculated using the person-year method. RESULTS: At baseline, the sample consisted of 104 subjects (59 female; 45 male) selected from 1,162 community dwellers aged over 65 year. During the five-year follow-up, 14 subjects died, 13 moved to other communities, and six refused to participate further. Eleven (10.6%) subjects were diagnosed with Alzheimer's disease (AD), five (4.8%) were diagnosed with vascular dementia (VaD), and six (5.8%) were diagnosed with dementia of other etiology. The annual conversion rate that MMI/ND shifted to AD is calculated on 8.5% per 100 person-year, and shifted to dementia on 16.1% per 100 person-year in this survey. CONCLUSIONS: The rate at which subjects with MMI/ND whose conditions shifted to dementia was the same as the rate that subjects with mild cognitive impairment (MCI) shifted to dementia in a previous report. It would be useful to identify groups of high-risk individuals for dementia by simple diagnostic methods.     

Three-dimensional patterns of hippocampal atrophy in mild cognitive impairment

OBJECTIVE: To measure hippocampal volumes in patients diagnosed as having subtypes of mild cognitive impairment (MCI) relative to those of elderly control subjects and those of patients with Alzheimer disease (AD) using 3-dimensional mesh reconstructions. DESIGN: A magnetic resonance imaging volumetric study of MCI subgroups (MCI, amnesic subtype [MCI-A]; and MCI, multiple cognitive domain subtype) using 3-dimensional mesh reconstructions of the structure. SETTING: Referral dementia clinic. SUBJECTS: Twenty-six subjects with MCI (MCI-A, n = 6; and MCI, multiple cognitive domain subtype, n = 20), 20 subjects with AD, and 20 controls who were equivalent in age, education, and sex distributions. MAIN OUTCOME MEASURES: Three-dimensional parametric mesh models of the hippocampus and total hippocampal volumes. RESULTS: The hippocampi of the patients with AD were significantly atrophic relative to those of the healthy controls. The MCI, multiple cognitive domain subtype, group did not differ from the controls, yet was significantly different from the MCI-A and the AD groups. The MCI-A patients had significant hippocampal atrophy compared with the controls, and did not differ significantly from the patients with AD. CONCLUSION: These data add to the growing evidence that there are multiple forms of MCI, that they have distinct neuropathological correlates, and that MCI, multiple cognitive domain subtype, is not a more advanced form of the MCI-A subtype.     

CSF levels of heart fatty acid binding protein are altered during early phases of Alzheimer's disease

Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-β (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aβ1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aβ1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Aβ1-42 ratio and MMSE annual decrease rate was also documented (p<0.0001). HFABP /Aβ1-42 ratio might be a useful predictor of conversion in MCI patients.     

Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease

BACKGROUND: Little is known about motor function in mild cognitive impairment (MCI) and its relation to the risk of Alzheimer disease (AD). OBJECTIVE: To examine motor function in persons with MCI and its relation to risk of AD. DESIGN: Longitudinal cohort study. SETTING: More than 40 Catholic religious orders across the United States. PARTICIPANTS: We studied 816 older Catholic clergy members from the Religious Orders Study. At the baseline evaluation, they were classified as having no cognitive impairment (n = 558), MCI (n = 198), or dementia (n = 60). MAIN OUTCOME MEASURES: Motor function was assessed at baseline using performance-based measures of upper and lower extremity function and a modified version of the motor section of the Unified Parkinson's Disease Rating Scale, from which previously established measures of parkinsonian signs were derived. Clinical evaluations for dementia and AD were repeated annually for up to 10 years. All analyses controlled for age, sex, educational level, and possession of at least 1 apolipoprotein E epsilon4 allele. RESULTS: At baseline, individuals with MCI had impaired motor function relative to those without cognitive impairment and superior motor function vs those with dementia. Among those with MCI, baseline levels of lower extremity motor performance, parkinsonian gait, and bradykinesia were inversely related to risk of AD, even after controlling for clinical stroke. Thus, a person with impaired lower limb performance or parkinsonian gait (10th percentile) was 2 to 3 times more likely to develop AD than a person with good lower limb function (90th percentile). CONCLUSIONS: Persons with MCI also have impaired motor function, and the degree of impairment in lower extremity function is related to the risk of AD.     

Mitochondrial fission proteins in peripheral blood lymphocytes are potential biomarkers for Alzheimer’s disease

Background and purpose: Expression of the mitochondrial fission proteins dynamin‐related protein 1 (Drp1), S‐nitrosylated Drp1 (SNO‐Drp1), and Fis1 has been found to be altered in brain tissues and skin fibroblasts from patients with Alzheimer’s disease (AD). The aim of this study was to determine whether these proteins are also changed in peripheral blood lymphocytes (PBL) of AD patients and whether these changes are specific and sensitive enough for AD diagnosis. Methods: Western blot analysis and enzyme‐linked immunosorbent assay (ELISA) were employed to quantify relative levels of Drp1, SNO‐Drp1, and Fis1 in PBL obtained from 91 controls, 82 AD, 26 mild cognitive impairment (MCI), 12 Parkinson’s disease (PD), and 36 vascular dementia (VaD) patients. Logistic regression and receiver operating characteristic (ROC) curve analysis were used to measure diagnostic accuracy of these proteins. Results: Compared with controls, SNO‐Drp1 and Fis1 levels were remarkably increased in PBL of AD and MCI patients, and Drp1 was significantly decreased in AD, MCI, and PD. None of these proteins were changed in VaD patients. Disease severity or duration had no major effects on levels of these proteins in AD PBL. ROC curve analysis showed that the specificity and sensitivity were 81% and 73% for Drp1, 84% and 82% for SNO‐Drp1, and 89% and 80% for Fis1 in identifying AD patients from control subjects. Conclusions: Altered mitochondrial fission proteins Drp1, SNO‐Drp1, and Fis1 in PBL were relatively sensitive and specific in identifying AD patients and could be serving as a biomarker in the procedure of diagnosis.     

Identification of VaD and AD prodromes: The Cache County Study

BackgroundIt is unclear whether vascular dementia (VaD) has a cognitive prodrome, akin to the mild cognitive impairment (MCI) prodrome to Alzheimer’s dementia (AD). To evaluate whether VaD has a cognitive prodrome, and if it can be differentiated from prodromal AD, we examined neuropsychological test performance of participants in a nested case-control study within a population-based cohort aged 65 or older.MethodsParticipants (n = 485) were identified from the Cache County Study, a large population-based study of aging and dementia. After an average of 3 years of follow-up, a total of 62 incident dementia cases were identified (14 VaD, 48 AD). We identified a number of neuropsychological tests (executive and memory) that discriminated between diagnosed VaD and AD cases. Multivariate analyses sought to differentiate between these same groups 3 years before clinical diagnosis.ResultsThe Consortium to Establish a Registry for Alzheimer’s Disease Word List Recognition Test correct recognition of foils (mean difference, 1.25; 95% confidence interval [CI], 0.42 to 2.07; p < 0.01), Logical Memory I (mean difference, 7.16; 95% CI, 0.78 to 13.55, p < 0.05), Logical Memory II delayed recall (mean difference, 8.67; 95% CI, 1.59 to 15.74, p < 0.05), and percent savings (mean difference, 51.07; 95% CI, 32.58 to 69.56, p < 0.0001) differentiated VaD from AD cases after adjustment for age, sex, education, and dementia severity. Three years before dementia diagnosis, word list recognition (“no” responses mean difference, 1.40; 95% CI, 0.64 to 2.17; p < 0.001, and “yes” responses mean difference, –1.14; 95% CI, –2.14 to –0.13; p < 0.03) discriminated between prodromal VaD and AD.ConclusionThese results suggest that VaD has a prodromal syndrome, the cognitive features of which are distinguishable from the cognitive prodrome of AD.     

Metabolic Syndrome,Mild Cognitive Impairment,and Dementia: A Meta-Analysis of Longitudinal Studies

ObjectiveA systematic review and a meta-analysis of both clinical and population-based studies was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to clarify whether Metabolic Syndrome (MetS) is a risk or a protective factor for incident dementia, Alzheimer disease (AD), and vascular dementia (VaD), and whether it's involved in progression to dementia in patients affected by mild cognitive impairment (MCI).MethodsSearch terms included (“metabolic syndrome” OR “syndrome x” OR “plurimetabolic syndrome”) AND (“dementia” OR “Alzheimer disease” OR “vascular dementia” OR “mild cognitive impairment” OR “MCI”). Research was restricted to articles published in English between January 1, 2000 and August 31, 2018. No age limit was set.ResultsAt the end of the selection procedure, nine longitudinal studies were selected for the meta-analysis: six studies enrolled cognitively well-functioning participants and three studies involved MCI patients. A total of 18,313 participants aged older than 40 years with mean MetS prevalence of 22.7% were followed on average for 9.41years. A fixed model was used to estimate pooled hazard ratios and 95% confidence intervals.ConclusionNo statistically significant pooled association emerged between MetS and incident dementia and AD. MetS increased the incidence of pure VaD. MetS increased the risk of progression from MCI to dementia. Follow-up length might be a key factor in investigating these associations further. Because MetS is constituted by a set of potentially modifiable factors, further studies with longer follow-up and repeated assessment of both MetS and cognitive status are desirable to draw definite conclusions.