Blood mRNA Expression in Alzheimer's Disease and Dementia With Lewy Bodies

ObjectivesThe objective of this study was to investigate the expression of genes in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), both at the mild cognitive impairment (MCI) and dementia stages, to improve our understanding of disease pathophysiology and investigate the potential for diagnostic and prognostic biomarkers based on mRNA expression.DesignCross-sectional observational study.SettingUniversity research center.ParticipantsPeople with MCI with Lewy bodies (MCI-LB, n=55), MCI-AD (n=19), DLB (n=38), AD (n=24) and a cognitively unimpaired comparison group (n=28).MeasurementsRibonucleic acid sequencing of whole blood. Differentially expressed genes (DEGs) were identified and gene set enrichment analysis was carried out.ResultsCompared with the cognitively unimpaired group, there were 22 DEGs in MCI-LB/DLB and 61 DEGs in MCI-AD/AD. DEGS were also identified when comparing the two disease groups. Expression of ANP32A was associated with more rapid cognitive decline in MCI-AD/AD. Gene set enrichment analysis identified downregulation in gene sets including MYC targets and oxidative phosphorylation in MCI-LB/DLB; upregulation of immune and inflammatory responses in MCI-AD/AD; and upregulation of interferon-α and -γ responses in MCI-AD/AD compared with MCI-LB/DLB.ConclusionThis study identified multiple DEGs in MCI-LB/DLB and MCI-AD/AD. One of these DEGs, ANP32A, may be a prognostic marker in AD. Genes related to mitochondrial function were downregulated in MCI-LB/DLB. Previously reported upregulation of genes associated with inflammation and immune responses in MCI-AD/AD was confirmed in this cohort. Differences in interferon responses between MCI-AD/AD and MCI-LB/DLB suggest that there are key differences in peripheral immune responses between these diseases.     

The Addenbrooke's Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening

There is a clear need for brief, but sensitive and specific, cognitive screening instruments as evidenced by the popularity of the Addenbrooke's Cognitive Examination (ACE). OBJECTIVES: We aimed to validate an improved revision (the ACE-R) which incorporates five sub-domain scores (orientation/attention, memory, verbal fluency, language and visuo-spatial). METHODS: Standard tests for evaluating dementia screening tests were applied. A total of 241 subjects participated in this study (Alzheimer's disease=67, frontotemporal dementia=55, dementia of Lewy Bodies=20; mild cognitive impairment-MCI=36; controls=63). RESULTS: Reliability of the ACE-R was very good (alpha coefficient=0.8). Correlation with the Clinical Dementia Scale was significant (r=-0.321, p<0.001). Two cut-offs were defined (88: sensitivity=0.94, specificity=0.89; 82: sensitivity=0.84, specificity=1.0). Likelihood ratios of dementia were generated for scores between 88 and 82: at a cut-off of 82 the likelihood of dementia is 100:1. A comparison of individual age and education matched groups of MCI, AD and controls placed the MCI group performance between controls and AD and revealed MCI patients to be impaired in areas other than memory (attention/orientation, verbal fluency and language). CONCLUSIONS: The ACE-R accomplishes standards of a valid dementia screening test, sensitive to early cognitive dysfunction.     

Hippocampal and insula volume in mild cognitive impairment with Lewy bodies

IntroductionDiagnostic criteria for prodromal dementia with Lewy bodies have recently been published. These include the use of imaging biomarkers to distinguish mild cognitive impairment with Lewy bodies (MCI-LB) from MCI due to other causes. Two potential biomarkers listed, though not formally included in the diagnostic criteria, due to insufficient evidence, are relatively preserved hippocampi, and atrophy of the insula cortex on structural brain imaging.MethodsIn this report, we sought to investigate these imaging biomarkers in 105 research subjects, including well characterised groups of patients with MCI-LB (n = 38), MCI with no core features of Lewy body disease (MCI-AD; n = 36) and healthy controls (N = 31). Hippocampal and insula volumes were determined from T1 weighted structural MRI scans, using grey matter segmentation performed with SPM software.ResultsAdjusting for age, sex and intracranial volume, there were no differences in hippocampal or insula volume between MCI-AD and MCI-LB, although in both conditions volumes were significantly reduced relative to controls.ConclusionOur results do not support the use of either hippocampal or insula volume to identify prodromal dementia with Lewy bodies.     

REM sleep behavior disorder and dementia: cognitive differences when compared with AD

OBJECTIVE: To determine whether the dementia associated with REM sleep behavior disorder (RBD) differs from Alzheimer's disease (AD) and, if so, whether differences in cognitive performance between RBD/dementia and AD resemble reported differences between dementia with Lewy bodies (DLB) and AD. METHODS: This retrospective study compares neurocognitive performance between 31 patients with degenerative dementia and polysomnography-confirmed RBD and 31 patients without brainstem Lewy body pathology who met Consortium to Establish a Registry for Alzheimer's Disease (CERAD) clinical and neuropathologic criteria for AD. The patient groups did not differ in dementia severity (based on Global Deterioration Scale score) or duration. RESULTS: RBD preceded or coincided with the onset of cognitive decline in 94% of the patients. All but one patient with RBD/dementia had one or more of the following clinical features of DLB: visual hallucinations, extrapyramidal signs, or fluctuating cognition/alertness. The data revealed significantly worse performance on attention, perceptual organization, visual memory, and letter fluency for the RBD/dementia group, whereas the AD group showed significantly worse performance on confrontation naming and verbal memory. CONCLUSIONS: Patients with RBD and degenerative dementia demonstrate a significantly different pattern of cognitive performance from patients with AD. Most of the patients in the RBD/dementia sample also meet criteria for possible or probable DLB, and the pattern of cognitive differences from AD is similar to reported comparisons between DLB and AD. The cognitive and clinical data provide evidence to suggest that the dementia associated with RBD may represent DLB.     

Early differentiation of dementia with Lewy bodies and Alzheimer’s disease: Heart rate variability at mild cognitive impairment stage

Objective

Our study aimed to investigate whether heart rate variability (HRV) could be a useful diagnostic screening tool at MCI (mild cognitive impairment) stage of Dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD).

Neuropsychological comparison of Alzheimer's disease and dementia with lewy bodies

BACKGROUND/AIMS: The present study examined the patterns of memory and cognitive performance associated with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: A battery of standardized neuropsychological tests was administered to individuals with these disorders as well as to a group of cognitively intact controls. The battery included measures of memory (learning, recall and recognition), language, visuospatial ability, psychomotor speed, executive functioning and mood. All subjects (n = 115) were evaluated at a memory disorder clinic and were diagnosed based on published criteria. RESULTS: The controls outperformed both dementia groups on all cognitive measures. With respect to memory, the DLB group scored significantly higher than the AD group on measures of word list free recall and recognition (p < or = 0.001). In other cognitive domains, the AD group performed significantly better than the DLB group on constructional praxis, sustained attention, phonemic fluency, spatial judgment, psychomotor speed and working memory (all p < or = 0.01). CONCLUSION: These findings support the usefulness of memory and other cognitive test score patterns as in distinguishing AD from DLB, particularly in mild to moderately demented populations that may not present with hallmark symptomology.     

Cognitive decline and amyloid accumulation in patients with mild cognitive impairment

Background/Aims: The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI. Methods: (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images. Results: At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function. Conclusion: Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia.     

Cognitive profiles in Alzheimer's disease and in mild cognitive impairment of different etiologies

There has been increasing interest in determining whether amnestic, nonamnestic and multiple-domain subtypes of mild cognitive impairment (MCI) reflect different disease etiologies. In this study, we examined the extent to which cognitive profiles of nondemented patients with MCI diagnosed with prodromal Alzheimer's disease (AD) differed from those MCI patients diagnosed with vascular disease. We also compared these diagnostic groups to mildly demented patients diagnosed with AD and normal elderly controls. Results indicate that a majority of both MCI-AD and MCI-vascular patients experienced amnestic features and that multiple-domain was the most common presentation. MCI-AD and MCI-vascular groups did not differ on neuropsychological measures tapping memory, language, visuospatial skills/praxis or executive function. Further both MCI groups could be distinguished from dementia patients with regards to performance on measures of memory but not on non-memory measures. Considerable variability was observed in the degree of memory impairment among MCI patients with scores as much as 6 standard deviations below expected mean values. MCI-AD and MCI-vascular patients frequently exhibit both common and overlapping amnestic and nonamnestic features. The implication of these findings for future clinical research is discussed.     

Clinical symptoms in mild cognitive impairment with Lewy bodies: Frequency,time of onset,and discriminant ability

Background and purpose

Mild cognitive impairment with Lewy bodies (MCI-LB) is associated with a range of cognitive, motor, neuropsychiatric, sleep, autonomic, and visual symptoms. We investigated the cumulative frequency of symptoms in a longitudinal cohort of MCI-LB compared with MCI due to Alzheimer disease (MCI-AD) and analysed the ability of a previously described 10-point symptom scale to differentiate MCI-LB and MCI-AD, in an independent cohort.

Methods

Participants with probable MCI-LB (n = 70), MCI-AD (n = 51), and controls (n = 34) had a detailed clinical assessment and annual follow-up (mean duration = 1.7 years). The presence of a range of symptoms was ascertained using a modified version of the Lewy Body Disease Association Comprehensive LBD Symptom Checklist at baseline assessment and then annually.

Results

MCI-LB participants experienced a greater mean number of symptoms (24.2, SD = 7.6) compared with MCI-AD (11.3, SD = 7.4) and controls (4.2, SD = 3.1; p < 0.001 for all comparisons). A range of cognitive, parkinsonian, neuropsychiatric, sleep, and autonomic symptoms were significantly more common in MCI-LB than MCI-AD, although when present, the time of onset was similar between the two groups. A previously defined 10-point symptom scale demonstrated very good discrimination between MCI-LB and MCI-AD (area under the receiver operating characteristic curve = 0.91, 95% confidence interval = 0.84–0.98), replicating our previous finding in a new cohort.

Conclusions

MCI-LB is associated with the frequent presence of a particular profile of symptoms compared to MCI-AD. Clinicians should look for evidence of these symptoms in MCI and be aware of the potential for treatment. The presence of these symptoms may help to discriminate MCI-LB from MCI-AD.     

Cognitive-behavioral profiles of neurodegenerative dementias: beyond Alzheimer's disease

The neurocognitive and behavioral profiles of vascular dementia and vascular cognitive impairment, dementia with Lewy bodies and Parkinson's disease with dementia, and dementia syndromes associated with frontotemporal lobar degenerations are compared and contrasted with Alzheimer's dementia (AD). Vascular dementia/vascular cognitive impairment is characterized by better verbal memory performance, worse quantitative executive functioning, and prominent depressed mood. Dementia with Lewy bodies and Parkinson's disease with dementia are equally contrasted with AD by defective processing of visual information, better performance on executively supported verbal learning tasks, greater attentional variability, poorer qualitative executive functioning, and the presence of mood-congruent visual hallucinations. The frontal variant of frontotemporal lobar degeneration (frontotemporal dementia) differs from AD by better multimodal retention on learning tasks, different patterns of generative word fluency, defective qualitative executive functioning, and by markedly impairment of comportment. For temporal variants of frontotemporal lobar degenerations, progressive aphasia and semantic dementia, worse language performance relative to AD is typically characteristic.     

Dementia with Lewy bodies may present as dementia and REM sleep behavior disorder without parkinsonism or hallucinations.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disturbance that commonly occurs in Dementia with Lewy bodies (DLB). Retrospective examination of DLB course has shown that RBD and cognitive decline may precede the onset of parkinsonism and visual hallucinations. Therefore, some patients with DLB may initially present with dementia and RBD, but would not meet current formal criteria for probable DLB at that time. The purpose of this study is to determine whether patients with dementia and RBD, who do not have parkinsonism or visual hallucinations, have cognitive profiles that can be distinguished from autopsy-confirmed definite AD, but not from clinically probable DLB. If so, this would support the hypothesis that the presence of RBD and dementia, as the only presenting symptoms, reflects the early manifestation of DLB. Results show that early dementia in probable DLB and dementia with RBD are neuropsychologically indistinguishable. Both groups differ from definite AD of a similar early stage with significantly worse visual perceptual organization, sequencing and letter fluency but significantly better confrontation naming and verbal memory. In addition, follow-up data from a subset of patients with dementia and RBD reveal the subsequent development of parkinsonism or hallucinations 1 to 6 years later. Results indicate that the presentation of dementia and RBD is suggestive of underlying Lewy body disease and not Alzheimer's disease. This provides further evidence in support of including RBD as one of the core diagnostic features of DLB.     

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.     

General measures of cognition

A general cognitive performance battery is needed as a primary outcome in vascular dementia clinical trials. Because there is considerable overlap between vascular dementia and Alzheimer's disease (AD) in the pattern of cognitive impairment, a reasonable approach to developing an optimal vascular dementia battery is to begin with a widely used AD measure and improve its sensitivity to the cognitive domains that are more prominent in vascular dementia. Thus the VaDAS-cog has evolved, which comprises the ADAS-cog with additional frontal lobe subtests covering attention, working memory, executive function, and verbal fluency. Validation of this new cognitive instrument will be supported by its successful use in vascular dementia clinical trials.     

Cognitive profiling of Parkinson disease patients with mild cognitive impairment and dementia

BackgroundPrevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD) is variable because different classification criteria are applied and there is lack of consensus about neuropsychological tests and cut-off used for cognitive profiling. Given the important therapeutic consequences for patient management, we aimed at identifying suitable diagnostic cognitive tests and respective screening cut-off values for MCI and dementia in PD (PDD).MethodsWe evaluated 105 PD patients using an extensive neuropsychological battery categorized as PD without cognitive impairment (PD-CNT) (35%), PD-MCI (47%) and PDD (18%) based on established criteria and calculated Receiver Operating Characteristic (ROC) curves.ResultsWe found different sensitivity and specificity among neuropsychological tests in detecting PD-MCI and PDD. In particular performance in attention/set shifting, verbal memory and language abilities, discriminated both PD-MCI and PDD from PD-CNT. Abilities involved mainly in semantic retrieval mechanisms discriminated PD-CNT from PD-MCI but also PD-MCI from PDD. Finally deficits in executive and visual-spatial abilities were only affected in PDD.ConclusionOur data point to an independent and different load of each test in defining different PD cognitive statuses. These findings can help selection of appropriate cognitive batteries in longitudinal studies and definition of stage-specific therapeutic targets.     

Mild Behavioral Impairment as a Marker of Cognitive Decline in Cognitively Normal Older Adults

ObjectiveMild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergent neuropsychiatric symptoms (NPS) that represent an at-risk state for incident cognitive decline and dementia in people with mild cognitive impairment (MCI). We undertook a study to determine whether MBI was associated with progressive changes in neuropsychological performance in people without significant cognitive impairment.MethodsA total of 9,931 older adults enrolled in the PROTECT study who did not have MCI or dementia undertook a comprehensive neuropsychological battery measuring attention, reasoning, executive function, and working memory at baseline and 1 year. MBI was ascertained using self-administration of the Mild Behavioral Impairment Checklist at 1 year, and participants were grouped according to MBI status: No Symptoms, Intermediate NPS and MBI. All assessments were completed online, and data analyzed using mixed-effects model repeated measures analysis of covariance.ResultsA total of 949 (10%) people had MBI. These individuals had significantly worse cognitive performance at baseline and significantly greater decline over 1 year in the four composite cognitive scores measuring attentional intensity (F [2,8578] = 3.97; p = 0.019), sustained attention (F [2,8578] = 18.63; p <0.0001), attentional fluctuation (F [2,8578] = 10.13; p <0.0001) and working memory (F [2,9895] = 13.1; p <0.0001).ConclusionOur novel findings show that MBI is associated with faster decline in attention and working memory in this cognitively normal sample. MBI may be an earlier marker of neurodegenerative disease than MCI, captured at the stage of subjective cognitive decline or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies.     

Mild cognitive impairment and abnormal brain metabolic expression in idiopathic REM sleep behavior disorder

BackgroundMild cognitive impairment (MCI) is a common feature of isolated rapid-eye-movement sleep behavior disorder (iRBD). Here, we assessed cognitive functions and MCI in a prospective iRBD cohort and investigated their association with disease-specific brain metabolic patterns.MethodsForty-four patients with polysomnography-confirmed iRBD performed a standardized battery of neuropsychological examinations every two years. We used previously established spatial covariance patterns from de novo drug-naïve Parkinson's disease with concomitant RBD (_denovoPDRBD-RP) and iRBD (iRBD-RP) using ¹⁸F-fluorodeoxyglucose PET scan. We compared those expressions between iRBD with normal cognition (iRBD-NC) and with mild cognitive impairment (iRBD-MCI), and evaluated whether they predict progressive cognitive deterioration.ResultsTwenty iRBD patients (45 %) had MCI at baseline and 12 patients (27 %, about 7 % per year) had clinically significant cognitive deterioration after 4 years. The iRBD-MCI and iRBD-NC groups showed similar rates of cognitive change, but iRBD-MCI consistently performed worse in the domains of verbal memory and executive function. Elevated _denovoPDRBD-RP expression predicted cognitive deterioration (hazard ratio = 5.98 [1.70–21.06]), whereas iRBD-RP did not.ConclusionsIncreased disease-specific brain metabolic patterns are associated with iRBD-MCI and impending cognitive deterioration with the risk of progression to Lewy body dementia.     

Multiple cognitive deficits in amnestic mild cognitive impairment

OBJECTIVE: To determine if more widespread cognitive deficits are present in a narrowly defined group of patients with the amnestic form of mild cognitive impairment (MCI). METHODS: From a larger sample of patients clinically diagnosed as meeting the criteria of Petersen et al. for amnestic MCI, we selected 22 subjects who had Clinical Dementia Rating scores of zero on all domains besides memory and orientation. These MCI subjects with presumably isolated memory impairments were compared to 35 age-matched normal controls and 33 very mild Alzheimer's disease (AD) patients on a battery of neuropsychological tests. RESULT: In addition to the expected deficits in episodic memory, the amnestic MCI group performed less well than the controls but better than the AD group on design fluency, category fluency, a set shifting task and the Stroop interference condition. Over half the amnestic MCI group (vs. none of the normal controls) scored at least 1 standard deviation below control means on 4 or more of the nonmemory cognitive tasks. CONCLUSIONS: Isolated memory impairment may be fairly uncommon in clinically diagnosed amnestic MCI patients, even when the criteria for amnestic MCI are fairly narrow. Additional cognitive impairments are likely to include fluency and executive functioning. These more diffuse deficits argue for comprehensive cognitive assessments, even when the patient and family are reporting only memory decline, and are consistent with the increase in attention paid to the heterogeneity of MCI.     

The influence of vascular risk factors on the survival rate of patients with dementia with Lewy bodies and Alzheimer disease

Background and purposeThe aim of this study was to determine whether dementia with Lewy bodies (DLB) progresses more rapidly than Alzheimer disease (AD) and to compare survival after dementia onset and mortality in both dementia groups.Material and methodsA medical records analysis of AD (n = 183) and DLB (n = 51) patients was performed to determine age at onset of symptoms, the date of first presentation to the psychiatric services, dementia severity at diagnosis (MMSE score), and mean disease duration before diagnosis. Categorical data regarding vascular risk factors were collected. Projected decline rate (MMSE/year), survival rate after the diagnosis of dementia, mean survival time after diagnosis and mortality rate were calculated and compared between DLB and AD groups.ResultsThe comparison of clinical and demographic parameters revealed no significant differences between groups, apart from a more pronounced decline rate in the DLB group. Diabetes, and to a lesser extent hypertension, influenced survival in AD, but not in DLB subjects. Overall, however, the difference in mortality rates and survival time between DLB and AD subjects cannot be attributed to the presence of any vascular risk factor analysed. DLB, independently of the presence of vascular risk factors, seems to be a more aggressive disorder than AD, when mortality and survival time are taken into account.ConclusionsMore rapid progression of cognitive decline and shorter duration of dementia were found in DLB in this naturalistic study. The findings may have important implications for the management and treatment of DLB and should be confirmed in prospective studies.     

Towards practical cognitive assessment for detection of early dementia: a 30-minute computerized battery discriminates as well as longer testing

Early detection of cognitive decline may lead to more effective treatment. Clinical cognitive assessment is essential for early detection, but must be brief with easily interpretable results. The present study defines and evaluates a 30-minute cognitive battery consisting of a subset of tests that comprise a longer computerized battery recently validated in detecting mild cognitive impairment (MCI). Participants were from three tertiary care memory clinics and an assisted living facility (final group: N=161) with consensus diagnoses of cognitively healthy, MCI, or mild dementia. A comprehensive NeuroTrax battery evaluated memory, executive function, visual spatial perception, verbal function, information processing speed, and motor skills. Validity of a single summary measure ('MCI Score') designed for dementia detection and built exclusively from tests of memory, executive function, and visual spatial perception was evaluated with receiver operating characteristic (ROC) analysis. Discriminant validity (area under the curve: AUC) was at least as large for the 6-parameter MCI Score as for a 20-parameter score necessitating administration of the entire battery. Further, the MCI Score had a larger AUC with reduced variance relative to its constituent parameters. AUC for distinguishing dementia was 0.886; AUC for distinguishing cognitively healthy was 0.823. Finally, the MCI Score discriminated among all three diagnostic groups (ANOVA; F[2,150]=52.54, p<0.001). Hence a reduced NeuroTrax battery (30 minutes) with MCI Score is a useful clinical tool for summarizing cognitive data relevant to early dementia detection.