Memory evaluation with a new cued recall test in patients with mild cognitive impairment and Alzheimer’s disease

Abstract Free delayed recall is considered the memory measure with the greatest sensitivity for the early diagnosis of dementia. However, its specificity for dementia could be lower, as deficits other than those of pure memory might account for poor performance in this difficult and effortful task. Cued recall is supposed to allow a better distinction between poor memory due to concurrent factors and impairments related to the neurodegenerative process. The available cued recall tests suffer from a ceiling effect. This is a prospective, longitudinal study aiming to assess the utility of a new memory test based on cued recall that avoids the ceiling effect in the early diagnosis of Alzheimers disease (AD). Twenty-five patients with mild cognitive impairment (MCI), 22 probable AD patients (NINCDS-ADRDA) at a mild stage, 22 elderly patients with subjective memory complaints (SMC) and 38 normal age-matched controls took part in the study. The patients underwent a thorough cognitive evaluation and the recommended screening procedure for the diagnosis of dementia. All patients were re-examined 12–18 months later. A newly devised delayed cued recall test using semantic cues (The RI48 Test) was compared with three established memory tests: the Ten Word-List Recall from CERAD, the Doors and the Shapes Tests from The Doors and People Test Battery. Forty-four % of the MCI patients fulfilled criteria for probable AD at follow-up. The RI48 Test classified correctly 88% of the MCI and SMC participants and was the best predictor of the status of MCI and mild AD as well as the outcome of the MCI patients. Poor visual memory was the second best predictor of those MCI patients who evolved to AD. A cued recall test which avoids the ceiling effect is at least as good as the delayed free recall tests in the early detection of AD.     

Differentiating Alzheimer’s disease from subcortical vascular dementia with the FAB test

Background The frontal assessment battery (FAB) test is a composite tool for assessing executive functions related to the frontal lobe. Neuropsychological and blood-flow studies indicate distinct patterns of deterioration of anterior and posterior cortical function in Alzheimer’s disease (AD) and subcortical vascular dementia (VD) patients. We predict that the FAB score may be useful for discriminating VD from AD. Objective To evaluate the clinical usefulness of the FAB test for differential diagnosis of AD and VD. Methods We compared FAB scores in 25 patients with AD, 27 patients with VD, and 80 age-matched normal control subjects. The AD group was matched for age, education and MMSE score with the VD group. The subtest scores in FAB were also compared among the three groups. Results The FAB scores were significantly decreased in both the AD and VD groups compared to the control group, and the reduction were greater in the VD group. Among the FAB subtests, mental flexibility (phonological verbal fluency) was the only subtest that significantly discriminated VD from the other two groups. Conclusions The FAB test can provide useful information for differentiating AD and VD at the bedside. Received in revised form: 20 January 2006     

Tomm40 polymorphisms in Italian Alzheimer’s disease and frontotemporal dementia patients

Chromosome 19 is one of the several prominent chromosomes related to the risk of developing late-onset Alzheimer’s disease (LOAD) and frontotemporal lobar degeneration (FTLD). However, only Apolipoprotein E (APOE) has been confirmed as a risk factor for both disorders. The aim of this study was to investigate a set of polymorphisms in the translocase of the outer mitochondrial membrane 40 (TOMM40) gene, located in close proximity to APOE, to clarify if the TOMM40 gene may be considered a risk factor for AD and FTLD, independently of APOE status. We performed a case–control study in a dataset of Italian LOAD and FTLD patients, analyzing the following three single-nucleotide polymorphisms (SNPs): rs157580, rs2075650 and rs157581. The analysis was made in 710 Italian subjects: 282 LOAD patients, 156 FTLD patients and 272 healthy subjects. Our results confirm the presence of an association between TOMM40 SNPs and LOAD in our Italian population, suggesting that genetic variations proximate to APOE contributes to the LOAD risk. Genotype and allele distribution of the TOMM40 polymorphisms between the FTLD group and controls did not show any statistical difference. When we analyzed haplotype distribution of the SNPs, taking into account the presence of the APOE allele, we observed a strong association between the ε4 allele and the GAC haplotype both in LOAD and FTLD patients. In contrast, this association did not hold for ε3/GAC. These results demonstrate that the TOMM40 gene does not have an APOE-independent role in the risk of developing LOAD and FTLD.     

Assessment of sleep satisfaction in patients with dementia due to Alzheimer’s disease

Sleep length and architecture are potential markers of progressive cognitive impairment, while neuropsychiatric symptoms and APOE4− haplotypes have been associated with more sleep complaints in patients with dementia due to Alzheimer’s disease (AD). In this cross-sectional study, we sought to investigate which factors might be related to sleep satisfaction in patients with AD. A total of 217 consecutive patients with AD were assessed for demographic features, neuropsychiatric symptoms, cognitive decline, functional impairment for activities of daily living, caregiver burden, APOE haplotypes, self-reported sleep satisfaction and length of sleep. Statistical comparisons were conducted with significance at p < 0.05. Concerning sleep complaints, 179 patients (82.5%) reported satisfactory sleep, while 38 (17.5%) were unsatisfied, with no relation to age, sex, APOE haplotypes, obesity, education, marital status, alcohol consumption or smoking found. Length of sleep (p = 0.011) and behavioural symptoms (p = 0.009) had significant associations with sleep satisfaction. Length of sleep was positively correlated with apathy (p = 0.014) and scores on the Clock Drawing Test (p = 0.015), and inversely correlated with anxiety (p = 0.015) and independence for instrumental activities of daily living (p = 0.003). Patients who were treated with memantine (p = 0.02) or anti-psychotics (p < 0.01) had longer duration of sleep. In conclusion, behavioural symptoms had strong associations with sleep satisfaction, which is highly correlated with length of sleep in patients with AD. Functional independence, apathy, anxiety, use of memantine or anti-psychotics, and scores on the Clock Drawing Test were significantly associated with length of sleep in this sample.     

Different mechanisms of corpus callosum atrophy in Alzheimer’s disease and vascular dementia

Abstract. Previous neuroimaging studies have indicated that corpus callosum atrophy in Alzheimers disease (AD) and large vessel occlusive disease (LVOD) is caused by interhemispheric disconnection, namely Wallerian degeneration of interhemispheric commissural nerve fibers originating from pyramidal neurons in the cerebral cortex. However, this hypothesis has not been tested from a neuropathological viewpoint. In the present study, 22 brains with AD (presenile onset, 9; senile onset, 13), 6 brains with Binswangers disease (BD), a form of vascular dementia and 3 brains with LVOD were compared with 6 non-neurological control brains.White matter lesions in the deep white matter and corpus callosum were quantified as a fiber density score by image analysis of myelin-stained sections. Axonal damage and astrogliosis were assessed by immunohistochemistry for amyloid precursor protein and glial fibrillary acidic protein, respectively.The corpus callosum thickness at the anterior part of the body was decreased in AD and LVOD,but not in BD significantly, as compared with the controls. The corpus callosum thickness correlated roughly with brain weight in AD (R = 0.50),and with the severity of deep white matter lesions in BD (R = 0.81). Atrophy of the brain and corpus callosum was more marked in presenile onset AD than in senile onset AD. With immunohistochemistry, the corpus callosum showed axonal damage and gliosis with a decreased fiber density score in BD and LVOD, but not in AD. Thus, corpus callosum atrophy was correlated with brain atrophy in AD, which is relevant to the mechanism of interhemispheric disconnection,whereas corpus callosum lesions in BD were secondary to deep white matter lesions. Corpus callosum atrophy in LVOD may indicate interhemispheric disconnection, but focal ischemic injuries may also be involved.     

Abhorring the vacuum: use of Alzheimer’s disease medications in frontotemporal dementia

There is no dedicated therapy for frontotemporal dementia (FTD). In order to treat the often devastating behavioral disturbances that interfere with both normal social functioning and the ability of caregivers to provide needed support, off-label medication usage is frequent. In addition to antidepressant and antipsychotic medications, which afford some benefits, US FDA-approved treatments for Alzheimer's disease are often used, including both cholinesterase inhibitors and memantine. Here, we review the various clinical manifestations of FTD, a general approach to treatment and the goals of any potential therapies. We review all of the existing literature on the use of cholinesterase inhibitors and memantine in FTD. While cholinesterase inhibitors do not currently have a place in FTD treatment, memantine may be helpful, although the results of two placebo-controlled trials with this agent are not yet available. Finally, we discuss our view that such approaches will probably become supplanted by rational, molecularly-based therapies currently in development.     

EEG microstates associated with salience and frontoparietal networks in frontotemporal dementia,schizophrenia and Alzheimer’s disease

ObjectiveThere are relevant links between resting-state fMRI networks, EEG microstate classes and psychopathological alterations in mental disorders associated with frontal lobe dysfunction. We hypothesized that a certain microstate class, labeled C and correlated with the salience network, was impaired early in frontotemporal dementia (FTD), and that microstate class D, correlated with the frontoparietal network, was impaired in schizophrenia.MethodsWe measured resting EEG microstate parameters in patients with mild FTD (n = 18), schizophrenia (n = 20), mild Alzheimer’s disease (AD; n = 19) and age-matched controls (old n = 19, young n = 18) to investigate neuronal dynamics at the whole-brain level.ResultsThe duration of class C was significantly shorter in FTD than in controls and AD, and the duration of class D was significantly shorter in schizophrenia than in controls, FTD and AD. Transition analysis showed a reversed sequence of activation of classes C and D in FTD and schizophrenia patients compared with that in controls, with controls preferring transitions from C to D, and patients preferring D to C.ConclusionThe duration and sequence of EEG microstates reflect specific aberrations of frontal lobe functions in FTD and schizophrenia.SignificanceThis study highlights the importance of subsecond brain dynamics for understanding of psychiatric disorders.     

Disease-specific profiles of apathy in Alzheimer’s disease and behavioural-variant frontotemporal dementia differ across the disease course

Journal of Neurology - Apathy is one of the most prevalent and disabling non-cognitive symptoms of dementia. This loss of motivation and pervasive decline in goal-directed behaviour represents a...     

Reduced 25-hydroxyvitamin D and risk of Alzheimer’s disease and vascular dementia

BackgroundVitamin D deficiency has been implicated as a risk factor for dementia in several cross-sectional studies. We tested the hypothesis that reduced plasma 25-hydroxyvitamin D (25[OH]D) is associated with increased risk of Alzheimer’s disease (AD) and vascular dementia in the general population.MethodsWe measured baseline plasma 25(OH)D in 10,186 white individuals from the Danish general population.ResultsDuring 30 years of follow-up, 418 participants developed AD and 92 developed vascular dementia. Multivariable adjusted hazard ratios for AD were 1.25 (95% confidence interval [CI], 0.95–1.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.29 (95% CI, 1.01–1.66) for less than the 25th seasonally adjusted 25(OH)D percentile vs. more than the 50th seasonally adjusted 25(OH)D percentile. Multivariable adjusted hazard ratios for vascular dementia were 1.22 (95% CI, 0.77–1.91) for 25(OH)D less than 50 nmol/L vs. greater than or equal to 50 nmol/L, and 1.22 (95% CI, 0.79–1.87) for less than or equal to the 50th vs. more than the 50th seasonally adjusted 25(OH)D percentile. Last, multivariable adjusted hazard ratios for the combined end point were 1.28 (95% CI, 1.00–1.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.27 (95% CI, 1.01–1.60) for less than the 25th vs. more than the 50th seasonally adjusted 25(OH)D.ConclusionsWe observed an association of reduced plasma 25(OH)D with increased risk of the combined end point of AD and vascular dementia in this prospective cohort study of the general population.     

Differential distribution of presenilin-1, Bax, and Bcl-XL in Alzheimer’s disease and frontotemporal dementia

We have previously reported that presenilin-1 (PS-1)-immunoreactive neurons survive in late-onset sporadic Alzheimer’s disease (AD). To examine if this is also the case in other dementing conditions, and if it is associated with changes in the expression of the main apoptosis-related proteins, a quantitative immunocytochemical study of presenilin-1, Bax, and Bcl-X_L in the cerebral cortex of non-demented and AD patients, and patients with frontotemporal dementia (FTD) was performed. In non-demented cases, the frequency of neurons showing PS-1 immunoreactivity was 25–60%, Bax immunoreactivity 36–54%, and Bcl-X_L immunoreactivity 26–63% depending on the cortical area. The frequency of NFT-free neurons which contained PS-1 or Bax was consistently increased in all of the areas in AD. In FTD cases, the percentage of PS-1-, but not Bax-immunoreactive neurons was increased only in areas displaying a substantial neuronal loss. Conversely, there was no difference in the densities of Bcl-X_L-containing neurons among the three diagnosis groups. These data suggest that surviving neurons in affected cortical areas in AD show a high expression of PS-1 and Bax, indicating that these proteins play a key role in the mechanisms of cell death in this disorder. In FTD, neurons containing PS-1 are preserved, further supporting a neuroprotective role for this protein in other neurodegenerative disorders. Received: 27 October 1998 / Revised: 4 January 1999 / Accepted: 5 January 1999     

Behavioral and autonomic reactivity to moral dilemmas in frontotemporal dementia versus Alzheimer’s disease

The personal/impersonal distinction of moral decision-making postulates intuitive emotional responses from medial frontal activity and rational evaluation from lateral frontal activity. This model can be analyzed in behavioral variant frontotemporal dementia (bvFTD), a disorder characterized by impaired emotional intuitions, ventromedial prefrontal cortex (vmPFC) involvement, and relative sparing of lateral frontal regions. Moral dilemmas were presented to 10 bvFTD, 11 Alzheimer’s disease (AD), and 9 healthy control (HC) participants while recording skin conductance responses, a measure of emotional arousal. We evaluated their personal versus impersonal conflict, subjective discomfort, and adherence to social norms. Replicating prior work, bvFTD participants were more willing to harm in the personal, but not the impersonal, dilemma compared to AD and HC groups. BvFTD participants had lower arousal and less of an increase in conflict on the personal versus the impersonal dilemma, in contrast to increased arousal and conflict for the AD and HC groups. Furthermore, bvFTD participants verbalized less discomfort, a correlate of low adherence to social norms. These findings support impaired emotional reactions to moral dilemmas in bvFTD and vmPFC lesions and the personal/impersonal model. It suggests a reversion to utilitarian-like considerations when emotional intuition is impaired in the brain.     

An advanced white matter tract analysis in frontotemporal dementia and early-onset Alzheimer’s disease

Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer’s disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics – fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter – the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally. Widespread but distinctive white matter alterations are a key feature of the pathophysiology of these two forms of dementia.     

Awareness impairment in Alzheimer’s disease and frontotemporal dementia: a systematic MRI review

Journal of Neurology - This review aims to define awareness impairment and related disturbances in neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal lobar...     

Recalling feature bindings differentiates Alzheimer’s disease from frontotemporal dementia

It has been challenging to identify clinical cognitive markers that can differentiate patients with Alzheimer’s disease (AD) from those with behavioral variant frontotemporal dementia (bvFTD). The short-term memory binding (STMB) test assesses the ability to integrate colors and shapes into unified representations and to hold them temporarily during online performance. The objective of this study is to investigate whether free recall deficits during short-term memory binding (STMB) test can differentiate patients with AD from those with bvFTD and controls. Participants were 32 cognitively intact adults, 35 individuals with AD and 18 with bvFTD. All patients were in the mild dementia stage. Receiver-operating characteristic (ROC) analyses were used to examine the diagnostic accuracy of the STMB. The results showed that AD patients performed significantly worse than controls and bvFTD patients in the STMB test, while the latter groups showed equivalent performance. The bound condition of the STMB test showed an AUC of 0.853, with 84.4% of sensitivity and 80% of specificity to discriminate AD from controls and an AUC of 0.794, with 72.2% of sensitivity and 80% of specificity to differentiate AD from bvFTD. Binding deficits seem specific to AD. The free recall version of the STMB test can be used for clinical purposes and may aid in the differential diagnosis of AD. Findings support the view that the STMB may be a suitable cognitive marker for AD.     

Muscle profile and cognition in patients with Alzheimer’s disease dementia

Introduction

Neurodegenerative disease is one of the main contributing factors affecting muscle atrophy. However, this intriguing brain-muscle axis has been explained by the unsubstantial mechanisms. Although there have been several studies that have evaluated the muscle profile and its relation to cognition in patients with dementia, there is still lack of data using standardized methods and only few published studies on Korean populations. The objective of this study is to evaluate the relationship of muscle mass and strength to cognition in patients with Alzheimer’s disease dementia (AD).

Methods

We recruited 91 patients with probable AD without weakness. We assessed patients’ basic demographic characteristics, vascular risk, body mass index, and global cognitive assessment scores. Muscle mass was measured using body dual-energy X-ray absorptiometry. Muscle strength was assessed by isokinetic knee extensor using an isokinetic device at an angular velocity of 60°/s in nm/kg.

Results

The muscle mass and strength were not related to each other in both male and female groups. Only muscle strength, but not muscle mass, was negatively related to cognition. After adjusting for covariates, the relationship between muscle strength and cognition still remained in the male group, however, was attenuated in the female group.

Conclusions

In patients with AD dementia, abundant muscle mass did not mean strong power. The simple lower-extremity muscle strength assessment is more effective in predicting cognition than a muscle mass measure in male patients.

     

CSF diagnosis of Alzheimer’s disease and dementia with Lewy bodies

Summary. Differential diagnosis of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is often crucial. CSF Tau protein and Amyloid-beta (Aβ) peptides have shown diagnostic value for the diagnosis of AD, but discrimination from DLB was poor. Herein, we investigate CSF of 18 patients with probable AD, 25 with probable DLB and 14 non-demented disease controls (NDC) by Aβ-SDS-PAGE/immunoblot and commercially available ELISAs for Aβ1-42 and tau. CSF Aβ peptide patterns and tau exhibited disease specific alterations among AD and DLB. The ratio of Aβ1-42 to Aβ1-38 and Aβ1-42 to Aβ1-37, respectively, in combination with absolute tau, yielded a sensitivity and specificity of 100 and 92%, respectively. We conclude that CSF Aβ peptide patterns and tau levels reflect disease-specific pathophysiological pathways of these dementias as distinct neurochemical phenotypes. Combined evaluation of these biomarkers provides a reasonable accuracy for differential diagnosis of AD and DLB.     

Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies

The aim of this study was to characterize myelin loss as one of the features of white matter abnormalities across three common dementing disorders. We evaluated post-mortem brain tissue from frontal and temporal lobes from 20 vascular dementia (VaD), 19 Alzheimer’s disease (AD) and 31 dementia with Lewy bodies (DLB) cases and 12 comparable age controls. Images of sections stained with conventional luxol fast blue were analysed to estimate myelin attenuation by optical density. Serial adjacent sections were then immunostained for degraded myelin basic protein (dMBP) and the mean percentage area containing dMBP (%dMBP) was determined as an indicator of myelin degeneration. We further assessed the relationship between dMBP and glutathione S-transferase (a marker of mature oligodendrocytes) immunoreactivities. Pathological diagnosis significantly affected the frontal but not temporal lobe myelin attenuation: myelin density was most reduced in VaD compared to AD and DLB, which still significantly exhibited lower myelin density compared to ageing controls. Consistent with this, the degree of myelin loss was correlated with greater %dMBP, with the highest %dMBP in VaD compared to the other groups. The %dMBP was inversely correlated with the mean size of oligodendrocytes in VaD, whereas it was positively correlated with their density in AD. A two-tier regression model analysis confirmed that the type of disorder (VaD or AD) determines the relationship between %dMBP and the size or density of oligodendrocytes across the cases. Our findings, attested by the use of three markers, suggest that myelin loss may evolve in parallel with shrunken oligodendrocytes in VaD but their increased density in AD, highlighting partially different mechanisms are associated with myelin degeneration, which could originate from hypoxic–ischaemic damage to oligodendrocytes in VaD whereas secondary to axonal degeneration in AD.     

Differential deposition of amyloid β peptides in cerebral amyloid angiopathy associated with Alzheimer’s disease and vascular dementia

Cerebral amyloid angiopathy (CAA) caused by deposition of amyloid β (Aβ) peptides in the cerebrovasculature, involves degeneration of normal vascular components and increases the risk of infarction and cerebral hemorrhage. Accumulating evidence suggests that sporadic CAA is also a significant contributor to cognitive decline and dementia in the elderly. However, the mechanisms by which CAA arises are poorly understood. While neuronal sources of Aβ peptides are sufficient to cause CAA in transgenic mice overexpressing the amyloid precursor protein, there is reason to believe that in aging man, vascular disease modulates the disease process. To better understand CAA mechanisms in dementia, we assessed the frontal cortex of 62 consecutive cases of Alzheimer’s disease (AD), vascular dementia (VaD), and mixed dementia (MD) using immunohistochemistry with antibodies to Aβ, smooth muscle actin and the carboxyl-terminal peptides to detect Aβ(40) and Aβ(42). While vascular Aβ deposition was invariably associated with smooth muscle degeneration as indicated by absence of smooth muscle cell actin reactivity, VaD/MD cases exhibited markedly more vascular Aβ(42) deposits and smooth muscle actin loss compared to AD cases with similar degrees of CAA and Aβ(40) deposition. This suggests that distinct mechanisms are responsible for the differential deposition of Aβ in CAA associated with AD and that associated with ischemic/cerebrovascular disease. It is plausible that experimental studies on the effects of cerebrovascular disease on Aβ production and elimination will yield important clues on the pathogenesis of CAA.