Resting state fMRI in Alzheimer's disease: beyond the default mode network

Using resting state (RS) functional magnetic resonance imaging (fMRI), the connectivity patterns of the default mode (DMN), frontoparietal, executive, and salience networks were explored in 13 Alzheimer's disease (AD) patients, 12 amnestic mild cognitive impairment (aMCI) patients, and 13 healthy controls. Compared with controls and aMCI, AD was associated with opposing connectivity effects in the DMN (decreased) and frontal networks (enhanced). The only RS abnormality found in aMCI patients compared with controls was a precuneus connectivity reduction in the DMN. RS fMRI group differences were only partly related to gray matter atrophy. In AD patients, the mean executive network connectivity was positively associated with frontal-executive and language neuropsychological scores. These results suggest that AD is associated with an alteration of large-scale functional brain networks, which extends well beyond the DMN. In AD, the limited resources of the DMN may be paralleled, in an attempt to maintain cognitive efficiency, by an increased prefrontal connectivity. A medial parietal RS fMRI signal change seems to be present since the early phase of AD.     

Carotid atherosclerosis and cognitive decline in patients with Alzheimer's disease

Aim of the study was to explore the correlation between the progression of carotid atherosclerosis and the evolution of cognitive impairment in 66 patients with Alzheimer's disease (AD). They underwent cognitive status evaluation and ultrasonography (US) to investigate carotid arteries intima-media thickness (IMT) and plaque index (PI). After a 12-month follow-up period, neuropsychological and US examinations were repeated to assess the progression of carotid atherosclerosis and of cognitive decline [in terms of changes in Mini Mental State Examination (MMSE) scores]. MMSE score changes were related to baseline IMT (p=0.018), changes in IMT (p<0.001) and PI (p=0.006), and "antihypertensive drug intake" (p<0.001). While the first three variables correlated with increased cognitive impairment, the last one was associated with a reduced extent of MMSE score decline. Results show a link between progression of carotid wall changes and of cognitive decline, and suggest a possible protective role of antihypertensive therapy. Given the potential clinical implications, our preliminary findings could stimulate further investigations into the role of vascular impairment in patients with AD.     

Olfaction in patients with mild cognitive impairment and Alzheimer's disease

Understanding of olfactory dysfunction in Alzheimer's disease (AD) remains limited. In particular, it is not known how early in the course of the disease olfactory deficits occur, and whether they are restricted to identification or involve other aspects of olfaction. We studied olfactory (odor detection thresholds, quality discrimination, and identification) and cognitive (attention, reasoning, memory, naming and fluency) functioning in patients with AD, with mild cognitive impairment (MCI), and in normal elderly control (NEC) participants. MCI patients were impaired in olfactory sensitivity and identification, while a discrimination deficit was accounted for by abnormal thresholds. AD patients were impaired in all three domains, and were worse than the MCI group. Odor discrimination (OD) and identification performance correlated more prominently than detection thresholds with performance on neuropsychological tests. We concluded that deficits in olfactory detection thresholds and identification occur early in AD, before clinical symptoms are fully developed, and decline further over the course of the disease. High detection thresholds, together with impaired identification, may be useful as an early indicator of AD.     

General and specific cognitive dysfunctions in patients with Alzheimer's disease.

The purpose of the present study was to investigate the effect of Alzheimer's disease (AD) on general and specific neuropsychological function. Thirty-five subjects diagnosed with AD were compared to 30 medically normal aging control subjects using measures from the Halstead-Reitan Battery (HRB). All AD subjects were classified as "probable" AD (NINCDS-ADRDA) and found to be in the "late confusional" to "early dementia" stages of the disease (Global Deterioration Scale, GDS = 4-5). The AD group performed significantly worse than the controls on all measures of general neuropsychological function and almost all measures of specific functions. However, no differences were found between groups on motor abilities or many simple sensory functions. The findings demonstrate dramatic brain-behavior changes involving both general and specific cognitive functions which go beyond memory dysfunction even in the earlier stages of the disease. The neuropsychological pattern found may be the basis of a useful clinical-behavioral AD pattern in the earlier stages of the disease.     

Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease

Increasing evidence supports a role of oxidative imbalance, characterized by impaired antioxidant enzymatic activity and increased reactive oxygen species (ROS) production, in mild cognitive impairment (MCI) and Alzheimer's disease (AD) pathogenesis. Hyperhomocysteinemia, another risk factor for AD, also contributes to oxidative damage. Plasma total homocysteine (tHcy) and ROS levels, and total antioxidant capacity (TAC) were determined in 71 AD, 36 MCI and 28 vascular dementia (VaD) patients as well as in 44 age-matched controls. tHcy levels were significantly increased in patients with AD and VaD an a trend towards an increase in multiple domain MCI was observed. TAC was significantly decreased in AD as well as MCI, but not in VaD patients. In AD patients, a negative correlation was found between TAC and disease duration. ROS levels did not differ among groups, but were correlated with age. In conclusion, a pattern characterized by increased tHcy levels and decreased TAC is present in AD as well as MCI patients. While increased tHcy levels were also found in VaD, TAC modifications occur specifically in AD. ROS levels appear to be correlated with age rather than with a specific dementing disorder, thus leading to the hypothesis that oxidative imbalance observed in AD could be due to a decreased TAC.     

Alzheimer's disease: anterior-posterior and lateral hemispheric alterations in cortical glucose utilization

We performed dynamic positron emission tomographic studies with [18F]fluorodeoxyglucose in 17 subjects with presumed Alzheimer's disease (AD) and 7 healthy aged subjects. Glucose metabolism was depressed by 27% in temporal-parietal cortex of the AD group, as compared to healthy aged controls. This focal impairment in temporal-parietal glucose use was found in all AD subjects. In addition, the AD group showed a striking lateral asymmetry of cortical metabolism not favoring either hemisphere, which has not been previously reported. Relationships between these focal changes and behavioral features of the illness were demonstrated. These results have important implications for the diagnosis and perhaps the etiology of Alzheimer's disease.     

40-Hz steady state response in Alzheimer's disease and mild cognitive impairment

The 40-Hz steady state response (SSR) reflects early sensory processing and can be measured with electroencephalography (EEG). The current study compared the 40-Hz SSR in groups consisting of mild Alzheimer's disease patients (AD) (n = 15), subjects with mild cognitive impairment (MCI) (n = 20) and healthy elderly control subjects (n = 20). All participants were naïve for psychoactive drugs. Auditory click trains at a frequency of 40-Hz evoked the 40-Hz SSR. To evaluate test-retest reliability (TRR), subjects underwent a similar assessment 1 week after the first. The results showed a high TRR and a significant increase of 40-Hz SSR power in the AD group compared to MCI and controls. Furthermore a moderate correlation between 40-Hz SSR power and cognitive performance as measured by ADAS-cog was shown.The results suggest that 40-Hz SSR might be an interesting candidate marker of disease progression.     

Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer's disease

In Alzheimer's disease (AD), brain lesions are marked by severe neuronal loss and retinal degeneration was previously mentioned in affected patients. Mild cognitive impairment (MCI) is a clinical syndrome that could be an early phase of AD. In this study, using optical coherence tomography (OCT), the retinal nerve fiber layer (RNFL) thickness was assessed in patients with mild AD, moderate to severe AD, amnestic MCI and control subjects. The results show that RNFL thickness is statistically reduced in patients with MCI, mild AD or moderate to severe AD compared to controls. In addition, no statistical difference was found between the results in MCI patients and mild AD patients. The RNFL seems to be involved early during the course of amnestic MCI and OCT tests could be carried out in patients with cognitive troubles.     

Blood pressure variability predicts cognitive decline in Alzheimer's disease patients

The aim of our study was to evaluate whether blood pressure variability influences the rate of cognitive decline in Alzheimer's disease (AD). Two hundred and forty AD patients were periodically evaluated for a 12-month period. The blood pressure (BP) status of each patient was defined through mean and coefficient of variation for both systolic and diastolic BP. Progression of cognitive decline was investigated using the Mini Mental State Examination administered at entry and at the end of follow-up. Among the considered BP indices, only systolic BP variability explained the decrease in the Mini Mental State Examination score after adjustment for confounding variables (multiple linear regression: R² = 0.603, adjusted R² = 0.513; p < 0.001; logistic regression model: odds ratio = 2.882, 95% confidence interval = 1.772–4.495; p < 0.001). The receiver operating characteristic analysis for evaluating the ability of systolic BP variability to predict a faster cognitive decline presented an area under the curve of 0.913 (95% confidence interval = 0.874–0.953; p < 0.001). Our results suggest that BP variability may be added to the list of the potential vascular risk factors and included in the evaluation of AD patients to better define their risk profile.     

Importance of symptomatic cerebral infarcts on cognitive performance in patients with Alzheimer's disease

The coexistence of cerebral infarcts and Alzheimer's disease (AD) is common, but the influence of symptomatic cerebral infarcts on cognition is uncertain in AD. We hypothesize that symptomatic cerebral infarcts may provide an additive cognitive factor contributing to dementia in the AD population. We studied 1,001 clinically probable or possible AD patients in the Alzheimer Disease Research Center (ADRC) database. Linear regression was used to evaluate for an association between symptomatic cerebral infarcts and memory, language, executive function, abstract reasoning, and visuospatial performance, separately. Models were adjusted for covariates including age, gender, education, ethnicity, hypertension, diabetes mellitus, heart disease, clinical dementia rating, the presence of silent cerebral infarcts, and multiplicity or location of infarcts. Clinical history of stroke was present in 107 patients, radiological infarcts in 308 patients, and 68 patients with both were considered to have symptomatic infarcts. Adjusting for all covariates, AD patients with symptomatic infarcts had more impairment of executive function (P < 0.05). The influence of cerebral infarcts is neither general nor diffuse, and the presence of clinical history may have a more important influence on executive performance in AD.     

Somatostatin and cognitive dysfunction in Alzheimer's disease

Multiple research groups have documented reductions in cortical somatostatin‐like immunoreactivity (SRIF) in Alzheimer's disease (AD). This study investigated the relationship between cerebral cortical SRIF levels and concurrent measures of specific neuropsychological functions in early‐to‐middle‐stage AD patients. Biopsy samples obtained from nondominant frontal cortex of 5 patients with histopathologically confirmed AD were assayed for SRIF. Concurrent measures of intelligence, memory, language, visuoperception, visuoconstruction, attention, concentration, reaction time, and overall dementia severity were obtained. Close associations were observed between SRIF and dementia severity, four‐choice visual reaction time, and visuoperceptual and visuoconstructional abilities. No relationship was observed between SRIF and the remaining neuropsychological measures. Results are consistent with the hypothesis that the functional deficits in AD are caused, in large part, by a loss of cortico‐cortical projection neurons and a subsequent dissociation of specific cortical functional areas from one another.     

Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer's disease

Soluble fractalkine plays a distinctive role in the inflammatory processes of the nervous system; however, the role of soluble fractalkine in Alzheimer's disease (AD) has not yet been investigated. In the present study, we evaluated the levels of plasma soluble fractalkine in patients with mild cognitive impairment (MCI), patients with AD and healthy controls. We also investigated the changes in the levels of plasma soluble fractalkine in patients with AD. A total of 102 patients with cognitive impairment, including 51 patients with MCI, 51 patients with AD, and 57 healthy control subjects, were enrolled in this study. The Mini-Mental Status Examination (MMSE) was used to evaluate the severity of cognitive impairment in patients with MCI and AD. The levels of plasma soluble fractalkine were measured using a specific enzyme-linked immunosorbent assay. There were significant group differences in the levels of plasma soluble fractalkine between the MCI, AD, and control groups. Post hoc analyses revealed significant differences between the MCI and control groups, the AD and control groups, and the MCI and AD groups. The level of plasma soluble fractalkine was significantly greater in the patients with mild to moderate AD than in the patients with severe AD. In addition, there was a positive correlation between MMSE score and plasma soluble fractalkine level in the patients with AD. This study provides preliminary evidence that soluble fractalkine is involved in the pathogenesis of AD.     

Effects of a multidisciplinary cognitive rehabilitation program for patients with mild Alzheimer's disease

OBJECTIVE:

To evaluate the effects of a multidisciplinary rehabilitation program on cognition, quality of life, and neuropsychiatric symptoms in patients with mild Alzheimer''s disease.

METHOD:

The present study was a single-blind, controlled study that was conducted at a university-based day-hospital memory facility. The study included 25 Alzheimer''s patients and their caregivers and involved a 12-week stimulation and psychoeducational program. The comparison group consisted of 16 Alzheimer''s patients in waiting lists for future intervention.

INTERVENTION:

Group sessions were provided by a multiprofessional team and included memory training, computer-assisted cognitive stimulation, expressive activities (painting, verbal expression, writing), physiotherapy, and physical training. Treatment was administered twice a week during 6.5-h gatherings.

MEASUREMENTS:

The assessment battery comprised the following tests: Mini-Mental State Examination, Short Cognitive Test, Quality of Life in Alzheimer''s disease, Neuropsychiatric Inventory, and Geriatric Depression Scale. Test scores were evaluated at baseline and the end of the study by raters who were blinded to the group assignments.

RESULTS:

Measurements of global cognitive function and performance on attention tasks indicated that patients in the experimental group remained stable, whereas controls displayed mild but significant worsening. The intervention was associated with reduced depression symptoms for patients and caregivers and decreased neuropsychiatric symptoms in Alzheimer''s subjects. The treatment was also beneficial for the patients'' quality of life.

CONCLUSION:

This multimodal rehabilitation program was associated with cognitive stability and significant improvements in the quality of life for Alzheimer''s patients. We also observed a significant decrease in depressive symptoms and caregiver burden. These results support the notion that structured nonpharmacological interventions can yield adjunct and clinically relevant benefits in dementia treatment.     

Quantitative EEG in Alzheimer's disease: Cognitive state,resting state and association with disease severity

Background

Quantitative electroencephalogram (qEEG) recorded during cognitive tasks has been shown to differentiate between patients with Alzheimer's disease (AD) and healthy individuals. However, the association between various qEEG markers recorded during mnestic paradigms and clinical measures of AD has not been studied in detail.

Objective

To evaluate if ‘cognitive’ qEEG is a useful diagnostic option, particularly if memory paradigms are used as cognitive stimulators.

Methods

This study is part of the Prospective Registry on Dementia in Austria (PRODEM), a multicenter dementia research project. A cohort of 79 probable AD patients was included in a cross-sectional analysis. qEEG recordings performed in resting states were compared with recordings during cognitively active states. Cognition was evoked with a face–name paradigm and a paired-associate word list task, respectively. Relative band powers, coherence and auto-mutual information were computed as functions of MMSE scores for the memory paradigms and during rest. Analyses were adjusted for the co-variables age, sex, duration of dementia and educational level.

Results

MMSE scores explained 36–51% of the variances of qEEG-markers. Face–name encoding with eyes open was superior to resting state with eyes closed in relative theta and beta1 power as well as coherence, whereas relative alpha power and auto-mutual information yielded more significant results during resting state with eyes closed. The face–name task yielded stronger correlations with MMSE scores than the verbal memory task.

Conclusion

qEEG alterations recorded during mnestic activity, particularly face–name encoding showed the highest association with the MMSE and may serve as a clinically valuable marker for disease severity.     

Gender differences in the cognitive impairment in Alzheimer's disease

Summary Introduction: There is evidence for gender differences in cognitive functioning. Men and women with Alzheimer's disease (AD) might also differ in the pattern of cognitive deficits. We hypothesised that gender differences in the cognitive deficits of Alzheimer's disease may be related to pre-existing gender differences in cognitive functioning. Method: The performances of 84 subjects with AD and 438 non-demented elderly, using the structured interview for the diagnosis of dementia of the Alzheimer type, multi-infarct dementia and dementias of other aetiology according to ICD-10 and DSM-III-R (SIDAM), were investigated. Subscores for different cognitive functions were compared between men and women. Confounding variables, i.e. age, degree of cognitive impairment, level of education, presence of lifetime diagnosis of major depression and of recent depressive symptoms, were accounted for by multiple regression analyses. Results: Non-demented elderly women had inferior visuoconstructive skills than men. In agreement, women with Alzheimer's disease also had inferior visuoconstructive skills, but in addition they tended to perform worse in items for intellectual abilities than men. Conclusion: Women seem to have minor weaknesses in spatial thinking compared to men. This may explain the inferior test results of non-demented and demented women in visuoconstructive tasks. However, our data also give some evidence for additional domain specific gender differences of cognitive impairment of AD that could not be observed in non-demented elderly, i.e. inferior test results in items for intellectual abilities in demented women compared with demented men. Gender differences in the neurodegenerative process of AD may add to gender differences in domain specific cognitive impairment. Further research on this topic is needed.     

Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease

Mild cognitive impairment (MCI) is a nosological entity proposed as an intermediate state between normal aging and dementia. MCI seems to represent an early stage of Alzheimer's disease (AD) and there is a great interest in the relationship between MCI and the progression to AD. Some studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment. The aim of the present work was to evaluate the serum levels of some enzymatic antioxidant defences like superoxide dismutase (SOD) and glutathione peroxidase (GPX), as well as lipid peroxidation markers like MDA (malondialdehyde), in MCI and AD patients, compared with age-matched healthy controls. The subjects of this study (45 patients) consisted of 15 individuals with mild cognitive impairment (MCI), 15 with Alzheimer's disease (AD) and 15 healthy age-matched controls. Biochemical analyses showed a similar decrease of the main enzymatic antioxidant defences (SOD and GPX) and increased production of lipid peroxidation marker (MDA) in the serum of the MCI and AD patients, compared to age-matched control group. This study clearly demonstrates that oxidative stress damage occurs in patients with MCI and AD. Moreover, some enzymatic markers of oxidative stress are similar in MCI and AD patients, suggesting that oxidative damage could be one important aspect for the onset of AD.     

Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease

Cognitive dysfunction is one of the most typical characteristics in various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (advanced stage). Although several mechanisms like neuronal apoptosis and inflammatory responses have been recognized to be involved in the pathogenesis of cognitive dysfunction in these diseases, recent studies on neurodegeneration and cognitive dysfunction have demonstrated a significant impact of receptor modulation on cognitive changes. The pathological alterations in various receptors appear to contribute to cognitive impairment and/or deterioration with correlation to diversified mechanisms. This article recapitulates the present understandings and concepts underlying the modulation of different receptors in human beings and various experimental models of Alzheimer's disease and Parkinson's disease as well as a conceptual update on the underlying mechanisms. Specific roles of serotonin, adrenaline, acetylcholine, dopamine receptors, and N-methyl-D-aspartate receptors in Alzheimer's disease and Parkinson's disease will be interactively discussed. Complex mechanisms involved in their signaling pathways in the cognitive dysfunction associated with the neurodegenerative diseases will also be addressed. Substantial evidence has suggested that those receptors are crucial neuroregulators contributing to cognitive pathology and complicated correlations exist between those receptors and the expression of cognitive capacities. The pathological alterations in the receptors would, therefore, contribute to cognitive impairments and/or deterioration in Alzheimer's disease and Parkinson's disease. Future research may shed light on new clues for the treatment of cognitive dysfunction in neurodegenerative diseases by targeting specific alterations in these receptors and their signal transduction pathways in the frontal-striatal, fronto-striato-thalamic, and mesolimbic circuitries.     

PSEN1 polymorphisms alter the rate of cognitive decline in sporadic Alzheimer's disease patients

Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimer's disease (AD), which account for around 5% of AD cases. Genetic associations for the remaining “sporadic” cases, other than the risks associated with the apolipoprotein (APOE) 4 allele are currently not fully established. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in PSEN1 are associated with a modified risk for sporadic AD or a modified disease phenotype. Eight tag SNPs were identified using linkage disequilibrium (LD) data from the International HapMap project providing coverage of the entire PSEN1 gene. These SNPs were investigated for AD susceptibility in a case-control haplotype association study (N = 714) and for genotype-specific effects on cognitive performance in AD patients (N = 169) using non-linear mixed effects modelling. Replication of a mild associated-risk of an intronic PSEN1 polymorphism with AD was achieved (P = 0.03). No other single SNPs or haplotypes were associated with AD risk. However, 3 SNPs were associated with an altered rate of cognitive decline underlining their role as genetic modifiers of disease.