Cerebral amyloid PET imaging in Alzheimer’s disease

The devastating effects of the still incurable Alzheimer’s disease (AD) project an ever increasing shadow of burden on the health care system and society in general. In this ominous context, amyloid (Aβ) imaging is considered by many of utmost importance for progress towards earlier AD diagnosis and for potential development of effective therapeutic interventions. Amyloid imaging positron emission tomography procedures offer the opportunity for accurate mapping and quantification of amyloid-Aβ neuroaggregate deposition in the living brain of AD patients. This review analyzes the perceived value of current Aβ imaging probes and their clinical utilization and, based on amyloid imaging results, offers a hypothesis on the effects of amyloid deposition on the biology of AD and its progression. It also analyzes lingering questions permeating the field of amyloid imaging on the apparent contradictions between imaging results and known neuropathology brain regional deposition of Aβ aggregates. As a result, the review also discusses literature evidence as to whether brain Aβ deposition is truly visualized and measured with these amyloid imaging agents, which would have significant implications in the understanding of the biological AD cascade and in the monitoring of therapeutic interventions with these surrogate Aβ markers.     

Cognitive correlates of cortical cholinergic denervation in Parkinson’s disease and parkinsonian dementia

We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer’s disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson’s disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N–[¹¹C]methyl–piperidin–4–yl propionate ([¹¹C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (–20.9%) and PD (–12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005). There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = –0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns). We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning. Supported by grants from the Department of Veterans Affairs, National Institute of Aging (Alzheimer Disease Research Center, AG05133), and The Scaife Family Foundation, Pittsburgh, PA, USA.     

EEG coherence in Alzheimer’s dementia

Summary. In Alzheimers dementia (AD) axonal disruption and cholinergic deficit lead to impaired cortical connectivity and to a decrease in EEG alpha coherence. The aim of the present study was to assess the usefulness of coherence parameters of the EEG for the diagnostics of AD. Quantitative EEG analyses were performed in 31 AD patients and 17 cognitively unimpaired depressive controls, both groups without psychopharmacological treatment. Differences between groups were examined and the diagnostic significance of EEG parameters was assessed by means of stepwise logistic regression analyses. In the AD patients global theta power was increased, left temporal alpha coherence and interhemispheric theta coherence were decreased. Left temporal alpha coherence and global theta power allowed an identification of AD patients with a sensitivity of 87% and a specificity of 77%. Quantitative analyses, especially the determination of left temporal alpha coherence, may enhance the usefulness of the EEG in the diagnostics of AD. Declaration of interest: Eisai GmbH, Frankfurt, supported S.B. in part during the studyReceived March 11, 2002; accepted June 10, 2002     

Mitochondrial dysfunction and cellular metabolic deficiency in Alzheimer’s disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. The pathology of AD includes amyloid-β (Aβ) deposits in neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau, as well as neuronal loss in specific brain regions. Increasing epidemiological and functional neuroimaging evidence indicates that global and regional disruptions in brain metabolism are involved in the pathogenesis of this disease. Aβ precursor protein is cleaved to produce both extracellular and intracellular Aβ, accumulation of which might interfere with the homeostasis of cellular metabolism. Mitochondria are highly dynamic organelles that not only supply the main energy to the cell but also regulate apoptosis. Mitochondrial dysfunction might contribute to Aβ neurotoxicity. In this review, we summarize the pathways ofAβ generation and its potential neurotoxic effects on cellular metabolism and mitochondrial dysfunction.     

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.     

Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia

Similar to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) is characterized by a profound degeneration of cortically-projecting cholinergic neurons of the basal forebrain (BF) and associated depletion of cortical cholinergic activity. We aimed to investigate subregional atrophy of the BF in DLB in vivo and compare it to the pattern of BF atrophy in AD. Structural MRI scans of 11 patients with DLB, 11 patients with Alzheimer’s disease, and 22 healthy controls were analysed using a recently developed technique for automated BF morphometry based on high-dimensional image warping and cytoarchitectonic maps of BF cholinergic nuclei. For comparison, hippocampus volume was assessed within the same morphometric framework using recently published consensus criteria for the definition of hippocampus outlines on MRI. The DLB group demonstrated pronounced and subregion-specific atrophy of the BF which was comparable to BF atrophy in AD: volume of the nucleus basalis Meynert was significantly reduced by 20–25 %, whereas rostral BF nuclei were only marginally affected. By contrast, hippocampus volume was markedly less affected in DLB compared to AD. Global cognition as determined by MMSE score was associated with BF volume in AD, but not in DLB, whereas visuoperceptual function as determined by the trail making test was associated with BF volume in DLB, but not in AD. DLB may be characterized by a more selective degeneration of the cholinergic BF compared to AD, which may be related to the differential cognitive profiles in both conditions.     

Cerebral cortical areas in which thickness correlates with severity of motor deficits of Parkinson’s disease

The pathology of Parkinson’s disease (PD) is not confined to the nigrostriatal dopaminergic pathway, but also involves widespread cerebral cortical areas. Such non-nigrostriatal lesions may contribute to disabling dopa-resistant parkinsonian motor deficits. We performed cortical thickness analysis to identify cerebral cortical brain areas in which thickness correlates with the severity of parkinsonian motor deficits. We performed T1-weighted brain magnetic resonance imaging studies in 142 PD patients. Motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) were measured, and subscores were calculated for bradykinesia, rigidity, tremor, and axial motor deficits. Using FreeSurfer software, we studied cortical areas in which thickness correlates with disease duration or the severity of parkinsonian motor deficits. The cortical thickness of the parieto-temporal association cortex, including the inferior parietal and posterior parietal cortices, showed a negative correlation with disease duration, total UPDRS motor score, and UPDRS subscores for bradykinesia and axial motor deficits. We found no cortical areas in which thickness correlated with subscores for tremor and rigidity. In addition to nigrostriatal dopaminergic deficit, progressive thinning of the parieto-temporal sensory association cortices related to disease duration seems to be related in part to the exacerbation of bradykinesia and the axial motor symptoms of PD.     

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.

     

Prevalence and correlates of cognitive asymmetry in a large sample of Alzheimer’s disease patients

Previous research has suggested that a significant minority of patients with Alzheimer’s disease (AD) exhibit asymmetric cognitive profiles (greater verbal than visuospatial impairment or vice versa) and that these patient subgroups may differ in demographic and other characteristics. Prior studies have been relatively small, and this investigation sought to examine correlates of asymmetry in a large patient sample (N = 438). Patients were classified into the following cognitive profile groups: low verbal, symmetric, and low visuospatial. Consistent with past research, 28.3% of participants were classified as having asymmetric cognitive profiles, with more participants in the low visuospatial subgroup. Low visuospatial participants were younger than members of the other subgroups, and low verbal participants performed worse on a measure estimating premorbid verbal intelligence. Findings regarding apolipoprotein E (ApoE) ε4 genotype were equivocal, although results provided some evidence for an effect of the ?4 allele on cognitive asymmetry. These results suggest systematic differences between neuropsychological asymmetry profiles that support the possibility of distinct subgroups of the disease.     

Progress in Alzheimer’s disease

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.     

Astrocytes in Alzheimer’s disease

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.     

Treatments in Alzheimer’s disease

Journal of Neurology -     

‘Free’ copper in serum of Alzheimer’s disease patients correlates with markers of liver function

Summary Non-ceruloplasmin bound copper (‘free’) seems slightly elevated in Alzheimer’s disease (AD) patients. To test the hypothesis of a correlation between ‘free’ copper and liver function in AD. We evaluated 51 AD patients and 53 controls through typical tests for chronic liver disease (AST, ALT, γ-GT, Albumin, prothrombin time – PT-, bilirubins), along with copper, ceruloplasmin, iron, cholesterol in the serum and apolipoprotein E epsilon4 (APOE4) genotype. Absolute serum copper and ‘free’ copper were higher, albumin was lower and PT longer in AD patients than in controls. ‘Free’ copper correlated negatively with markers of liver function, in that albumin and albumin/PT ratio (r = −0.43, p = 0.004), and positively with direct bilirubin. Copper and ‘free’ copper were higher in the APOE4 carriers. These results suggest that abnormalities in copper metabolism might have an effect on liver function in AD.     

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.