Search

While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimer’s disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60 ± 10 years, range 36–86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Aβ42/Aβ40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by ε4 genotype interactions were found for P-tau231 (β = 1.82; p < 0.05) and IP (β = 1.6; p < 0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in ε4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Aβ changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study. © 2007 Elsevier Inc. All rights reserved.

Objectives—To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) Methods—A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau231), amyloid beta (Aβ) Aβ42/Aβ40 ratio, isoprostane (IP) as well as P-tau231/Aβ42/40 and T-tau/Aβ42/40 ratios. Results—At baseline and at follow-up MCI-AD showed higher levels P-tau231, T-tau, IP, Ptau231/Aβ42/40 and T-tau/Aβ42/40 ratios and lower Aβ42/Aβ40 than MCI-MCI or NL-NL. Baseline P-tau231 best predicted MCI-AD (80%, p

We examined whether cerebral metabolic rates for glucose (CMRglc) on 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) are altered in cognitively normal apolipoprotein E (ApoE) E4 carriers with subjective memory complaints (SMC).Twenty-eight middle-aged normal subjects (NL) were examined, including 13 E4 carriers (E4+; 6 with SMC [SMC+] and 7 without SMC [SMC-]) and 15 noncarriers (E4-; 7 SMC+ and 8 SMC-). Subjects received an FDG-PET scan and a lumbar puncture to measure CSF total (T-Tau) and hyperphosphorylated tau(231) (P-Tau), 40 and 42 amino acid forms of beta-amyloid (Abeta40 and Abeta42), and F(2)-isoprostane (IP).As compared with E4-, E4+ subjects showed decreased CMRglc in AD-related brain regions and associated higher CSF IP, P-Tau, T-Tau, and P-Tau/Abeta42 levels (p's.05). As compared with SMC-, SMC+ subjects showed reduced parietotemporal and parahippocampal gyrus (PHG) CMRglc. A significant ApoE by SMC status interaction was found, with the E4+/SMC+ showing the lowest PHG CMRglc and the highest CSF IP, P-Tau, and P-Tau/Abeta42 levels as compared with all other subgroups (p'sor = .05). The combination of CSF and CMRglc measures significantly improved the accuracy of either measures alone in discriminating ApoE groups (86% accuracy, odds ratio [OR] = 4.1, p.001) and E4+/SMC+ from all other subgroups (86% accuracy, OR = 3.7, p = .005). Parahippocampal gyrus CMRglc was the most accurate discriminator of SMC groups (75% accuracy, OR = 2.4, p.001).Normal E4 carriers with SMC show altered AD-related CSF and FDG-PET measures. Longitudinal studies are needed to assess whether these brain abnormalities foreshadow clinical decline.

Neuroimaging is being increasingly used to complement clinical assessments in the early detection of Alzheimer's disease (AD). Structural magnetic resonance imaging (MRI) and metabolic positron emission tomography (FDG-PET) are the most clinically used and promising modalities to detect brain abnormalities in individuals who might be at risk for AD but who have not yet developed symptoms. The knowledge of established risk factors for AD enabled investigators to develop enrichment strategies for longitudinal imaging studies to reduce the sample sizes and study duration. The present review focuses on the results obtained by MRI and FDG-PET studies that examined the preclinical AD stages in several at risk populations: (1) individuals from families with autosomal dominant early-onset AD (FAD), (2) patients with mild cognitive impairment (MCI), particularly in memory, who are at very high risk for declining to AD with an estimated decline rate of 10-30% per year, (3) normal young and middle-age subjects carriers of known susceptibility genes for late-onset AD such as the Apolipoprotein E (ApoE) E4 allele, and (4) as age is the main risk factor for AD, normal elderly individuals followed to the onset of MCI and AD. Overall, these studies show that the use of imaging for the early detection of AD is successful even in the earlier stages of disease when clinical symptoms are not fully expressed and the regional brain damage may be limited.

The goal of this article is to review the role of structural neuroimaging in the diagnosis of Alzheimer's disease (AD). We present relevant neuroanatomy, highlight progress in the domain of AD imaging, and review the clinical characteristics of the prodromal phase of AD. We describe the history of the diagnostic issue by examining at cross-section and longitudinally the differences between patients who have AD and normal controls. We also present how subsequent works applied these characteristic traits to the early detection of the prodromal disease and to prediction of future decline. The article delineates the differences between subjects who have mild cognitive impairment and AD, which illustrate the spreading of the pathology with disease progression. The last section describes problems encountered in the differential diagnosis.

Background Subjective cognitive impairment (SCI) has been a common, but poorly understood condition, frequently occurring in older persons. Methods The past and the emerging literature on SCI and synonymously named conditions is reviewed. Results Findings include: (1) There is support from at least one longitudinal study for a long-standing concept of SCI as a pre–mild cognitive impairment (MCI) condition lasting ∼15years. (2) There are complex relationships between SCI and depression and anxiety. (3) Differences in SCI subjects from age-matched non-SCI persons are being published in terms of cognitive tests, hippocampal gray matter density, hippocampal volumes, cerebral metabolism, and urinary cortisol levels. Psychometric and dementia test score differences between SCI and MCI subjects have long been evident. (4) Predictive electrophysiologic features of subsequent decline in SCI subjects are being published. Conclusions Studies of therapeutic agents in SCI treatment and resultant Alzheimer's disease prevention appear to be feasible. These trials are also necessary from a public health perspective.

Alzheimer's disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

Background/Aims: Subjective memory complaint (SMC) in normal individuals may predict future cognitive decline. The goal of this study was to examine whether the probability of decline increases with growing intensity of complaint. Methods: Normal subjects over the age of 50 years were included in a longitudinal retrospective study (mean follow-up time = 8 years). All subjects (n = 230) underwent cognitive and medical examination at baseline. The presence of SMC was determined based on Global Deterioration Scale staging. A subgroup of 83 participants also received baseline assessment for the intensity of SMC. Logistic regression was used to predict outcome from baseline variables. Three outcome groups were established at the final visit: nondeclining, declining and diagnostically unstable (i.e. the diagnosis changed over time: from normal to mild cognitive impairment, then back to normal). Results: The presence of SMC was a predictor of future decline but also increased the likelihood of the unstable diagnosis. Increasing intensity of SMC did not further raise the risk for decline. High intensity of complaints and more pronounced affective symptoms predicted the unstable clinical diagnosis. Conclusions: The presence of SMC contributes to the risk of future decline, however, the increasing intensity of the perceived impairment does not further enhance the risk.

The molecular and cellular mechanisms responsible for the etiology and pathogenesis of Alzheimer's disease (AD) have not been defined; however, inflammation within the brain is thought to play a pivotal role. Studies suggest that peripheral infection/inflammation might affect the inflammatory state of the central nervous system. Chronic periodontitis is a prevalent peripheral infection that is associated with gram-negative anaerobic bacteria and the elevation of serum inflammatory markers including C-reactive protein. Recently, chronic periodontitis has been associated with several systemic diseases including AD. In this article we review the pathogenesis of chronic periodontitis and the role of inflammation in AD. In addition, we propose several potential mechanisms through which chronic periodontitis can possibly contribute to the clinical onset and progression of AD. Because chronic periodontitis is a treatable infection, it might be a readily modifiable risk factor for AD.

The goal of this article is to review the role of structural neuroimaging in the diagnosis of Alzheimer's disease (AD). We present relevant neuroanatomy, highlight progress in the domain of AD imaging, and review the clinical characteristics of the prodromal phase of AD. We describe the history of the diagnostic issue by examining at cross-section and longitudinally the differences between patients who have AD and normal controls. We also present how subsequent works applied these characteristic traits to the early detection of the prodromal disease and to prediction of future decline. The article delineates the differences between subjects who have mild cognitive impairment and AD, which illustrate the spreading of the pathology with disease progression. The last section describes problems encountered in the differential diagnosis.

Mood disorders are associated with structural, metabolic and spectroscopic changes in prefrontal regions. In the case of depression associated with stroke, there is little information about the biochemical profile of these regions, as assessed by proton magnetic resonance spectroscopy ((1)H-MRS). In a group of first-ever stroke patients, we studied the association between post-stroke depression and (1)H-MRS measurements in unaffected frontal lobes. Twenty-six patients with a first ischemic stroke located outside the frontal lobes were included in the study. Single voxel proton magnetic resonance spectroscopy ((1)H-MRS) was performed to assess N-acetylaspartate/creatine (NAA)/Cr, glutamate+glutamine (Glx)/Cr, choline (Cho)/Cr and myo-inositol (mI)/Cr ratios. Patients were assessed within the first 10 days after stroke and again four months later. The diagnosis of depression was made on the basis of clinical observation, interview and Hamilton Depression Rating Scale scores. In a group of 26 patients, eight (31%) met criteria for depression at the first assessment, and nine (35%) met criteria for depression at follow-up. Patients with depression in the immediate post-stroke phase had significantly higher Glx/Cr ratios in the contralesional hemisphere than non-depressive patients. No biochemical differences were found between the groups at 4-month follow-up. These findings suggest that post-stroke depression is accompanied by changes in frontal lobe glutamate/glutamine levels, perhaps reflecting abnormalities in glutamatergic transmission in the immediate post-stroke period.

Background Although substantial numbers of stroke patients suffer from apathy, its causes are still poorly understood. Previous studies suggest that dysfunction of the frontal lobes is implicated in the pathophysiology of motivation. Our aim was to investigate the association between proton magnetic resonance spectroscopy (H 1 -MRS) measurements in unaffected frontal lobes and apathy in a group of first-time stroke patients. Methods 31 patients with a first-time ischemic stroke located outside the frontal lobes and 20 healthy subjects were included in the study. The authors performed single voxel H 1 -MRS in order to measure the N -acetylaspartate/creatine (NAA)/Cr, glutamate + glutamine (Glx)/Cr, choline (Cho)/Cr and myo-inositol (mI)/Cr ratios in the frontal lobes. Patients were assessed between days 7 and 12 post stroke. Diagnosis of apathy was made on the basis of clinical observation, interview and Apathy Scale. Results 13 out of 31 patients (42%) demonstrated apathy. Patients with apathy had lower NAA/Cr ratios in the right frontal lobe than non-apathetic subjects. The patient group was divided into two subgroups: Those with left hemisphere strokes, and those with right hemisphere strokes. Of these subjects, significantly lowered NAA/Cr ratios were found in the right hemispheres of apathetic patients in the subgroup with left-sided brain lesions. Conclusions These findings point to the association between apathy and frontal lobe integrity, suggest different reactions of the hemispheres and indicate that changes in the NAA/Cr ratio are related to the apathy.

Genetic factors may play a role in susceptibility to stroke. The angiotensin converting enzyme (ACE) gene is a candidate gene for two phenotypically different types of stroke affecting small perforating arteries: spontaneous intracerebral hemorrhage (SIH) and ischemic stroke due to small vessel disease (SVD). The authors report evidence that ACE gene DD homozygosity of the I/D polymorphism in intron 16 is an independent risk factor for SIH, and not for SVD stroke, in a Polish population.

Dysarthria is a leading disability in ALS patients with motor neurone degeneration in the bulbar region. Although different approaches have been tried in the past, currently, no test is available to detect and follow the progression of dysarthria. We studied 53 patients with definite (n=27) or probable (n=26) ALS (the bulbar onset group n=15, the limb onset group n=38, mean age 53.66/29–76 years/) according to El Escorial criteria. Each patient was seen by a neurologist every 10–12 weeks and clinical performance was assessed using the Norris scale. To evaluate dysarthria we developed a computer-based acoustic method. All patients had computer-analysed speech sound tests done three times. The most significantly affected vowels were selected for further studies. A method based on the Euclidian principle was used and the results were compared with 30 age, sex-matched, healthy control subjects. Our results demonstrated the existence of a specific dysarthria profile in ALS patients with most significantly affected vowels: ‘B’, ‘O’, ‘I’, ‘W’, ‘T’ in the bulbar group, and: ‘B’, ‘I’, ‘T’, ‘W’, ‘O’ in the limb group. This study suggests that it is possible to detect and monitor the progression of the disease based on the acoustic analysis of only several sounds. Abnormalities detected in the dysarthria profile may appear prior to any clinical symptoms of the disease.