Differential Diagnosis Of Alzheimer's Disease Research Articles

A Comparison of F-18 FDG PET in Differential Diagnosis of Alzheimer's Disease with Parkinsonism and Dementia with Lewy Bodies Disease

have pointed out haemodynamic changes of the medial temporal lobe in 61.11% of 144 TGA patients examined during the acute phase. A follow-up SPECT showed that the lesions disappeared after 12 months. Conclusions: These observations claim that TGA may be considered a complex epiphenomenon, and the sum of the trigger factors can be responsible for this event. Given the good prognosis and the lack of association with organic abnormalities, we advance the hypothesis that TGA may be related to psychological disturbances causing transient alteration in brain metabolism in memory-relevant structures and, consequently, amnesia.

SU‐GG‐I‐158: A Comparison of F‐18 FDG‐PET Imaging in Differential Diagnosis of Alzheimer's Disease with Parkinsonism and Dementia with Lewy Bodies Disease

Purpose: Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD). The aim of this study was to investigate the diagnostic value of metabolism in the diagnosis of DLB and AD in comparison with [F‐18]fluoro‐2‐deoxy‐D‐glucose(FDG)—PET imaging. Investigations which could help improve the accuracy of discrimination between DLB and AD would be a major advance. Methods: All Subjects underwent 18F‐FDG‐PET and MRI. We compared regional cerebral metabolic images by a voxel‐by‐voxel analysis with statistical parametric mapping (SPM) among DLBD, AD and NC subjects, and evaluated differences of hypometabolic regions. All PET scans be visually rated from equivalent slices, each image volume was registered to match a 18F‐FDG‐PET template in standard MNI (Montreal Neurological Institute) space using statistical parametric mapping. Accurate normalization is essential for quantitative pattern analysis to neurodegenerative disease; the cerebellum or pons was often used as a reference region in the MR image, which assumed no significant regional influence of physiological fluctuations for quantitative. Results: 18F‐FDG‐PET revealed evidence of diffuse hypometabolism in both DLBD and AD with Parkinsonism marked declines in association cortices with relative sparing of subcortical structures and primary somatomotor cortex, a pattern reported previously in AD. Unlike AD, DLBD subjects also had hypometabolism in the occipital association cortex and primary visual cortex. Significant changes in hypometabolism in the volume of interest were assessed in the posterior cingulate gyrus, precuneus and parietal cortices. The severity of the decrease in metabolism in AD patients was significantly greater than in vascular dementia and frontotemporal dementia patients and controls. Conclusion: These findings indicate the presence of diffuse cortical abnormalities in DLBD and suggest that FDG‐PET may be useful in discriminating DLBD from AD.

Neurobehavioral differences between Alzheimer's disease and frontotemporal dementia: A meta-analysis

The differential diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) remains a difficult clinical issue. A recent meta-analysis by Hutchinson and Mathias (2007) found that many cognitive tests do not adequately differentiate between these types of dementia. However, their study did not examine the ability of neurobehavioral scales to distinguish between AD and FTD. The data from 33 studies, published between January 1994 and December 2008, examining the neurobehavioral symptoms of persons with AD (N = 2,305) and FTD (N = 971) were therefore analyzed. Weighted Cohen's d effect sizes, percentage overlap statistics, confidence intervals, and fail-safe Ns were calculated for each scale. The most discriminating measures were the Schedules for Clinical Assessment in Neuropsychiatry and the Scale for Emotional Blunting. The Middelheim Frontality Score and the Frontal Behavior Inventory also had excellent discriminative ability, surpassing the cognitive tests examined previously. Numerous other scales additionally showed large and significant differences between the AD and FTD groups, highlighting the importance of assessing neurobehavioral symptoms in this context. While these latter measures may be useful in providing a clinical profile of patients with dementia, greater overlap in the scores of patients with AD and FTD limits their usefulness in the context of differential diagnosis.

Molecular Imaging in Alzheimer’s Disease

The most sensitive and accurate method for molecular imaging in human Alzheimer’s disease (AD) is positron emission tomography (PET). The most widely available PET tracer, which is also used in clinical oncology, is 18F-2-fluoro-2-deoxy-D-glucose (FDG). FDG is an imaging biomarker for early and differential diagnosis of AD. Even higher molecular specificity and sensitivity for detection of AD before dementia onset is provided by high-affinity ligands for fibrillary amyloid. 11C-Pittsburgh Compound B is widely being used in research laboratories, while new 18F-labeled ligands are currently undergoing formal clinical trials as amyloid imaging agents and are expected to become commercially available for clinical use in the near future. A large variety of tracers is being developed and used in dementia research for activated microglia and multiple neurotransmitter systems to study disease pathophysiology, biological correlates of clinical symptoms, and new possibilities for treatment. Current studies in humans are investigating cholinergic, serotonergic, and dopaminergic neurotransmission.

Differential recognition of vascular and parenchymal beta amyloid deposition

By phage display, llama-derived heavy chain antibody fragments were selected from non-immune and immune libraries and tested for their affinity and specificity for beta amyloid by phage-ELISA, immunohistochemistry and surface plasmon resonance. We identified eight distinct heavy chain antibody fragments specific for beta amyloid. While three of them recognized vascular and parenchymal beta amyloid deposits, the remaining five heavy chain antibody fragments recognized vascular beta amyloid specifically, failing to bind to parenchymal beta amyloid. These heavy chain antibody fragments, selected from different libraries, demonstrated differential affinity for different epitopes when used for immunohistochemistry. These observations indicate that the llama heavy chain antibody fragments are the first immunologic probes with the ability to differentiate between parenchymal and vascular beta amyloid aggregates. This indicates that vascular and parenchymal beta amyloid deposits are heterogeneous in epitope presence/availability. The properties of these heavy chain antibody fragments make them potential candidates for use in in vivo differential diagnosis of Alzheimer disease and cerebral amyloid angiopathy. Continued use and characterization of these reagents will be necessary to fully understand the performance of these immunoreagents.

CSF phospho-tau is independent of age, cognitive status and gender of neurological patients

CSF phospho-tau (p-tau(181)) levels have shown good diagnostic utility in differential diagnosis of Alzheimer disease (AD). Unlike total-tau (t-tau), age related changes of this promising biomarker are sparsely studied. The aim of the study was to determine whether p-tau(181) is dependent on age, cognitive status or gender in patients with different neurological diseases who underwent diagnostic lumbar puncture and who had no clinical evidence of neurodegenerative diseases. CSF levels of p-tau(181) and total-tau (t-tau) of 46 neurologic patients (age range 22-89 years; 22 male, 24 female) were analyzed. Clinical diagnoses were cerebral ischaemia (n = 6), multiple sclerosis (n = 13), epileptic seizures (n = 3), polyneuropathy (n = 9) and other neurological diagnoses (n = 15). Cognitive performance was assessed by the German version of the CERAD battery. The mean level of p-tau(181) was in accordance with previous findings in neurological patients (42.8 +/- 15.3 pg/ml) and did not differ between neurological diseases. In contrast to t-tau (r = 0.38; P = 0.009), p-tau(181) did not correlate significantly to age (r = 0.15; P = 0.308). No influence of cognitive status or gender on p-tau(181) levels could be detected. The study corroborates the independence of p-tau(181) from age, cognitive status, gender and a wide spectrum of neurological diseases. The findings suggest that neither age related neurodegenerative processes nor ischaemic or inflammatory processes are accompanied by tau protein phosphorylation. In contrast, the data support the view that p-tau(181) seems to be a sign of the highly AD-specific pattern of tau phosphorylation during formation of neurofibrillary tangles.

Role of neuropsychological assessment in the differential diagnosis of Alzheimer's disease and vascular dementia.

The prevalence of dementia increases significantly from the age of 65 years, doubling every five years thereafter. Alzheimer’s disease (AD) and vascular dementia (VaD) constitute the two main dementia types. Differentiating them encompasses anamnesis, neurological examination, laboratory and neuroimaging exams and neuropsychological assessment. Neuropsychological assessment produces different findings for each dementia type, and reveals those areas most impaired as well as those most preserved. The aim of the present article was to describe the role of neuropsychology in diagnosing dementia and achieving a differential diagnosis between AD and VaD. A general overview follows of the most widely known instruments used to assess cognitive function in dementia, and the cognitive changes seen in AD and VaD. The conclusion drawn was that there is significant overlap in cognitive changes between both these dementia types, while each type has its own specific characteristics which are identifiable and quantifiable on neuropsychological assessments and provide the basis for reaching a differential diagnosis.

The value of quantitative EEG in differential diagnosis of Alzheimer's disease and subcortical vascular dementia

The value of quantitative EEG in differential diagnosis of Alzheimer's disease and subcortical vascular dementia

Pupilometry as a useful functional procedure for differential diagnosis of Alzheimer's disease and vascular dementia

Pupilometry as a useful functional procedure for differential diagnosis of Alzheimer's disease and vascular dementia

Differentiating Alzheimer's Disease From Vascular Dementia With EEG Functional Neuroimaging

Differential diagnosis of Alzheimer's disease (AD) and vascular dementia (VaD) is challenging because early symptoms are similar despite different underlying neuropathology. In previous research, we found that a computerized associative memory task coupled with high resolution EEG measures differentiated mild AD from healthy controls (85% sensitivity, 93% specificity). We extend this functional imaging technique to identify differential diagnostic markers in AD and VaD. Participants included untreated patients newly diagnosed with probable AD (N = 8), VaD (N = 8), and controls (N = 8). Patients were matched for MMSE scores, and all participants were matched for age and gender. Each participant completed a 20minute computerized memory task. Stimuli consisted of simple visual images paired with associatively related auditory words. Participants were required to respond Old or New by button press on each trial. EEG (128 channel) was recorded continuously during the task. We examined ERP components including the N100, P100, N200, P300, P400, P600, a difference wave at 700 ms, and behavioral responses (d'). Each variable was assessed individually using binary logistic regression, and sensitivity and specificity profiles were constructed. Next, the best classifiers were entered into regression analyses in pairs, and then in groups of three. Good discrimination was achieved by several combinations of 2 and 3 variables, with sensitivity ranging from 62% to 87.5%, and specificity from 75% to 87.5%. The best classification between AD and VaD groups was achieved by a centro-parietal N200 amplitude difference combined with the 700ms difference wave (87.5% sensitivity and 87.5% specificity). These same ERP variables also discriminated between VaD patients and controls (75% sensitivity and 75% specificity). The behavioral measure (d' statistic) discriminated between controls and the two patient groups, but not between AD and VaD groups. Despite similarity in early symptoms in AD and VaD, differences in the underlying neuropathology may produce a reliably different signature in the EEG signal. We found that specific combinations of ERP effects generated during a controlled memory test provide good sensitivity/specificity with respect to AD, VaD, and matched controls. Such functional biomarkers may offer a clinically useful aid in differential diagnosis of common forms of dementia.

Amyloid Imaging in Alzheimer’s Disease and Other Dementias

With the advent of new therapeutic strategies aimed at reducing β-amyloid (Aβ) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aβ burden in vivo. Molecular neuroimaging techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid, are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). (11)C-PiB PET has proven useful in the discrimination of dementias, showing significantly higher PiB retention in grey matter of AD patients when compared with healthy controls or patients with frontotemporal dementia. (11)C-PiB PET also appears to be more accurate than FDG for the diagnosis of AD. Despite apparently underestimating the Aβ burden in the brain, (11)C-PiB PET is an optimal method to differentiate healthy controls from AD, matching histopathological reports in aging and dementia and reflecting the true regional density of Aβ plaques in cortical areas. High striatal Aβ deposition seems to be typical for carriers of familial forms of AD, whilst ApoE ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non- ε4 carriers. Characterization of the binding properties of PiB has shown that despite binding to other misfolded proteins in vitro, PiB is extremely selective for Aβ at the concentrations achieved during a PET scan. Aβ burden as assessed by PET does not correlate with measures of cognition or cognitive decline in AD. Approximately 30% of apparently healthy older people, and 50-60% of people with mild cognitive impairment, present with cortical (11)C-PiB retention. In these groups, Aβ burden does correlate with episodic memory and rate of memory decline. These observations suggest that Aβ deposition is not part of normal ageing, supporting the hypothesis that Αβ deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations, coupled with different disease-specific tracers and biomarkers are required not only to confirm this hypothesis, but also to better elucidate the role of Αβ deposition in the course of Alzheimer's disease.

The value of quantitative EEG in differential diagnosis of Alzheimer's disease and subcortical vascular dementia

Objective To investigate whether quantitative EEG may be useful in differential diagnosis of AD and SVD and to determine the correlation between dementia and abnormalities in EEG. Materials and methods The group under study was consisted of 62 patients with AD (mean age: 73.6 yrs; M 51%), 31 with SVD (mean age: 75.2 yrs, M 43%) and a control group of 14 healthy subjects (mean age: 69.5 yrs, M 43%). The patients were divided into subgroups of those with mild, moderate and marked dementia. EEG findings were classified using eight-degree scale according to the presence of slow waves, and then quantitative analysis was carried out by calculating the alpha/slow wave power ratios and the mean frequencies in all and some selected derivations. Results A significant difference between visual EEGs and QEEGs in AD and SVD was found. Only QEEG parameters differed in AD and SVD subgroups with the same degree of cognitive impairment: the mean wave frequencies of waves in temporal derivations in subgroups with mild and moderate dementia and alpha/delta waves power ratio in subgroups with moderate dementia. Conclusions Visual EEGs and QEEGs could be used in addition to the differential diagnosis between AD and SVD, but only selected parameters of QEEG could be useful in differentiating between AD and SVD subgroups with the same degree of dementia.

Voxel-based correlation between coregistered single-photon emission computed tomography and dynamic susceptibility contrast magnetic resonance imaging in subjects with suspected alzheimer disease

Current diagnosis of Alzheimer disease is made by clinical, neuropsychologic, and neuroimaging assessments. Neuroimaging techniques such as magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) could be valuable in the differential diagnosis of Alzheimer disease, as well as in assessing prognosis. To compare SPECT and MRI in a cohort of patients examined for suspected dementia, including patients with no objective cognitive impairment (control group), mild cognitive impairment (MCI), and Alzheimer disease (AD). 24 patients, eight with AD, 10 with MCI, and six controls, were investigated with SPECT using (99m)Tc-hexamethylpropyleneamine oxime (HMPAO, Ceretec; GE Healthcare Ltd., Little Chalsont UK) and dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with a contrast-enhancing gadobutrol formula (Gadovist; Bayer Schering Pharma, Berlin, Germany). Voxel-based correlation between coregistered SPECT and DSC-MR images was calculated. Region-of-interest (ROI) analyses were then performed in 24 different brain areas using brain registration and analysis of SPECT studies (BRASS; Nuclear Diagnostics AB, Stockholm, Sweden) on both SPECT and DSC-MRI. Voxel-based correlation between coregistered SPECT and DSC-MR showed a high correlation, with a mean correlation coefficient of 0.94. ROI analyses of 24 regions showed significant differences between the control group and AD patients in 10 regions using SPECT and five regions in DSC-MR. SPECT remains superior to DSC-MRI in differentiating normal from pathological perfusion, and DSC-MRI could not replace SPECT in the diagnosis of patients with Alzheimer disease.

The early diagnosis and differential diagnosis of Alzheimer’s disease with clinical methods

Alzheimer's disease is a progressive and fatal neurodegenerative disorder in which the novel drugs can slow down the progression in the early phase. Our purpose was to find biological markers, which would detect neuropathology in the prodromal and early phase of Alzheimer's disease. Beside the routine diagnostic methods, neuropsychological test, auditory event related potential and special laboratory tests were performed among subjects with Alzheimer's disease, vascular dementia, mild cognitive impairment and major depression compared to a healthy control group. Visual Paired Associate Learning was impaired in all patient groups, in major depression it seemed to be reversible. In amnestic mild cognitive impairment and in dementia a longer latency of late component of auditory evoked potential, P300, was found. Reduced paraoxonase activity in the serum and increased Nepsilon(gamma-glutamyl)lysine isodipeptide concentration in the cerebrospinal fluid were detected in both dementia groups. Characteristic changes of Visual Paired Associate Learning and P300 might predict the conversion to Alzheimer's disease in mild cognitive impairment. The paraoxonase activity and the isodipeptide concentration can be sensitive markers of the pathomechanism of neurodegeneration. A combined use of the above-mentioned methods can help in the early prediction and diagnosis of Alzheimer's disease.

Memory profiling with paired associate learning in Alzheimer's disease, mild cognitive impairment, and healthy aging.

Mild cognitive impairment (MCI) is associated with increased risk of developing Alzheimer's disease (AD), but up to 40% of cases do not develop AD. Examining a case's specific memory profile may help distinguish which MCI cases will progress to AD: An encoding profile is suggestive of incipient AD, whereas a retrieval profile suggests an alternative etiology. Paired associate learning (PAL) tasks are sensitive for preclinical and early detection of AD, but existing tasks do not enable memory profiling. We developed a novel PAL task enabling the differentiation of memory profiles in 19 people with AD, 17 people with amnestic MCI, and 33 normal elderly controls. Unexpectedly, the AD group demonstrated a retrieval profile for PAL using yes-no recognition, although an encoding profile was evident for forced-choice recognition and for the California Verbal Learning Test--Second Edition (Delis, Kramer, Kaplan, & Ober, 2000). There was considerable heterogeneity within the AD and MCI groups as well as intraindividual discordance for memory profiles. The findings challenge the clinical application of memory profiling in the differential diagnosis of AD, and, by extension, question its potential application in the assessment of MCI.

Neue Perspektiven der Bildgebung in der Diagnostik bei Demenzen

Neuroimaging is an essential part of the etiological diagnosis of dementia. In this review, techniques that enhance the information extracted from routine magnetic resonance imaging (MRI) are presented. In addition, novel techniques of MR acquisition and analyses are reported that may become part of routine diagnostics in the future. These include automated analysis of structural MRI, proton MR spectroscopy, diffusion tensor imaging, perfusion MRI, and functional MRI. From nuclear medicine, the key techniques of fluorodeoxyglucose positron emission tomography (FDG-PET) and dopamine transporter single photon emission computed tomography (SPECT) for early and differential diagnosis of Alzheimer's dementia and Lewy body dementia and the innovation of amyloid PET are presented.

A comparison of 99mTc-exametazime and 123I-FP-CIT SPECT imaging in the differential diagnosis of Alzheimer's disease and dementia with Lewy bodies

The aim of this study is to investigate the diagnostic value of perfusion 99mTc-exametazime single photon emission computed tomography (SPECT) in the diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) in comparison with dopaminergic 123I-2beta-carbomethoxy-3beta-(4-iodophenyl)-n-(3-fluoropropyl) nortropane (FP-CIT) SPECT imaging. Subjects underwent 99mTc-exametazime scanning (39 controls, 36 AD, 30 DLB) and 123I-FP-CIT scanning (33 controls, 33 AD, 28 DLB). For each scan, five raters performed visual assessments blind to clinical diagnosis on selected transverse 99mTc-exametazime images in standard stereotactic space. Diagnostic accuracy of 99mTc-exametazime was compared to 123I-FP-CIT results for the clinically relevant subgroups AD and DLB using receiver operating characteristic (ROC) curve analysis. Inter-rater agreement for categorizing uptake was "moderate" (mean kappa = 0.53) for 99mTc-exametazime and "excellent" (mean kappa = 0.88) for 123I-FP-CIT. For AD and DLB, consensus rating matched clinical diagnosis in 56% of cases using 99mTc-exametazime and 84% using 123I-FP-CIT. In distinguishing AD from DLB, ROC analysis revealed superior diagnostic accuracy with 123I-FP-CIT (ROC curve area 0.83, sensitivity 78.6%, specificity 87.9%) compared to occipital 99mTc-exametazime (ROC curve area 0.64, sensitivity 64.3%, specificity 63.6%) p = 0.03. Diagnostic accuracy was superior with 123I-FP-CIT compared to 99mTc-exametazime in the differentiation of DLB from AD.

The ART of Loss: Aβ Imaging in the Evaluation of Alzheimer’s Disease and other Dementias

Molecular neuroimaging based on annihilation radiation tomographic (ART) techniques such as positron emission tomography (PET), in conjunction with related biomarkers in plasma and cerebrospinal fluid (CSF), are proving valuable in the early and differential diagnosis of Alzheimer's disease (AD). With the advent of new therapeutic strategies aimed at reducing beta-amyloid (Abeta) burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Abeta burden in vivo. Abeta burden as assessed by molecular imaging matches histopathological reports of Abeta plaque distribution in aging and dementia and appears more accurate than FDG for the diagnosis of AD. Abeta imaging is also a very powerful tool in the differential diagnosis of AD from fronto-temporal dementia (FTD). Although Abeta burden as assessed by PET does not correlate with measures of cognitive decline in AD, it does correlate with memory impairment and rate of memory decline in mild cognitive impairment (MCI) and healthy older subjects. Approximately 30% of asymptomatic controls present cortical (11)C-PiB retention. These observations suggest that Abeta deposition is not part of normal ageing, supporting the hypothesis that Abeta deposition occurs well before the onset of symptoms and is likely to represent preclinical AD. Further longitudinal observations are required to confirm this hypothesis and to better elucidate the role of Abeta deposition in the course of Alzheimer's disease.

Amyloid Beta Protein and Tau in Cerebrospinal Fluid and Plasma as Biomarkers for Dementia: A Review of Recent Literature

This review addresses recent developments in amyloid beta (Abeta), total tau (t-tau), and phosporylated tau (p-tau) protein analysis, in cerebrospinal fluid (CSF) and plasma as biomarkers for dementia. Recent research focused on the protection of patients with mild cognitive impairment (MCI) into dementia and the differential diagnosis of Alzheimer's Disease (AD). A combination of Abeta42 and t-tau in CSF can discriminate between patients with stable MCI and patients with progressive MCI into AD or other types of dementia with a sufficient sensitivity and specificity. Regression analyses demonstrated that pathological CSF (with decreased Abeta42 and and increased tau levels) is a very strong predictor for the progression of MCI into AD. Furthermore, CSF measurements of p-tau and Abeta42 can assist in diagnosing vascular dementia or frontotemporal dementia in the differential diagnosis of AD indicated by a reasonable sensitivity and specificity. Whether tau in combination with Abeta42 or in combination with the Abeta37/Abeta42 or Abeta38/Abeta42 ratio aids in the discrimination between AD and Lewy Body dementia remains to be elucidated. Cross-sectional research could not demonstrate significant differences for Abeta40 and Abeta42 in plasma between AD and controls. However, a recently published longitudinal study showed high baseline Abeta40 levels, especially when combined with low baseline Abeta 42 levels, are a strong risk factor for the development of dementia. This emphasizes the importance of performing longitudinal studies in addition to cross-sectional ones. The origin of plasma Abeta and its transport between CSF and plasma, however, needs further clarification. In conclusion, progress has been made regarding Abeta and tau as biomarkers for dementia, both for differentiation between stable MCI and progressive MCI patients and for the differential diagnosis of AD. Future research should aim to validate these recently published results, preferably in pathologically confirmed AD patients. In addition, it is important to standardise research in terms of study design (longitudinal, minimal follow-up period of 5 years), type of researched parameters ( total or p-tau, type of Abeta peptides), type of matrix (CSF and plasma) and data analysis (establishment of predefined cut-off values, type of ratio, type of marker combination).

60. A new tool for differential diagnosis of Alzheimer’s disease, L-DIMENSION

60. A new tool for differential diagnosis of Alzheimer’s disease, L-DIMENSION