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Diagnostic value of FDG-PET and HMPAO-SPET in patients with mild dementia and mild cognitive impairment: Metabolic index and perfusion index
Abstract
The diagnostic potential of F-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (PET) and technetium-99m hexamethylpropylene amine oxime single-photon emission tomography (SPET) in early detection and differential diagnosis of early dementia was evaluated including a comparison of metabolic and perfusion indices (PI).
Twenty-four patients with initial clinical suspicion of beginning dementia were examined, 12 of them with mild cognitive impairment. All patients underwent SPET and PET within 2 weeks. Data were compared with the final clinical diagnosis at follow-up - 9 with Alzheimer's disease (AD), 1 with frontotemporal dementia, 1 with vascular dementia (VD), 7 with mixed type of dementia (MIX) and 6 without any type of dementia. Metabolic indices (MI) and PI were compared with each other. The regional cerebral blood flow difference (rCBFdiff) calculated as local uptake difference between the right and left hemisphere was measured for patients with VD and MIX.
PET showed higher sensitivity and specificity in identifying the different types of early dementia (44--91 and 78--89%, respectively) than SPET (11--64 and 79--89%, respectively), especially in detecting AD (sensitivity 44%, specificity 83%) and MIX (sensitivity 71%, specificity 78%). Especially in patients with mild cognitive impairment, PET was the superior imaging modality for predicting dementia. Using PET, dementia could be excluded in all patients who did not develop dementia during the follow-up. In all patients, a weak correlation between PI and MI was observed (rho=0.64, p<0.002). The rCBFdiff in patients with VD and MIX ranged from 7 to 37%.
In this study on patients with initial suspicion of beginning dementia who underwent both imaging modalities, PET and SPET, PET was the superior imaging method, especially in the detection of early AD or MIX.
... 18 Accepted Article of non-comparative studies have reported higher accuracy for the diagnosis of AD [9]. Headto-head evidence is however limited, with few studies directly comparing the accuracy of CBF-SPECT and 18 F-FDG PET within the same patients [10][11][12][13][14][15][16][17][18][19]. A notable exception is a head-to-head study by O'Brien et al, who compared the accuracy of 18 F-FDG PET and CBF-SPECT amongst three groups of patients; those with AD (n=38), Dementia with Lewy Bodies (DLB, n=30) and healthy controls (n=30) [16]. ...
... The study did not however compare accuracy within a clinically referred cohort of patients; limiting the direct applicability of the results to both clinical practice and health economic modeling. Only two head-to-head studies have examined clinically referred subjects [10,11]. The findings were inconsistent, the sample sizes were small and accuracy was compared to clinical diagnosis despite its inherent limitations. ...
... This feature is relatively unique to our study, with the majority of published papers assessing accuracy between highly selected groups of patients with well-established dementia diagnoses and healthy controls. Only two small studies have directly compared CBF-SPECT and 18 F-FDG PET amongst the true target population of patients clinically referred for the assessment of dementia [10,11]. These studies had a combined total of 79 patients. ...
Background
Clinical diagnosis of Alzheimer's disease (AD) is only 70% accurate. Reduced cerebral blood flow (CBF) and metabolism in parieto‐temporal and posterior cingulate cortex may assist diagnosis. Whilst widely accepted that ¹⁸F‐FDG PET has superior accuracy to CBF SPECT for AD, there is very limited head‐to‐head data from clinically relevant populations and these studies relied on clinical diagnosis as the reference standard.
Aim
To directly compare the accuracy of CBF‐SPECT and ¹⁸F‐FDG PET in patients referred for diagnostic studies in detecting β‐amyloid PET confirmed AD.
Methods
126 patients, 56% with mild cognitive impairment and 44% with dementia, completed both CBF‐SPECT and ¹⁸F‐FDG PET as part of their diagnostic assessment, and subsequently underwent β‐amyloid PET for research purposes. Transaxial slices and Neurostat 3D‐SSP analyses of ¹⁸F‐FDG PET and CBF‐SPECT scans were independently reviewed by five nuclear medicine clinicians blinded to all other data. Operators selected the most likely diagnosis and their diagnostic confidence. Accuracy analysis used final diagnosis incorporating β‐amyloid PET as the reference standard.
Results
Clinicians reported high diagnostic confidence in 83% of ¹⁸F‐FDG PET compared to 67% for CBF‐SPECT (p=0.001). All reviewers showed individually higher accuracy using ¹⁸F‐FDG PET. Based on majority read, the combined AUROC in diagnosing AD was 0.71 for ¹⁸F‐FDG PET and 0.61 for CBF‐SPECT (p=0.02). The sensitivity of ¹⁸F‐FDG PET and CBF‐SPECT was 76% vs 43% (p<0.001), whilst specificity was 74% vs 83% (p=0.45).
Conclusion
¹⁸F‐FDG PET is superior to CBF‐SPECT in detecting Alzheimer's disease amongst patients referred for the assessment of cognitive impairment.
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... In disease states of the central nervous system including dementia, the ability of neurons to take up metabolites such as glucose is impaired. By identifying regions of hypometabolism, functional neuroimaging techniques, including positron emission tomography (PET), can theoretically assist in the clinical evaluation and differentiation of dementia syndromes [1][2][3][4][5]. ...
... A number of PET studies have identified distinct patterns of brain metabolic abnormalities indicative of a disruption of neuronal function in individuals diagnosed with various dementia syndromes, including Alzheimer's disease (AD) [6][7][8]; frontotemporal dementia (FTD( [9][10][11]; vascular dementia (VD) [12]; primary progressive aphasia (PPA) [13,14]; dementia with Lewy bodies (DLB) [15][16][17]; and depression [18,19]. PET studies are therefore increasingly being used as an adjunct in the clinical evaluation of patients with suspected dementia, particularly to aid in early detection [1,17,20], or when a clinical diagnosis is problematic [2,7,16,21,22]. However, the actual sensitivity and specificity of PET in the diagnosis of dementia in young adults with the onset of dementia syndrome prior to the age of 65 years is unclear. ...
... Multiple PET studies have shown that individuals diagnosed with AD demonstrate a characteristic pattern of glucose hypometabolism, and the condition can be distinguished from healthy controls with 93-94% sensitivity and 93-99% specificity [23,24]). The capability of PET to differentiate AD from other types of dementia is more variable, with sensitivity values as high as 93-94% [21,25] but as low as 44% [1], and specificity values ranging from 63 to 80% [1,22,25]. ...
... 176,177,179 Recent longitudinal studies have provided insight into the value of FDG-PET in predicting the progression of MCI. Dobert et al. 187 followed 24 patients with MCI for approximately 18 months after a baseline scan. The scan had a sensitivity of 44% and a specificity of 83% for predicting progression to AD; if the diagnosis of mixed VaD/AD was included, then sensitivity rose to 71% and specificity decreased to 78%. ...
... The scan had a sensitivity of 44% and a specificity of 83% for predicting progression to AD; if the diagnosis of mixed VaD/AD was included, then sensitivity rose to 71% and specificity decreased to 78%. 187 A large longitudinal study of patients over 5 years after a baseline FDG-PET had a sensitivity of 78% and a specificity of 81% for the final clinical diagnosis of dementia. Drzezga et al. 188 followed 22 patients with MCI over 1 year with a baseline and follow-up FDG-PET, neuropsychological test, and MRI. ...
... On the other hand, a methodologically flawed study that evaluated regions of interest from one hemisphere to the other found considerably lower accuracy for both PET and SPECT. 187 Silverman 10 summarized the comparison of PET and SPECT well, noting that the sensitivity and specificity of PET and SPECT have considerable overlap. The application of quantitative analysis greatly enhances both PET and SPECT. ...
As the world population ages, the incidence of dementing illnesses will dramatically increase. The number of people afflicted with dementia is expected to quadruple in the next 50 years. Since the neuropathology of the dementias precedes clinical symptoms often by several years, earlier detection and intervention could be key steps to mitigating the progression and burden of these diseases. This review will explore methods of evaluating, differentiating, and diagnosing the multiple forms of dementia. Particular emphasis will be placed on the diagnosis of mild cognitive impairment-the precursor to dementia. Anatomical imaging; cerebrospinal fluid markers; functional neuroimaging, such as positron emission tomography and single photon emission tomography; and molecular imaging, such as amyloid marker imaging, will be assessed in terms of sensitivity and specificity. Cost will also be a consideration, as the growing population afflicted with dementia represents an increasingly large financial encumbrance to the healthcare systems of every nation. In the face of expensive new markers and limited availability of cyclotrons, single photon emission computer tomography (SPECT) provides relatively high sensitivity and specificity at a comparatively low overall cost.
... Two studies provided 18 F-FDG PET information on the diagnosis of AD and dementia using longitudinal clinical followup assessment as the reference standard ( Table 2). Although no formal description of patient recruitment was provided, one study appeared to consecutively recruit its sample from a primary care center (34). In this study, 24 patients with initial clinical suspicion of mild dementia, 12 of them with mild cognitive impairment, underwent 18 F-FDG PET at baseline, and the final diagnosis was based on variable longitudinal clinical follow-up (average of 16 6 12 mo). ...
... This study reported an 18 F-FDG PET diagnostic sensitivity of 44% for the diagnosis of purely defined AD, with a specificity of 83%, whereas the sensitivity of 18 F-FDG PET for mixed AD and vascular diagnosis dementia was 71%, with a specificity of 78%. However, the sensitivity of 18 F-FDG PET in the diagnosis of AD or mixed AD and vascular dementia versus absence of dementia was 91.7%, with a specificity of 88.9% (34). Using 18 F-FDG PET, progressive dementia was excluded in all 6 patients who did not develop dementia during the follow-up period. ...
... The present review identified a total of 11 subsequent papers that met the stringent review eligibility criteria. These papers included 4 studies using postmortem diagnosis as a gold standard to determine the diagnostic accuracy of 18 F-FDG PET for AD (16,39,41,42), 2 studies using longitudinal clinical assessment of at least 1 y as an acceptable gold standard to determine the diagnostic accuracy of 18 F-FDG PET for AD (34,35), 2 large multicenter studies (42,51), 2 studies from a predominantly primary care setting (34,35), 8 studies using comparison groups that included subjects with other types of dementia or cognitive complaints (16,34,35,39,41,42,51,94), and 3 studies that performed subgroup analyses of the severity of dementia (39,42,88). ...
Imaging that can detect pathophysiologic change in the brain holds great promise for diagnostic assessment of patients with Alzheimer disease (AD) and dementia. Although a previous metaanalysis centering on literature from 1990 to 2000 showed a summary accuracy of 86% for (18)F-FDG PET for AD diagnosis, the clinical value was considered uncertain because of methodologic shortcomings. Review of the recent literature since 2000 demonstrates that the evidence for (18)F-FDG PET in assessment of dementia has increased with new studies that include autopsy confirmation, wide-diagnostic-spectrum recruitment in primary care settings, historical and prospective cohort studies, and multicenter data analyses. These data support the role of (18)F-FDG PET as an effective and useful adjunct to other diagnostic information in the assessment of patients with symptoms of dementia. Findings are in line with recently revised diagnostic criteria of AD that for the first time recognize the unique role of biomarker evidence in disease definition.
... In disease states of the central nervous system including dementia, the ability of neurons to take up metabolites such as glucose is impaired. By identifying regions of hypometabolism, functional neuroimaging techniques, including positron emission tomography (PET), can theoretically assist in the clinical evaluation and differentiation of dementia syndromes [1][2][3][4][5]. ...
... A number of PET studies have identified distinct patterns of brain metabolic abnormalities indicative of a disruption of neuronal function in individuals diagnosed with various dementia syndromes, including Alzheimer's disease (AD) [6][7][8]; frontotemporal dementia (FTD( [9][10][11]; vascular dementia (VD) [12]; primary progressive aphasia (PPA) [13,14]; dementia with Lewy bodies (DLB) [15][16][17]; and depression [18,19]. PET studies are therefore increasingly being used as an adjunct in the clinical evaluation of patients with suspected dementia, particularly to aid in early detection [1,17,20], or when a clinical diagnosis is problematic [2,7,16,21,22]. However, the actual sensitivity and specificity of PET in the diagnosis of dementia in young adults with the onset of dementia syndrome prior to the age of 65 years is unclear. ...
... Multiple PET studies have shown that individuals diagnosed with AD demonstrate a characteristic pattern of glucose hypometabolism, and the condition can be distinguished from healthy controls with 93-94% sensitivity and 93-99% specificity [23,24]). The capability of PET to differentiate AD from other types of dementia is more variable, with sensitivity values as high as 93-94% [21,25] but as low as 44% [1], and specificity values ranging from 63 to 80% [1,22,25]. ...
The aim of this study was to evaluate the diagnostic accuracy of positron emission tomography (PET) using F18 fluorodeoxyglucose (FDG) in the differential diagnosis of early-onset Alzheimer's disease (AD) and other dementias in a community-dwelling population.
A prospective sample of 102 individuals presenting consecutively to a primary care centre for examination of suspected early-onset dementing diseases. The mean age of symptom onset of dementia in our patients was 60.06 +/- 4.28 years (mean +/- 1 SD, 95% lower confidence intervals (CI) 54.75, upper 63.37). Patients were evaluated using standard clinical criteria for the diagnosis of dementia. Functional neuroimaging data was obtained and nuclear medicine physicians blind to the clinical diagnosis generated FDG-PET diagnoses. Final clinical diagnoses based on all available data were then established and compared against PET diagnoses.
Forty-nine patients received a final clinical diagnosis of early-stage AD (MMSE score 20.97 +/- 5.10). There were 29 non-AD demented patients, 11 depressed patients and a miscellaneous group of 13 patients. Among patients with AD, the sensitivity and specificity of FDG-PET was 78% (95% CI: 66-90%) and 81% (95% CI: 68-86%), respectively. The positive likelihood ratio (PLR) for a FDG-PET scan positive for the diagnosis of AD was 4.11 (95% CI: 2.29-7.32) and negative likelihood ratio (NLR) for a negative FDG-PET scan in the absence of AD was 0.27 (95% CI: 0.16-0.46). The pre-test probability was 48% and post-test probability was 79.02%. The specificity of FDG-PET in the differential diagnosis of other dementias, including frontotemporal dementia, was greater than 95%. Recruitment methods in this study provide a sample that may be more representative of patients in the general population and indicate that FDG-PET imaging can contribute to the diagnosis of AD in younger adults with major increases in the positive likelihood rates and post-test probability.
The high specificity of FDG-PET suggests this technique might help in the diagnosis of frontotemporal dementia and other forms of early-onset dementia.
... This result is consistent with the literature [19,20]. As shown in (Fig. 1), however, the reduction level of ePIB was lower than that of dFDG, as reported previously using perfusion single-photon emission tomography (SPECT) [30,31]. Interestingly, the relationships between both images were common in every stage of AD. ...
... An alternative method of describing blood flow from the current data set would be use the arterial input function and modeling derivation of the K1 index, which would be representative of blood flow and initial extraction fraction of the tracer. However, previous studies with 15 O-H 2 O PET/ 18 F-FDG PET [37], blood flow SPECT/ 18 F-FDG PET [30,31], and arterial spin-labeled perfusion MRI/ 18 F-FDG PET [39] validated the similarity between cerebral blood flow and 18 F-FDG PET. Therefore, we considered ePIB as an index of blood flow by showing the similarity between ePIB and dFDG. ...
Background
Amyloid imaging with positron emission tomography (PET) often comes with glucose metabolic imaging in diagnosis of Alzheimer’s disease (AD).
Objective
The present purpose was to explore the clinical valence of early amyloid-β (Aβ) PET scans to determine whether they could substitute for other imaging biomarkers (early and delayed Aβ images of ¹¹C-Pittsburgh compound B (PIB) and ¹⁸F-fluorodeoxyglucose (FDG) images) in the AD spectrum.
Methods
Thirty healthy control subjects, 20 patients with mild cognitive impairment, and 45 patients with AD underwent ¹¹C-PIB and ¹⁸F- FDG PET. Image analyses were performed with three-dimensional stereotactic surface projection and Brodmann’s area regions-of-interest methods. Since early accumulation of PIB (ePIB) reflects blood flow, we classified all subjects according to the level of ePIB in the posterior cingulate gyrus, precuneus, and lateral parietal cortex. We compared the PET parameters (ePIB, delayed-phase PIB accumulation or dPIB, FDG) to determine whether ePIB-based categorization reflected Aβ deposition in a Braak stage-related fashion.
Results
We found that ePIB images were similar to ¹⁸F-FDG images and that the progress of Aβ deposition deduced from the reduction in ePIB index was similar to the pathological progress of Braak staging. A decrease in the ePIB level in the posterior cingulate gyrus, precuneus, and parietal cortex was shown to correspond to greater and wider Aβ deposition in the medial frontal, anterior, and posterior cingulate gyri.
Conclusions
The early-phase ¹¹C-PIB index can be an alternative to the neurogenerative markers of glucose hypometabolism and reflects the Braak stage of Aβ deposition in the living AD brain.
... Dobert examined 24 subjects with suspected early dementia, 12 of which fulfilled criteria for MCI (Dobert et al., 2005). All subjects received FDG-PET and HMPAO-SPECT scans within 2 weeks. ...
... with MCI being a heterogeneous group with variable progression; also, the gold standard autopsy confirmed that studies are difficult because of the often long period between diagnosis and death (Ebmeier, 2010). The only head-to-head study carried out has already been mentioned (Dobert et al., 2005). This included 12 patients with MCI (mini mental state examination 25-28). ...
Perfusion single photon emission computed tomography (SPECT) and 18F fluorodeoxyglucose positron emission tomography (FDG-PET) both have clinical utility for the differential diagnosis of dementia. Although PET is often viewed by some as more accurate and therefore preferential, the extent to which published evidence supports this is not clear. The aim of this review was to address the question by reviewing studies of SPECT and PET imaging in dementia diagnosis, with a particular focus on all published head-to-head studies.
A MEDLINE search was carried out using the following keywords: "PET" and "SPECT" and "dementia" or "Mild Cognitive Impairment," together with "alzheimers" or "DLB" or "lewy body" or "frontotemporal" or "FTD" or "Picks." Articles were included up to February 2013, limited to human studies and in English language.
Published studies of SPECT accuracy show that it is a useful tool for differential diagnosis, with sensitivities of 65-85% for diagnosing Alzheimer's disease (AD) and specificities (for other neurodegenerative dementias) of 72-87%. PET studies generally report higher accuracy, with sensitivities of 75-99% for AD and specificities of 71-93%. However, there have been few direct head-to-head comparisons, with some indicating SPECT and PET to be equally useful in dementia diagnosis and others favouring PET. Many of these studies are limited with respect to numbers and methodically with poorly matched control groups.
Overall, although studies suggest superiority of PET over SPECT, the evidence base for this is actually quite limited. We suggest that further direct comparative studies, including health economic and patient preference evaluations, are needed to help direct future service provision. Copyright © 2013 John Wiley & Sons, Ltd.
... In a study enrolling 197 subjects but sensitivity barely reached 75% [47]. Similar results were obtained in a smaller study comparing SPECT and PET techniques [48]. In a study with 76 MCI patients the converters showed reductions of flow in bilateral temporoparietal areas and precunei in comparison to non-converters with encouraging predictive values [49]. ...
... The experience of PET (Positron Emission Tomography) in MCI patients is limited and the findings are not specific for AD. PET discriminated AD from normality and MCI with only 44% sensitivity and 83% specificity [48]. Metabolic reduction of glucose in the entorhinal cortex predicted cognitive decline in a cohort of 48 normal elderly people as well as temporal neocortex metabolic reductions [72]. ...
Mild Cognitive Impairment is a common condition defined as transitional state between normality and dementia of Alzheimer type. Clinically is characterized by subjective and objective memory loss beyond the expected for age and educational level, although a broad range of cognitive inefficiencies may appear, with preservation of daily living activities. Approximately half the patients convert to dementia within 3 years. Since no all patients convert to dementia it is essential to find reliable predictors so as to start the appropriate treatment as soon as possible.
Extensive Medline-based search for articles dealing with predictors of conversion to dementia in Mild Cognitive Impairment (MCI).
There is a substantial body of literature dealing with predictors of dementia in patients with MCI. These predictors range from a simple delayed recall task on Mini-Mental to sophisticated radiological techniques and CSF biomarkers. Comprehensive neuropsychological tests rarely surpass 70% sensitivity and specificity. The presence of the APOE epsilon 4 allele has been associated with increased risk of conversion but the sensitivity is quite low. CSF biochemical markers are being developed with encouraging results. beta-amyloid 42 protein is usually lower in converters than in people with stable cognitive status and tau protein is higher. The sensitivity is substantial but specificity is so far low. An epitope of tau protein (P231) looks more specific of Alzheimer's disease and therefore a promising biomarker. In the blood, high beta-amyloid protein levels indicate risk of conversion but only a few studies have been published. Hippocampal or entorhinal atrophy on MRI is one of the most used radiological markers of conversion but quantification of atrophy is not simple as it is subject to artifacts and anatomic variations. Proton Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) are emerging as the most promising predictive tools. The highest degree of accuracy (>90%) has been achieved by means of PET plus either memory performance or APOE4 genotype. However, the samples of the published studies are mostly small, and these instruments are not widely available.
There is no enough evidence to recommend specific techniques for predictions. Until an accurate marker is developed, a combined use of cognitive tests, APOE genotype, and a neuroradiological technique is probably the best option for prediction purposes depending on availability and experience.
... Although single photon emission tomography (SPECT) is still used, studies have shown clear superiority of FDG-PET and consequently, SPECT is becoming less utilized in expert centres (Dö bert et al., 2005;Mosconi et al., 2008). PET provides a higher imaging sensitivity by identifying half of the bvFTD cases that remain undetected by MRI techniques (Kerklaan et al., 2014). ...
The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, $50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuro-imaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a 5 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T 1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18 F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening Abbreviations: ALS = amyotrophic lateral sclerosis; bvFTD = behavioural variant of frontotemporal dementia; FTLD = fronto-temporal lobar degeneration; NfL = neurofilament light chain; PPD = primary psychiatric disorders
... Although single photon emission tomography (SPECT) is still used, studies have shown clear superiority of FDG-PET and consequently, SPECT is becoming less utilized in expert centres (Dö bert et al., 2005;Mosconi et al., 2008). PET provides a higher imaging sensitivity by identifying half of the bvFTD cases that remain undetected by MRI techniques (Kerklaan et al., 2014). ...
The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.
... Mosconi et al. [15], Poljansky et al. [50] and Banzo et al. [51] were cross-sectional studies comparing FDG-PET in MCI of uncertain origin versus FTLD patients, whose clinical stage was dementia; Bergeron et al. [52] did not include the target population; and Morbelli et al. [53] did not report diagnostic accuracy. Finally, Döbert et al. [54] did not reach the minimum sample size, nor reported validated measures of test performance. The data extraction table for this PICO is availa b l e a t ( h t t p s : / / d r i v e . ...
Purpose:
We aim to report the quality of accuracy studies investigating the utility of [18F]fluorodeoxyglucose (FDG)-PET in supporting the diagnosis of prodromal Alzheimer's Disease (AD), frontotemporal lobar degeneration (FTLD) and prodromal dementia with Lewy bodies (DLB) in mild cognitive impairment (MCI) subjects, and the corresponding recommendations made by a panel of experts.
Methods:
Seven panellist, four from the European Association of Nuclear Medicine, and three from the European Academy of Neurology, produced recommendations taking into consideration the incremental value of FDG-PET, as added on clinical-neuropsychological examination, to ascertain the aetiology of MCI (AD, FTLD or DLB). A literature search using harmonized population, intervention, comparison, and outcome (PICO) strings was performed, and an evidence assessment consistent with the European Federation of Neurological Societies guidance was provided. The consensual recommendation was achieved based on Delphi rounds.
Results:
Fifty-four papers reported the comparison of interest. The selected papers allowed the identification of FDG patterns that characterized MCI due to AD, FTLD and DLB. While clinical outcome studies supporting the diagnosis of MCI due to AD showed varying accuracies (ranging from 58 to 100%) and varying areas under the receiver-operator characteristic curves (0.66 to 0.97), no respective data were identified for MCI due to FTLD or for MCI due to DLB. However, the high negative predictive value of FDG-PET and the existence of different disease-specific patterns of hypometabolism support the consensus recommendations for the clinical use of this imaging technique in MCI subjects.
Conclusions:
FDG-PET has clinical utility on a fair level of evidence in detecting MCI due to AD. Although promising also in detecting MCI due to FTLD and MCI due to DLB, more research is needed to ultimately judge the clinical utility of FDG-PET in these entities.
... The use of single-photon emission computed tomography is not recommended. 10 More recent diagnostic techniques using biomarkers (including the use of positron emission tomography) are not recommended for routine use. 11 Clinical cognitive assessment should include examination with a screening tool with established reliability and validity. ...
About 9% of Australians aged 65 years and over have a diagnosis of dementia. Clinical practice guidelines aim to enhance research translation by synthesising recent evidence for health and aged care professionals. New clinical practice guidelines and principles of care for people with dementia detail the optimal diagnosis and management in community, residential and hospital settings. The guidelines have been approved by the National Health and Medical Research Council. The guidelines emphasise timely diagnosis; living well with dementia and delaying functional decline; managing symptoms through training staff in how to provide person-centred care and using nonpharmacological approaches in the first instance; and training and supporting families and carers to provide care. © 2016 AMPCo Pty Ltd. Produced with Elsevier B.V. All rights reserved.
... 117 FDG-PET can improve diagnostic accuracy and lead to earlier treatment, better planning for future care, and less suffering and uncertainty for patients and their families. 93,118,119 The addition of FDG-PET to clinical information alone also increases physician confidence in the diagnosis of AD and other neurodegenerative diseases. 93 In healthy individuals, subcortical gray matter, such as the putamen, caudate nucleus, and thalamus, tend to demonstrate relatively high FDG uptake. ...
In this review we present the most recent advances in nuclear medicine imaging as a diagnostic and management tool for dementia. The clinical diagnosis of dementia syndromes can be challenging for physicians, particularly in the early stages of disease. Given the growing number of individuals affected by dementia, early and accurate diagnosis can lead to improved clinical management of patients. Although tests are available for exclusion of certain causes of cognitive impairment, the results rarely allow the clinician to make a definitive diagnosis. For this reason, information obtained from imaging ("imaging biomarkers") is playing an increasingly important role in the workup of patients with suspected dementia. Imaging biomarkers also provide indispensable tools for clinical and preclinical studies of dementing illnesses to elucidate their pathophysiology and to develop better therapies. A wide range of imaging has been used to diagnose and investigate neurodegenerative disorders including structural, cerebral perfusion, glucose metabolism, neurochemical, and molecular imaging. In the first section, we discuss the imaging methods used in clinical practice to diagnose dementia as well as explore additional experimental modalities that are currently used as research tools. In the second section, a comprehensive review covering the myriad aspects of vascular disease as a cause of dementia is presented and illustrated with MRI- and PET-focused case examples. In the third section, advances in imaging Alzheimer disease pathology are emphasized by reviewing current approaches for PET imaging with β-amyloid imaging agents. We provide an outline for the appropriate use criteria for β-amyloid imaging agents in dementia. In addition, the recognition of the importance of neocortical neurofibrillary tangles as related to Alzheimer disease progression has led to the development of promising tau imaging agents such as [18F]T807. The last section provides a history brain trauma as a cause of chronic traumatic encephalopathy. Although the recognition of cognitive deficits from brain trauma dates back to the early part of last century, recent advances in our understanding of the neurobiology has led to the hope of developing molecular imaging methods for earlier diagnoses and treatment. This has become increasingly important given the raised public and physician awareness of the high incidence of this pathology in military conflicts and sports-related injuries. Overall advancements in nuclear medicine imaging have led to an improvement in the detection and accurate identification of dementia and its underlying causes. With both primary and secondary causes of dementia demonstrating often overlapping presentations, nuclear medicine imaging can play a key role not only in the diagnosis but the understanding of dementia. With earlier diagnosis and better understanding comes the hope of improved treatments or possibly someday a cure.
... When FDG-PET disagrees with the clinical diagnosis, the correct pathological diagnosis is in fact more likely to be congruent with FDG-PET than with clinical diagnosis [13,14], whereas incongruent FDG-PET findings were often rated as confusing or useless by the clinicians in our study. However, in FDG-PET studies using clinical diagnosis at longitudinal assessment [32][33][34] or postmortem diagnosis [13,14,20,35], FDG-PET result showed overall high sensitivity and specificity for the different dementing disorders. Moreover, we should emphasize that the goal of the study was not to assess FDG-PET accuracy, which has already been studied (see [7] for a review), but rather evaluating its clinical impact in real-life practice. ...
Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and management following the second FDG-PET were examined. Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34% , led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated ≥12 months after the first one. In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG-PET 12 months later can greatly clarify the diagnosis and improve management.
... Similar results of specific impairments in parietotemporal brain regions and posterior cingulum as seen with 18 F-FDG PET have also been found studying CBF [70][71][72][73]. Both CMRglc and CBF have been suggested to be able to predict conversion from MCI to AD, although 18 F-FDG PET seems to be somewhat superior [74,75]. Studies have also been able to show a clear relationship between CMRglc and CBF [73]. ...
... The capability of the neuroimaging modalities continues to improve, and their role in defining the preclinical state of AD is evolving. Like other biomarkers, accuracy of diagnosis is critical to their continued clinical utility and potential use as part of novel investigative strategies (see Table 2) [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. In the following sections, specific strengths and weaknesses of the current technologies are reviewed. ...
The increasing number of afflicted individuals with late-onset Alzheimer's disease (AD) poses significant emotional and financial burden on the world's population. Therapeutics designed to treat symptoms or alter the disease course have failed to make an impact, despite substantial investments by governments, pharmaceutical industry, and private donors. These failures in treatment efficacy have led many to believe that symptomatic disease, including both mild cognitive impairment (MCI) and AD, may be refractory to therapeutic intervention. The recent focus on biomarkers for defining the preclinical state of MCI/AD is in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment. The ability of biomarkers to adequately define the at-risk state may ultimately allow novel or repurposed therapeutic agents to finally achieve the disease-modifying status for AD. In this review, we examine current preclinical AD biomarkers and suggest how to generalize their use going forward.
... Ishii and colleagues compared F-18-FDG-PET with IMP-SPECT in patients with DLB; reductions of tracer uptake were found in posterior parietal and to a lesser extent in occipital cortex, with PET appearing to be more sensitive to abnormalities [86]. Clinical utility in predicting outcome appears greater for FDG-PET than for SPECT [87,88], although opinions about their respective merits differ [1][2][3]. ...
Although research interest within functional imaging has moved towards applications of MRI, such as BOLD and perfusion imaging, there is a wealth of clinical experience in emission tomographic imaging techniques that make the use of these modalities relevant for the decades to come. This review touches upon the technical and practical issues that distinguish SPECT from PET, describes perfusion and metabolic changes observed in the dementias, compares the clinical utility of the two techniques, and reports data on clinical sensitivity and specificity, as well as diagnostic head-to head comparisons in dementia, and specifically Alzheimer's disease. While few centres have a genuine choice between PET and SPECT, either appears to be good enough to help with the differential diagnosis of dementia in difficult cases.
... Similar results have been obtained in studies of changes in cerebral blood flow (CBF) in AD patients13141516 . Although both CMRglc and CBF have been suggested to be able to predict conversion from MCI to AD, FDG-PET seems to be somewhat superior [17,18]. One study however directly compared the diagnostic accuracy of CMRglc measured with FDG- PET and CBF measured by IMP-SPECT and observed no significant difference between the two measurements in diagnostic accuracy, and the two measurements correlated significantly in the parietotemporal cortex and posterior cingulate cortex/precuneus [16] . ...
Amyloid imaging with positron emission tomography (PET) is presently used in Alzheimer's disease (AD) research. In this study we investigated the possibility to use early frames (ePIB) of the PIB scans as a rough index of CBF by comparing normalised early PIB values with cerebral glucose metabolism (rCMRglc). PIB-PET and FDG-PET were performed in 37 AD patients, 21 subjects with mild cognitive impairment (MCI) and 6 healthy controls (HC). The patients were divided based on their PIB retention (amyloid load) as either PIB positive (PIB+) or PIB negative (PIB-). Data of the unidirectional influx K(1) from a subset of the subjects including 7 AD patients and 3 HC was used for correlative analysis. Data was analysed using regions of interest (ROI) analysis. A strong, positive correlation was observed across brain regions between K(1) and ePIB (r=0.70; p≤0.001). The ePIB values were significantly lower in the posterior cingulate (p≤0.001) and the parietal cortices (p=0.002) in PIB+ subjects compared to PIB-, although the group difference were stronger for rCMRglc in cortical areas (p≤0.001). Strong positive correlations between ePIB and rCMRglc were observed in all cortical regions analysed, especially in the posterior cingulate and parietal cortices (p≤0.001). A single dynamic PIB-PET scan may provide information about pathological and functional changes (amyloidosis and impaired blood flow). This might be important for diagnosis of AD, enrichment of patients in clinical trials and evaluation of treatment effects. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
... Despite controversies as to whether early treatment with currently approved FDA medications could delay or prevent dementia conversion (Gauthier & Touchon, 2005; Petersen & Morris, 2005; Salloway et al., 2004), neuropsychologists are being requested to identify individuals with MCI who are likely to progress to a dementia state. Furthermore, scientific initiatives developing biological (Andreasen & Blennow, 2005; Schoonenboom et al., 2005) and neuroimaging markers of MCI (Chetelat et al., 2005; Dobert et al., 2005; Medina et al., 2005; Meyer, Quach, Thornby, Chowdhury, & Huang, 2005 ) depend on accurate knowledge of cognitive status in order to differentiate normal from impaired populations in a variety of research endeavors. These facts further emphasize the need for normative data that accurately represent individuals of various ages, background and abilities. ...
This study presents normative data of commonly used neuropsychological tests administered to 75 individuals with high levels of intelligence (estimated IQ > or = 120). Participants were living independently in the community with ages ranging from 44 to 86. To avoid including individuals with an incipient dementia, we selected subjects who scored within the normal range on all cognitive tests for at least a two-year period. The norms are presented in table format to help clinicians easily identify a typical cognitive performance in highly intelligent individuals and to provide a useful guide for detecting abnormal cognitive decline in individuals at risk for progressive dementia.
... Such RoIs have been defined in a three-dimensional space array, to involve the entire structure in its complete extension. By assuming that AD pathology relatively spares cerebellum, mean radioactive count for each RoI was then divided by radioactive count of cerebellum, used as reference, to obtain a metabolic semiquantitative index, helpful to make interand intra-subjects comparisons, according to a previously published procedure [11]. ...
One major goal of drug development would be the establishment of biomarkers as objective indicators of normal biological and pathogenetic processes, or pharmacological response to a therapeutic intervention. A potential approach is to investigate proteins in CSF linked to key neuropathological features of Alzheimer's disease (AD). Recently CSF phosphorylated-Tau (p-Tau) levels have been reported to reflect neurofibrillary changes within the brain of patients with AD, however the use of serial CSF investigations in order to monitor the disease progression is not applicable. PET with FDG reveals characteristic patterns in AD patients, however so far no correlation between in vivo metabolic information and pathological features has been reported. In the present study, we tested whether CSF Tau levels correlate with metabolic rate for glucose consumption in a cohort of 28 AD patients. We found a statistically significative correlation between both CSF total and p-TAU protein and relative metabolic indexes obtained from 18FDG-PET scans in parietal, temporal and occipital lobes bilaterally. These results indicate the existence of a correlation between impairment of cerebral metabolism, estimated throughout FDG-PET, and CSF Tau protein levels.
Vascular contributions to cognitive impairment and dementia (VCID) is a spectrum of cognitive deficits caused by cerebrovascular disease, for which insulin resistance is a major risk factor. A major cause of VCID is chronic cerebral hypoperfusion (CCH). Under stress, sustained hypothalamic-pituitary-adrenal axis (HPA) activation can result in insulin resistance. Little is known about the effects of CCH on the HPA axis. We hypothesized that CCH causes sustained HPA activation and insulin resistance. Male rats were subjected to bilateral carotid artery stenosis (BCAS) for 12 weeks to induce CCH and VCID. BCAS reduced cerebral blood flow and caused memory impairment. Plasma adrenocorticotropic hormone was increased in the BCAS rats (117.2 ± 9.6 vs. 88.29 ± 9.1 pg/mL, BCAS vs. sham, p = 0.0236), as was corticosterone (220 ± 21 vs. 146 ± 18 ng/g feces, BCAS vs. sham, p = 0.0083). BCAS rats were hypoglycemic (68.1 ± 6.1 vs. 76.5± 5.9 mg/dL, BCAS vs. sham, p = 0.0072), with increased fasting insulin (481.6 ± 242.6 vs. 97.94± 40.02 pmol/L, BCAS vs. sham, p = 0.0003) indicating BCAS rats were insulin resistant (HOMA-IR:11.71 ± 6.47 vs. 2.62 ± 0.93; BCAS vs. control, p = 0.0008). Glucose tolerance tests revealed that BCAS rats had lower blood glucose AUCs than controls (250 ± 12 vs. 326 ± 20 mg/dL/h, BCAS vs. sham, p = 0.0075). These studies indicate that CCH causes sustained activation of the HPA and results in insulin resistance, a condition that is expected to worsen VCID.
Biomarkers are playing a progressively leading role in both clinical practice and scientific research in dementia. Although amyloid and tau biomarkers have gained ground in the clinical community in recent years, neurodegeneration biomarkers continue to play a key role due to their ability to identify different patterns of brain involvement that sign the transition between asymptomatic and symptomatic stages of the disease with high sensitivity and specificity. Both ¹⁸F-FDG positron emission tomography (PET) and perfusion single photon emission computed tomography (SPECT) have proved useful to reveal the functional alterations underlying various neurodegenerative diseases. Although the focus of nuclear neuroimaging has shifted to PET, the lower cost and wider availability of SPECT make it a still valid alternative for the study of patients with dementia. This review discusses the principles of both techniques, compares their diagnostic performance for the diagnosis of neurodegenerative diseases and highlights the role of SPECT to characterize patients from low- and middle-income countries, where special care of additional costs is particularly needed to meet the new recommendations for the diagnosis and characterization of patients with dementia.
Frontotemporal dementia (FTD) covers a range of heterogeneous neurodegenerative syndromes, predominantly affecting the frontal and temporal lobes (frontotemporal lobar degeneration or FTLD). Most patients present with behavioural deficits, executive dysfunction and language difficulties. FTD presents as clinically recognized subtypes with behavioural manifestation (FTD-b) and primary progressive aphasia (PPA), which can be divided into semantic dementia (SD), progressive nonfluent aphasia (PNFA) and logopenic aphasia (LPA). FTD is a common type of dementia, particularly at younger age. The underlying neuropathological process of FTLD leads to the clinical phenotype and can be characterized roughly in tauopathy (FTD-TAU) and TAR DNA-binding protein (TDP-43) pathology. Genetics is an important causal factor for FTD, and genetic heterogeneity is reflected by the identification of mutations in causative genes. Diagnostic criteria have modest sensitivity, and it may be challenging to differentiate FTD from psychiatric disorders or other types of dementia, especially AD. Advances in molecular imaging have increased the accuracy of FTD diagnosis, and nuclear imaging techniques improve the understanding of the molecular basis of FTD, which is important to develop rational therapies. Although currently no effective treatment is available for FTD, early and correct diagnosis is necessary for adequate clinical management, because of prognostic implications and for genetic counselling.
Objectives: Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) is a longitudinal ongoing study initiated in 2018 that takes place in the Cognitive Disorders Clinic of Aiginition Hospital of the National and Kapodistrian University of Athens. Its aim is to address several research questions concerning the preclinical and prodromal stage of Alzheimer’s disease and explore potential markers for early detection, prediction, and primary prevention of dementia.
Methods: We here present the design and the preliminary baseline characteristics of ALBION. The sample of our study consists of people aged over 50 who are concerned about their memory but are cognitively normal (CN) or have mild cognitive deficits. Each participant undergoes an extensive assessment including several demographic, medical, social, environmental, clinical, nutritional, neuropsychological determinants and lifestyle activities. Furthermore, we are collecting data from portable devices, neuroimaging techniques and biological samples (blood, stools, CSF). All participants are assessed annually for a period of ten years.
Results: In total, 47 participants have completed the initial evaluation up to date and are divided in two groups, CN individuals (N=26) and MCI patients (N=21), based on their cognitive status. The participants are, on average, 64 years old, 46.3% of the sample is male with an average of 12.73 years of education. MCI patients report more comorbidities and have a lower score in the MMSE test. Regarding APOE status, 2 participants are ε4 homozygotes and 10 ε4 heterozygotes. CSF analyses (Aβ42, Τ-tau, P-tau) revealed no differences between the two groups.
Conclusion: The ALBION study offers an opportunity to explore preclinical dementia and identify new and tailored markers, particularly relating to lifestyle. Further investigation of these populations may provide a wider profile of the changes taking place in the preclinical phase of dementia, leading to potentially effective therapeutic and preventive strategies.
Les indications neurologiques de la TEP au 18F-FDG se superposent à celles de la tomographie par émission monophotonique (TEMP) au 99mTc-HMPAO. Les avantages de la TEP par rapport à la TEMP (i.e. quantification absolue, meilleure résolution spatiale, moindre temps d’acquisition) en font une technique d’imagerie fonctionnelle qui tend à remplacer la scintigraphie conventionnelle (TEMP). Devant une franche évolution des pratiques au CHRU de Tours, il semblait pertinent de faire un état des lieux de l’utilisation respective de ces deux examens et notamment de les comparer en termes d’intérêt clinique et de dosimétrie/radioprotection (RP).
Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative syndrome, predominantly affecting the frontal and temporal lobes. Most patients present with behavioural deficits, executive dysfunction and language difficulties. FTD presents as two clinically recognized subtypes: the behavioural manifestation (FTD-b) and primary progressive aphasia (PPA), which can be divided into semantic dementia (SD) and progressive nonfluent aphasia (PNFA). FTD is second to Alzheimer’s disease (AD) as the major cause of young-onset dementia. Neuropathological characteristics of FTD roughly can be divided in tauopathy (FTD-TAU) and ubiquitin pathology (FTD-U). Almost half of FTD occurs familial, and genetic heterogeneity is reflected by the identification of mutations in causative genes. Diagnostic criteria have modest sensitivity, and it may be challenging to differentiate FTD from other types of dementia, especially AD. Functional imaging, especially FDG-PET, improves early diagnosis, and frontotemporal hypometabolism correlates with clinical symptoms. Besides functional markers, nuclear imaging techniques may be helpful to detect specific markers of pathology or deficits of different neurotransmitter systems, depending on degeneration of subcortical nuclei, and may provide valuable insight in the pathophysiology of FTD. Although currently no effective treatment is available for FTD, early and correct diagnosis is necessary for adequate clinical management, because of prognostic implications and for genetic counselling.
Subjective complaints about cognitive deficits are a frequent symptom among the aged population. Accordingly, physicians are regularly confronted with elderly patients describing themselves as cognitively impaired. In this context the term mild cognitive impairment (MCI) defines a syndrome with mild but persistent cognitive deficits which do not yet meet the diagnostic criteria for manifest dementia. According to epidemiological studies MCI is associated with an increased risk to develop Alzheimer's dementia (AD) at follow up. This article reviews current concepts for the diagnosis of MCI as well as its natural course and associated neurobiological findings. The latter ore also relevant to increase the sensitivity and specificity of an early (preclinical) diagnosis of AD. Furthermore, recommendations for a structured diagnostic approach and therapeutic management are given.
The new diagnostic criteria for Alzheimer's disease (AD) acknowledges the interest given to biomarkers to improve the specificity in subjects with dementia and to facilitate an early diagnosis of the pathophysiological process of AD in the prodromal or pre-dementia stage. The current availability of PET imaging biomarkers of synaptic dysfunction (PET-FDG) and beta amyloid deposition using amyloid-PET provides clinicians with the opportunity to apply the new criteria and improve diagnostic accuracy in their clinical practice. Therefore, it seems essential for the scientific societies involved to use the new clinical diagnostic support tools to establish clear, evidence-based and agreed set of recommendations for their appropriate use. The present work includes a systematic review of the literature on the utility of FDG-PET and amyloid-PET for the diagnosis of AD and related neurodegenerative diseases that occur with dementia. Thus, we propose a series of recommendations agreed on by the Spanish Society of Nuclear Medicine and Spanish Society of Neurology as a consensus statement on the appropriate use of PET imaging biomarkers.
Copyright © 2015 Elsevier España, S.L.U. y SEMNIM. All rights reserved.
To objectify and quantify inter- and intra-observer variability of brain 18-FDG PET-CT interpretation in the context of cognitive and functional impairment amongst the elderly.
25 patients underwent brain 18-FDG PET-CT for investigation of dementia/MCI and frail elderly patients. Three observers interpreted studies in two forms: standardised datasets reconstructed by an outside observer and individualised reconstructions. Observers graded regional 18-FDG uptake in 11 brain areas and gave overall impressions on studies as pathological/normal. One observer repeated this process following a 3-month interval. The Kappa statistic was used to calculate inter- and intra-observer agreement on grading of regional 18-FDG uptake and overall impressions of studies as pathological/normal.
Moderate inter-observer agreement was observed across standardised and individualised dataset reconstructions when 11 regional brain areas were compared cumulatively and overall impressions on studies were given as pathological vs normal. Higher levels of inter-observer agreement were found when comparing high versus low grading of regional uptake and when reporting standardised reconstructions. Intra-observer agreement between standardised vs individualised dataset reconstructions were moderate-to-fair across 11 brain regions cumulatively. Temporal intra-observer agreement of individualised dataset reconstructions comparing normal vs pathological opinions showed strong agreement (κ = 0.884 [95 % CI 0.662; 1.000)].
Despite a strong agreement in final diagnosis, this study demonstrates a moderate inter- and substantial intra-observer reproducibility in reporting brain 18-FDG PET-CT. Such results suggest that the visual analysis approach is different between nuclear physicians but leads to the same final diagnosis.
The purpose of this study was to clarify the concordance of diagnostic abilities and interobserver agreement between (18) F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and brain perfusion single photon-emission computed tomography (SPECT) in patients with Alzheimer's disease (AD) who were diagnosed according to the research criteria of the National Institute of Aging-Alzheimer's Association Workshop.
Fifty-five patients with "AD and mild cognitive impairment (MCI)" (n = 40) and "non-AD" (n = 15) were evaluated with (18) F-FDG PET and (99m) Tc-ethyl cysteinate dimer (ECD) SPECT during an 8-week period. Three radiologists independently graded the regional uptake in the frontal, temporal, parietal, and occipital lobes as well as the precuneus/posterior cingulate cortex in both images. Kappa values were used to determine the interobserver reliability regarding regional uptake.
The regions with better interobserver reliability between (18) F-FDG PET and (99m) Tc-ECD SPECT were the frontal, parietal, and temporal lobes. The (99m) Tc-ECD SPECT agreement in the occipital lobes was not significant. The frontal, temporal, and parietal lobes showed good correlations between (18) F-FDG PET and (99m) Tc-ECD SPECT in the degree of uptake, but the occipital lobe and precuneus/posterior cingulate cortex did not show good correlations. The diagnostic accuracy rates of "AD and MCI" ranged from 60% to 70% in both of the techniques.
The degree of uptake on (18) F-FDG PET and (99m) Tc-ECD SPECT showed significant correlations in the frontal, temporal, and parietal lobes. The diagnostic abilities of (18) F-FDG PET and (99m) Tc-ECD SPECT for "AD and MCI," when diagnosed according to the National Institute of Aging-Alzheimer's Association Workshop criteria, were nearly identical. Copyright © 2014 John Wiley & Sons, Ltd.
This paper describes the guideline for perfusion brain imaging with SPECT-technique published by the Association of the Scientific Medical Societies in Germany (AWMF).The purpose of this guideline is to provide practical assistance for indication, examination procedures, findings and their interpretation also reflecting the present state of the art. Information and instruction are given regarding indication, preparation of the patients and examination procedures of brain perfusion SPECT, including preparation and quality control of the tracer as well as the radiation dosimetry, technical performance of image acquisition with the gamma-camera and image processing. Also advices for interpretation of findings are given. In addition, possible pitfalls are described.
In 2009, the diagnosis of Alzheimer's disease remains difficult. None of the clinical, biological or imaging approaches is itself sufficient to reach it. Despite the fact that the clinical approach remains essential, new neuro-imaging techniques have recently been developed (structural, metabolic, molecular or functional) to better diagnose this disease but also to try to decipher its pathophysiology. In this review we will highlight the recent developments of these neuro-imaging tools and consider how they can help to make a precise and early diagnosis of Alzheimer's disease.
Molecular imaging might address two different aspects of dementia management: the early and etiologic diagnosis of the neurodegenerative disease causing the troubles, and the follow-up and treatment evaluation of the disease. Tracers available for these different purposes target either specific processes, such as the presence of beta amyloid in the case of Alzheimer disease, or processes that relate to the global functional state of the brain. Benefits and disadvantages of these different tracers vary according to the function of the goals pursued.
The concept of mild cognitive impairment (MCI) stems from an appreciation of the gradual cognitive decline experienced by individuals with a slowly progressive degenerative dementia. Alzheimer's disease (AD) is the most common cause of dementia recognized today. The term “MCI” was first used to describe the cognitive state of individuals with mild subjective and objective deficits in cognition that have minimal impacts on daily function as defined by a Global Deterioration Scale (GDS) score of three. In 1986, the National Institutes of Mental Health convened a workgroup on age-related changes in memory and developed the concept of age-associated memory impairment (AAMI). Clinical criteria for MCI are (1) a memory complaint, preferably corroborated by an informant; (2) objective evidence for memory impairment; (3) normal general cognitive function; (4) intact activities of daily living; and (5) not demented. Once the clinical subtype of MCI has been determined, then the etiology of the clinical syndrome can be evaluated. MCI has become an extremely important area of investigation in the field of aging and dementia. Research on MCI has included various areas: epidemiology, clinical diagnoses, neuropsychology, neuroimaging, neuropathology, mechanism of disease, and treatment.
The goal of the present chapter is to provide an overview of the major findings from studies of neuroimaging in dementia,
particularly from patients with Alzheimer’s disease (AD). The major emphasis is on findings from a variety of imaging modalities
and the use of these measures for early diagnosis and as biomarkers of disease progression. In this chapter, we first describe
the basic neurobiological changes and clinical symptoms associated with AD and related cognitive decline. Next, we discuss
results from studies in AD utilizing structural neuroimaging techniques, including computerized tomography (CT), traditional
structural magnetic resonance imaging (MRI), and other MRI techniques [diffusion tensor imaging (DTI), perfusion MRI, magnetic
resonance spectroscopy (MRS)]. Next, we explore findings from functional MRI studies, including task-related activation studies
and resting and functional connectivity research. We, then, discuss results from the use of nuclear medicine techniques in
AD, including single-photon emission computerized tomography (SPECT) and positron emission tomography (PET) studies. Neuroimaging
in other dementias is also briefly discussed, with particular emphasis on differential diagnosis of dementia type. Finally,
we explore future directions for neuroimaging of early AD and dementia.
This chapter describes mild cognitive impairment (MCI) as a degree of cognitive impairment, which is abnormal for a given individual, and yet is insufficient to warrant a diagnosis of dementia. The chapter explains that the diagnosis of MCI requires only a subjective complaint of cognitive deterioration and some objective evidence of cognitive impairment on standardized neurocognitive testing. MCI has been included in the American academy of neurology practice parameters as a clinical entity worthy of recognition, in that it carries increased risk of symptom progression to dementia, and gives patients and physicians better insight into the presence or absence of underlying disease. The chapter identifies patients who may be most benefited by therapeutics aimed at slowing the biochemical processes that give rise to neurodegeneration. If such therapeutics is shown to be effective, the diagnosis of mild cognitive impairment stands to become one of the most vital to both individuals and to society at large.
The boundary between vascular dementia and Alzheimer disease (AD) continues to be unclear. Some posit that gradually progressive vascular dementia, as with small vessel disease, is simply vascular disease plus AD. Because AD presents a characteristic pattern on fluorodeoxyglucose positron emission tomography, we sought to determine whether the fluorodeoxyglucose pattern of vascular dementia resembled more AD or the pattern in nondemented patients with severe microvascular brain disease.
Vascular disease patients were selected on the basis of confluent white matter lesions on both hemispheres. Among them, with a similar degree of vascular disease on MRI, neuropsychological testing separated groups with dementia and without dementia. Patients with AD and healthy controls were also studied. The 4 groups, with 12 subjects each, were matched by age, gender, and educational level. Fluorodeoxyglucose distribution was analyzed using both voxel-based and volume of interest methods.
The AD group had the characteristic pattern of bilaterally decreased metabolism in parieto-temporal association cortex and precuneus. By contrast, patients with vascular disease and dementia had a similar anatomic pattern to that of the vascular patients without dementia, but with greater metabolic abnormalities, particularly in the frontal lobes and deep nuclei.
The anatomy of metabolic abnormalities in vascular disease with dementia suggests that, at least in some cases, dementia with vascular disease may be independent of AD. The metabolic abnormality involves the thalamus, caudate, and frontal lobe, a pattern concordant with the neuropsychological findings of impaired executive function characteristic of vascular dementia.
The aim of this study was to map metabolic compensation and depression in Alzheimer's disease (AD) on a voxel-by-voxel basis.
Twenty-one healthy elderly subjects and 25 AD patients underwent cerebral MR and FDG-PET imaging. All images were processed with SPM2, and whole-brain gray matter (GM) atrophy and hypometabolism maps were computed. Metabolic compensation and depression were assessed using Biological Parametric Mapping software.
GM atrophy and hypometabolism mapped to similar regions, with varying degrees of severity. Significant metabolic compensation was found in the amygdala, while exceeding hypometabolism was mainly located in the posterior cingulate cortex.
Metabolic depression can be due to both distant effects of atrophy and to additional hypometabolism-inducing factors, such as amyloid deposition. Conversely, metabolic compensation could reflect spared synaptic plasticity of the surviving neurons. The investigation of the metabolic compensation mechanism could help in the comprehension of the AD underlying pathology.
The introduction of biological markers in the clinical management of Alzheimer's disease (AD) will not only improve diagnosis relating to early detection of neuropathology with underlying molecular mechanisms, but also provides tools for the assessment of objective treatment benefits. In this review, we identify a number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy of AD, and hold promise as meaningful biomarkers in the early diagnostic process, as well as for the tracking of disease-modifying pharmacological effects. These neurobiological measures appear to relate closely to pathophysiological, neuropathological, and clinical data, such as hyperphosphorylation of tau, abeta metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, and functional and cognitive decline, as well as risk of future decline. As a perspective, the important role of biomarkers in the development of innovative drug treatments for AD and the related regulatory process is discussed.
Long-term studies will be pivotal in order to examine the efficacy of preventive and early therapeutic interventions during the preclinical phase of dementia. Biomarkers will be of importance due to the large sample sizes and the necessary logistic efforts, high drop-out rates and slow clinical progression. The validity of functional and even structural imaging methods is currently investigated with early and promising results; it is presently unclear whether conventional csf-markers of Alzheimer's disease (beta-amyloid and tau-proteins) are sufficiently sensitive to monitor the effects of early interventions. It also remains doubtful whether modifications of these methods will ever be useful and available for practical purposes.
The purpose of this study was to evaluate and compare the diagnostic ability of 2-[(18)F]-fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography (PET) and N-isopropyl-p-(123)I iodoamphetamine single photon emission computed tomography (IMP-SPECT) using three-dimensional stereotactic surface projections (3D-SSP) in patients with moderate Alzheimer's disease (AD).
FDG-PET and IMP-SPECT were performed within 3 months in 14 patients with probable moderate AD. Z-score maps of FDG-PET and IMP-SPECT images of a patient were obtained by comparison with data obtained from control subjects. Four expert physicians evaluated and graded the glucose hypometabolism and regional cerebral blood flow (rCBF), focusing in particular on the posterior cingulate gyri/precunei and parietotemporal regions, and determined the reliability for AD. Receiver operating characteristic (ROC) curves were applied to the results for clarification. To evaluate the correlation between two modalities, the regions of interest (ROIs) were set in the posterior cingulate gyri/precunei and parietotemporal region on 3D-SSP images, and mean Z-values were calculated.
No significant difference was observed in the area under the ROC curve (AUC) between FDG-PET and IMP-SPECT images (FDG-PET 0.95, IMP-SPECT 0.94). However, a significant difference (P < 0.05) was observed in the AUC for the posterior cingulate gyri/precuneus (FDG-PET 0.94, IMP-SPECT 0.81). The sensitivity and specificity of each modality were 86%, and 97% for FDG-PET and 70% and 100% for IMP-SPECT. We could find no significant difference between FDG-PET and IMP-SPECT in terms of diagnosing moderate AD using 3D-SSP. There was a high correlation between the two modalities in the parietotemporal region (Spearman's r = 0.82, P < 0.001). The correlation in the posterior cingulate gyri/precunei region was lower than that in the parietotemporal region (Spearman's r = 0.63, P < 0.016).
Variants of the apolipoprotein E allele appear to account for most cases of late-onset Alzheimer's disease, and persons with two copies of the epsilon 4 allele appear to have an especially high risk of dementia. Positron-emission tomography (PET) has identified specific regions of the brain in which the rate of glucose metabolism declines progressively in patients with probable Alzheimer's disease. We used PET to investigate whether these same regions of the brain are affected in subjects homozygous for the epsilon 4 allele before the onset of cognitive impairment.
Apolipoprotein E genotypes were established in 235 volunteers 50 to 65 years of age who reported a family history of probable Alzheimer's disease. Neurologic and psychiatric evaluations, a battery of neuropsychological tests, magnetic resonance imaging, and PET were performed in 11 epsilon 4 homozygotes and 22 controls without the epsilon 4 allele who were matched for sex, age, and level of education. An automated method was used to generate an aggregate surface-projection map that compared regional rates of glucose metabolism in the two groups.
The epsilon 4 homozygotes were cognitively normal. They had significantly reduced rates of glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as in previously studied patients with probable Alzheimer's disease. They also had reduced rates of glucose metabolism in additional prefrontal regions, which may be preferentially affected during normal aging.
In late middle age, cognitively normal subjects who are homozygous for the epsilon 4 allele for apolipoprotein E have reduced glucose metabolism in the same regions of the brain as in patients with probable Alzheimer's disease. These findings provide preclinical evidence that the presence of the epsilon 4 allele is a risk factor for Alzheimer's disease. PET may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease.
Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined.
To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia.
Positron emission tomography (PET) studies of [(18)F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000.
Regional distribution of [(18)F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses.
Progressive dementia was detected by PET with a sensitivity of 93% (191/206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P<.001).
In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur.
Young normal subjects, old normal subjects, and patients with senile dementia of the Alzheimer's type (SDAT) were studied with both computed tomography (CT) and positron emission transaxial tomography (PETT). Increases in ventricular size with both aging and disease were measured. Regional glucose metabolic rate was not affected by age, but was markedly reduced in SDAT patients. These data indicate that in normal aging, structural brain changes may be more salient than biochemical changes. Although both structural and biochemical changes occur in SDAT, the biochemical changes are more marked. The results suggest that PETT is potentially more useful than CT in the in vivo diagnosis of SDAT.Keywords: Key Words:; Computed tomography; Global Deterioration Scale; Hemispheric glucose metabolic rate; Pearson product-moment correlations; Positron emission transaxial tomography; Senile dementia of the Alzheimer's type.
Unlabelled:
Hexamethylpropyleneamine oxime (HMPAO) SPECT and 18F-FDG PET depict similar aspects of perfusion and metabolic abnormalities in Alzheimer's disease (AD), but the correspondence between them is not known in detail. We therefore used statistical parametric mapping to detect and compare abnormal brain areas objectively and quantitatively.
Methods:
Twenty-six patients with probable AD (mean age +/- SD, 66 +/- 9 y; mean Mini-Mental State Examination score, 22.5 +/- 4.2) and 6 nondemented healthy volunteers (mean age, 63 +/- 11 y) were studied with HMPAO SPECT and 18F-FDG PET. All images underwent the same processing steps, including 12-mm gaussian smoothing, spatial normalization, and z transformation with respect to normal average and SD. Thresholding of z maps was used to detect abnormal voxels.
Results:
The overall correlation between PET and SPECT across the entire brain was significant but not close (average r = 0.43). The best correspondence was found in the temporoparietal and posterior cingulate association cortices. There, the number of abnormal voxels for PET correlated strongly with the number for SPECT (r = 0.90 at a z threshold of -2.25), but tracer uptake reductions were significantly more pronounced for PET than for SPECT. Discordant findings were most frequently seen in the temporobasal and orbitofrontal areas (PET low, SPECT high) and in the cerebellum, parahippocampal cortex, and midcingulate cortex (PET high, SPECT low). The correlation between dementia severity and the number of abnormal voxels was closer for PET than for SPECT. Separation of patients from healthy volunteers by counting the number of abnormal voxels was possible over a much wider range of z thresholds with PET than with SPECT.
Conclusion:
Correspondence between 18F-FDG PET and HMPAO SPECT is limited to the main finding of temporoparietal and posterior cingulate functional impairment in mild to moderate AD. The distinction between healthy volunteers and patients is less sensitive to threshold selection with PET than with SPECT, and findings in the frontal, temporobasal, and temporomesial cortices and in the cerebellum may differ between the 2 techniques.
SPECT studies of regional cerebral perfusion with a high-resolution system were compared to PET studies of regional cerebral glucose utilization (rCMRglc) in 21 patients with probable Alzheimer's disease (AD). Ten normal subjects were also evaluated with SPECT and 10 with PET.
rCMRglc (for PET) and counts (for SPECT) in the associative cortices were normalized to the average rCMRglc, and counts in the calcarine cortex and basal ganglia were considered as a "reference area" to obtain a ratio. The ratio differences between patients and controls were tested with ANOVA performed separately for PET and SPECT.
The difference between probable AD patients and controls was significant for both PET (p < 0.00001) and SPECT (p < 0.005); this difference was significant for the frontal, temporal and parietal cortices (p < 0.0001) for PET, and for the temporal (p < 0.005) and parietal (p < 0.001) cortices for SPECT. Temporo-parietal defects were detected in all subjects with PET and in 90% with SPECT.
PET and SPECT are able to detect characteristic temporo-parietal abnormalities in probable AD. However, the presence of abnormalities in other associative areas is better evaluated with PET.
The aim of this SPECT study was to determine the initial abnormality and longitudinal changes in regional cerebral blood flow (rCBF) in early Alzheimer's disease (AD) using statistical parametric mapping (SPM).
rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer SPECT in 32 patients complaining of mild cognitive impairment, with a Mini-Mental State Examination score more than 24 at the initial study, and 45 age-matched healthy volunteers. All patients satisfied the diagnostic criteria of AD during the follow-up period of at least 2 y. Follow-up SPECT studies were performed on the patients at a mean interval of 15 mo. We used the raw data (absolute rCBF parametric maps) and the adjusted rCBF images of relative flow distribution (normalization of global cerebral blood flow [CBF] for each subject to 50 mL/100 g/min with proportional scaling) to compare these groups with SPM.
In the baseline study, the adjusted rCBF was significantly and bilaterally decreased in the posterior cingulate gyri and precunei of patients compared with healthy volunteers. In the follow-up study, selected reduction of the adjusted rCBF was observed in the left hippocampus and parahippocampal gyrus. These areas showed the most prominent reduction in absolute rCBF on each occasion. Moreover, further decline of the absolute rCBF was longitudinally observed in extensive areas of the cerebral association cortex.
SPM analysis showed the characteristic early-AD rCBF pattern of selective decrease and longitudinal decline, which may be overlooked by a conventional region-of-interest technique with observer a priori choice and hypothesis. This alteration in rCBF may closely relate to the pathophysiologic process of this disease.
The purpose of this study was to confirm with pathologic verification 2 beliefs related to Alzheimer's disease (AD): (a) the long-standing impression that bilateral temporo-parietal hypometabolism, as noted on FDG PET imaging, is the metabolic abnormality associated with Alzheimer's disease (AD) and (b) that the sensitivity, specificity, and diagnostic accuracy of the metabolic pattern of bilateral temporo-parietal hypometabolism allows differentiation between other degenerative causes of dementia.
Twenty two individuals (8 women, 14 men) with difficult-to-characterize memory loss or dementia (using standard clinical criteria), and who eventually received pathologic confirmation of diagnosis, were evaluated. FDG PET brain scans were obtained and visually graded by an experienced nuclear medicine physician as to the presence of classic bilateral temporo-parietal hypometabolism as seen in Alzheimer's type dementia. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the metabolic pattern of bilateral temporo-parietal hypometabolism were determined using pathologic diagnosis as the gold standard.
The clinical diagnosis of possible or probable AD was determined as the primary cause of dementia in 12 patients. The sensitivity and specificity of the clinical diagnosis for probable AD were 63% and 100%, respectively. The sensitivity and specificity of the clinical diagnosis for possible and probable AD were 75% and 100%, respectively. The sensitivity, specificity, and diagnostic accuracy of bilateral temporo-parietal hypometabolism being associated with AD were 93%, 63%, and 82%, respectively.
This study confirms that bilateral temporo-parietal hypometabolism is indeed the classic metabolic abnormality associated with AD. Furthermore, in individuals with dementia whose FDG PET scans indicated a metabolic pattern other than bilateral temporo-parietal hypometabolism, a cause of dementia other than AD should be suspected. These observations may be of clinical importance in differentiating dementia syndromes. The sensitivity, specificity, and diagnostic accuracy of FDG PET are acceptable as tests to be used in the evaluation of dementia and particularly to confirm the clinical suspicion of AD.
It is well established that regional cerebral metabolic rates for glucose assessed by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia.
The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg/100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study.
The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p</=0.005 and 80% power in a 1-year, double-blind, placebo-controlled treatment study.
These findings indicate that brain metabolism as assessed by FDG PET during mental rest is a sensitive marker of disease progression in Alzheimer's disease over a 1-year period. These findings also support the feasibility of using FDG PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease.
Neuropathological evidence suggests that the earliest changes in Alzheimer's disease selectively affect the parahippocampal regions of the brain. This study was conducted to determine if otherwise healthy elderly subjects with mild cognitive impairment had structural volume deficits affecting the parahippocampal gyrus.
Magnetic resonance imaging (MRI) was used to compare global and regional brain volumes in 21 subjects with mild cognitive deficits defined according to the criteria for aging-associated cognitive decline, 22 cognitively intact comparison subjects, and 12 patients with Alzheimer's disease.
Compared with the cognitively intact subjects, the subjects with aging-associated cognitive decline had a significantly smaller mean volume of the right parahippocampal gyrus. The subjects with aging-associated cognitive decline had a mean parahippocampal volume that was intermediate between that of the Alzheimer's disease patients and that of the cognitively intact subjects.
Parahippocampal atrophy underlies the observed cognitive deficits in aging-associated cognitive decline. These findings support the hypothesis that aging-associated cognitive decline represents a preclinical stage of Alzheimer's disease.
To clarify the olfactory deficit hypothesis regarding Alzheimer's disease, the authors compared olfactory function in patients with Alzheimer's disease, subjects with mild cognitive impairment, and healthy comparison subjects.
Olfactory function of 14 patients with mild Alzheimer's disease, eight subjects with mild cognitive impairment, and eight healthy age-matched comparison subjects was assessed with both psychophysical tests and olfactory event-related potentials.
Group comparison of the psychophysical test results showed a significant main effect of diagnosis for odor detection threshold, odor discrimination, and odor identification. These results correlated only partially with those obtained from olfactory event-related potentials. Seven Alzheimer's disease patients and four with mild cognitive impairment showed no olfactory event-related potentials, suggesting hyposmia, while all comparison subjects had clearly discernible responses. Patients with Alzheimer's disease were significantly more likely to be nonresponders. In the four Alzheimer's disease patients and four subjects with mild cognitive impairment who had clear electrophysiological responses, amplitudes and latencies of the various event-related potential components were normal, i.e., similar to those of the comparison subjects, although 12 of the 14 Alzheimer's disease patients and seven of the eight mildly impaired subjects were classified as functionally anosmic with psychophysical methods.
The electrophysiological results confirm prior findings of olfactory dysfunction in patients with Alzheimer's disease and preclinical Alzheimer's disease. Investigations of larger study groups with detailed cognitive examination and postmortem diagnosis may resolve the intriguing possibility of early diagnosis and discrimination of Alzheimer's disease subtypes through chemosensory event-related potentials in addition to existing biomarkers.
Zusammenfassung
Ziel der vorliegenden Untersuchung war es, zu prüfen, ob die HMPAO-SPECT zur Differenzierung zwischen der Demenz vom Alzheimer-Typ (DAT) und der Major Depression (MD) beitragen kann. Es wurden ECT-Befunde von 77 Patienten mit Gedächtnisstörungen beurteilt, davon hatten 48 eine DAT und 29 eine MD. Zunächst wurden die Defekte in der SPECT einer Hirn-Region zugeordnet und der Grad der Ausprägung (-1/-2/-3) bewertet. Anschließend wurden die einzelnen Befunde in eine von 7 Befundkategorien eingeordnet. In einigen dieser 7 Gruppen ergaben sich deutliche Häufungen der Fälle mit DAT bzw. MD. 35% aller DAT-Patienten wiesen bilaterale Defekte mit deutlicher (>-1) parietaler/parietotemporaler Minderperfusion auf, dagegen zeigte kein Patient mit MD dieses Muster. Unilaterale Defekte wiesen 62% der MD-, aber nur 31% der DAT-Patienten auf. Die Untersuchung zeigt, daß nur 35% der Patienten mit DAT das bislang als »pathognomonisch« bezeichnete Befundmuster aufwiesen. Dieses Perfusionsmuster kann aber - wenn es vorliegt - als sicheres Kriterium zur Abgrenzung gegen eine MD gewertet werden. Darüber hinaus lassen sich keine eindeutigen (»krankheitstypischen«) Perfusionsmuster erkennen, wenngleich unilaterale Defekte mehr auf eine MD hindeuten.
One of the main issues in clinical psychology deals with the documentation and control of therapeutic effects. Especially if we try to measure of the effects of drugs expected to influence cognitive performance, we sometimes find conditions that restrict the application of psychometric tests as they exist in general psychology.
Criteria for the diagnosis of vascular dementia (VaD) that are reliable, valid, and readily applicable in a variety of settings are urgently needed for both clinical and research purposes. To address this need, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of VaD. Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features. These criteria are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible). They await testing and validation and will be revised as more information becomes available.
In a prospective study of more than 200 cases of dementia and 119 controls, annual technetium-99mnon-ADAlzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the DiagnosticandStatisticalManualofMentalDisorders (3rd ed., rev.; DSM-III-R) criteria, and all histopathological diagnoses according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Early data from this cohort have suggested that the combination of both MTL atrophy seen on CT with parietotemporal hypoperfusion on SPECT may predict the pathology of AD. The diagnostic sensitivity, specificity, accuracy, and positive and negative predictive values of the NINCDS-ADRDA and DSM-III-R criteria could be assessed in this cohort against the gold standard of histopathology. The diagnostic potential of CT evidence of MTL atrophy alone, SPECT evidence of parietotemporal hypoperfusion alone, and the combination of both of these scan changes in the same individual could then be compared against the diagnostic accuracy of clinical operational criteria in the pathologically confirmed cases. Furthermore, all of these modalities could be compared with the diagnostic accuracy of apolipoprotein E4 (Apo E4) genotyping to predict AD in the histopathologically confirmed cohort. In this population, NINCDS was 100% specific, 49% sensitive, and 66% accurate; was only 61% specific, but 93% sensitive and 77% accurate; and the combination of both and possible-ADnon-AD” dementias later in the course of the disease suggests the concept of medial temporal lobe dementia. This could explain some of the overlap of clinical profiles in the dementias, particularly as the dementia progresses, making clinical differential diagnosis difficult. In this context, the use of SPECT can significantly enhance specificity.
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.
Normative data were collected in a study population of 150 randomly selected elderly subjects. Using the SIDAM (Structured Interview for the Diagnosis of Dementia of the Alzheimer Type, multi-infarct dementia, and dementias of other etiology according to DSM-III-R and ICD-10), both the dimensional and the categorical aspects of dementia and "mild cognitive impairment" are considered. With the SIDAM score (SISCO) [range 0 (minimum)-55 (maximum, no cognitive impairment)] and the SIDAM Mini-Mental State Examination (MMSE) (range 0-30), appropriate cutoffs for the category of DSM-III-R and ICD-10 dementia and "mild cognitive impairment" were defined. MMSE scores of 0-22 were found to be indicative of DSM-III-R and ICD-10 dementia. For "mild cognitive impairment," MMSE scores ranged from 23-27 according to a DSM-III-R definition (ICD-10: 23-28). An MMSE score of 22 or less was found to differentiate between DSM-III-R/ICD-10 dementia and "mild cognitive impairment," with a specificity of 92% (ICD-10: 95.6) and a sensitivity of 96% (ICD-10: 96%). With the SIDAM-based DSM-III-R/ICD-10 diagnoses of dementia as the criterion, the SISCO was 97.3% specific (ICD-10: 99%) and 94% sensitive (ICD-10: 94%) in detecting dementia. A SISCO of 0-33 was highly indicative of DSM-III-R and ICD-10 dementia. For "mild cognitive impairment," a SISCO between 34-47 (ICD-10: 34-51) was found. The SISCO covers a broader range of cognitive functions than the MMSE and is more useful in detecting even very mild cognitive decline. Furthermore, the newly defined category of "mild cognitive impairment" could be validated successfully by means of GDS Stages 2-3 and CDR Stage 0.5. These findings confirm the value of the SIDAM as a short diagnostic instrument for measurement and diagnosis of dementia and "mild cognitive impairment."
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed brief, comprehensive, and reliable batteries of clinical and neuropsychological tests for assessment of patients with the clinical diagnosis of Alzheimer's disease (AD). We administered these batteries in a standardized manner to more than 350 subjects with a diagnosis of AD and 275 control subjects who were enrolled in a nationwide registry by a consortium of 16 university medical centers. The tests selected for this study measured the primary cognitive manifestations of AD across a range of severity of the disorder, and discriminated between normal subjects and those with mild and moderate dementia. The batteries also detected deterioration of language, memory, praxis, and general intellectual status in subjects returning for reassessment 1 year later. Interrater and test-retest reliabilities were substantial. Long-term observations of this cohort are in progress in an effort to validate the clinical and neuropsychological assessments and to confirm the diagnosis by postmortem examinations. Although information on validation is limited thus far, the CERAD batteries appear to fill a need for a standardized, easily administered, and reliable instrument for evaluating persons with AD in multicenter research studies as well as in clinical practice.
Twenty-one patients with a clinical diagnosis of dementia of the Alzheimer's type (DAT) and 29 healthy, age-matched controls were studied using positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose to measure regional cerebral glucose consumption in the resting state. Reductions in ratio measures of relative metabolism in some parietal, temporal, and frontal regions were found in mild, moderate, and severe DAT groups. A significant increase in right/left metabolic asymmetry, particularly in parietal regions, also was seen in mild and moderate groups. Only in the severely demented patients was the absolute cerebral metabolic rate reduced significantly from control values. Fourteen patients had repeated PET studies, but only those patients with moderate to severe dementia showed a decline in IQ over 6 to 15 months. There were no significant changes in metabolic measures over time. PET is useful in quantifying regional cerebral dysfunction in DAT, even in the early stages of the disease.
Accurate clinical staging of dementia in older subjects has not previously been achieved despite the use of such methods as psychometric testing, behavioural rating, and various combinations of simpler psychometric and behavioural evaluations. The Clinical Dementia Rating (CRD), a global rating device, was developed for a prospective study of mild senile dementia--Alzheimer type (SDAT). Reliability, validity, and correlational data are discussed. The CRD was found to distinguish unambiguously among older subjects with a wide range of cognitive function, from healthy to severely impaired.
Cognitive decline associated with old age and consistent with the diagnosis of primary degenerative dementia is a unique clinical syndrome with characteristic phenomena and progression. The authors describe a Global Deterioration Scale for the assessment of primary degenerative dementia and delineation of its stages. The authors have used the Global Deterioration Scale successfully for more than 5 years and have validated it against behavioral, neuroanatomic, and neurophysiologic measures in patients with primary degenerative dementia.
Positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose (FDG) demonstrates a typical pattern of impairment of regional metabolic rates of glucose (rCMRGlu) in most patients with a clinical diagnosis of probable Alzheimer's disease (AD): reduction of rCMRGlu in temporo-parietal association cortex, more variably also in prefontal cortex, but relative preservation of primary visual and sensoriomotor cortex, striatum, and cerebellum. Apart from early stages, both hemispheres are affected, but pronounced asymmetries may be present. With the exception of Parkinson's disease with dementia, the complete pattern is rarely seen in other dementing conditions, which usually lead to more global, frontal or multifocal metabolic impairment. Severity of dementia is mainly correlated with temporo-parietal rCMRGlu reduction, probably irrespective of the cause of dementia, and the neuropsychological profile is related to the asymmetry of metabolic alterations. Procedures are available for assessment of the typical pattern that yield comparable results in different laboratories, and have a high accuracy for discrimination between normals and probable AD. Diagnostic accuracy is better for presenile than for senile dementia of Alzheimer type, and for moderate to severe cases than for mild dementia. A definitive judgment of the diagnostic value of FDG PET in AD is hindered by the lack of sufficient data with diagnosis confirmed at autopsy.
The aim of the present study was to see whether HMPAO-SPECT may contribute to the differentiation between dementia of the Alzheimer type (DAT) and major depression (MD). The results in 77 patients with memory impairment were evaluated. 48 patients suffered from DAT and 29 from MD. Initially, the defects in SPECT imaging were attributed to a cerebral region and the degree of decrease was evaluated (-1/-2/-3). Thereafter, the results were classified by 7 categories. In some of these categories an accumulation of cases of either DAT or MD was found. 35% of the patients suffering from DAT had bilateral defects with distinct (> -1) parietal/parietotemporal hypoperfusions, but no patient with MD showed this perfusion pattern. 62% of the patients with MD had unilateral defects but only 31% of the patients with DAT. The present study demonstrates that only 35% of all patients suffering from DAT show a perfusion pattern, thought earlier as "pathognomonic" for this disease. This perfusion pattern--if it exists--may be used as a safe criterion to exclude MD. Beyond that no clearcut ("specific") perfusion pattern may be recognized but unilateral defects point to MD.
Single photon emission computed tomography (SPECT) of regional cerebral blood flow (RCBF) has been employed experimentally in the assessment of patients with dementia. The standard with which the SPECT diagnosis has been compared previously has been the initial clinical diagnosis. Recognizing that histopathologic diagnosis would be a more reliable standard, the authors compared SPECT diagnoses and clinical diagnoses with histopathologic diagnoses in a series of 18 patients who had been referred by the Alzheimer Disease Research Center. SPECT RCBF studies were carried out prospectively in 15 patients with an inhaled xenon-133 SPECT technique and in three patients with technetium-99m hexamethyl-propylene-amine oxime and triple-camera-scanner SPECT. When compared with histopathologic diagnosis, clinical diagnosis was correct in 15 of 18 patients; visual scanning diagnosis, in 13 of 18; and Xe-133-SPECT diagnosis based on quantitative ratios in regions of interest, in 14 of 15 (13 of 13 with Alzheimer disease).
The accurate clinical diagnosis of degenerative cortical brain disorders is a necessary prerequisite for patient management and the critical evaluation of new treatments. This study has evaluated the ability of single photon emission tomography (SPET) to differentiate between Alzheimer's disease (AD) and different forms of non-Alzheimer lobar atrophy (LA), using a multi-purpose system in widespread routine clinical use. 99mTc-HMPAO SPET was carried out in patients with AD and three clinical syndromes associated with LA: frontotemporal dementia (FTD), progressive non-fluent aphasia (PA) and semantic dementia (SD). Principal component (PC) analysis was performed on regional cerebral blood flow (rCBF) data and inter-group comparisons were performed for PC scores using multiple t-tests. Three PCs explained 86.5% of the variation in rCBF values between individual patients and normal controls. The first PC reflected the average rCBF value and separated patient groups from normal controls but failed to distinguish between patient groups. The second PC reflected anterior-posterior asymmetry and separated AD from all three forms of LA. This PC also separated FTD and SD from controls but failed to distinguish between FTD, PA and SD. The third PC reflected left-right asymmetry and separated PA from all other groups. 99mTc-HMPAO SPET is able to differentiate between degenerative cortical brain disorders in a simple and physiological meaningful way, thereby showing considerable potential as a routine tool in the clinical evaluation and differentiation of AD and LA.
To evaluate single photon emission computed tomographic (SPECT) imaging of regional cerebral blood flow in the diagnosis of Alzheimer disease (AD) and the differential diagnosis of the dementias.
Regional cerebral blood flow SPECT was performed with inhaled xenon-133 in 261 patients and with injected technetium-99m hexamethyl-propyleneamine oxime (HMPAO) in 162 patients with possible dementia. In 16 patients, both agents were used in 1 day. SPECT images obtained in elderly healthy control subjects (with Xe-133 in 15, with Tc-99m HMPAO in 14) were available. In each patient without AD, further classification of disease was attempted. Histopathologic correlation was available in 54 patients (with autopsy in 51, with biopsy in three).
SPECT diagnoses were true-positive in 37, true-negative in eight, false-positive in three, and false-negative in six patients. Sensitivity was 86% (37 of 43; 95% confidence limits = .72, .95); specificity, 73% (eight of 11; confidence limits = .39, .94); positive predictive value, 92% (37 of 40; confidence limits = .80, .98); and negative predictive value, 57% (eight of 14; confidence limits = .29, .82).
Regional cerebral blood flow SPECT may assist in the early and late diagnoses of AD and in the differential-diagnosis of the dementias when there is a complicated or confusing clinical picture.
The aim of the present study was to investigate neuropsychological functions in dementia of the Alzheimer type (DAT) with respect to morphological changes that were revealed by quantitative magnetic resonance imaging (MRI).
Twenty patients with DAT (NINCDS-ADRDA criteria) and 10 healthy age and sex matched controls were included. The neuropsychological function was evaluated on a test battery covering the severity of dementia, verbal and visual memory, concentration and attention, language skills and general intelligence as well as activities of daily living. 3D MRI sequences were acquired using a 1.5 T Siemens MAGNETOM. Whole brain volume, total intracranial volume (TIV), volume of the frontal and temporal lobes and volumes of the amygdalahippocampus complex (AHC) were assessed using the newly developed software NMR Win.
Apart from TIV all morphometric parameters differed significantly between the diagnostic groups. AHC volumes discriminated best between the groups, with only a small overlap. AHC atrophy exceeded generalized atrophy. These findings were confirmed when the data were reanalysed after dividing the DAT patients into a mildly and moderately affected group. The severity of dementia was significantly correlated with the volumes of the AHC and the volumes of the temporal lobes bilaterally, but not with the whole brain volume and the volumes of the frontal lobes.
These results underline the important role of the temporal substructures for aetiology and progression of DAT. They indicate that the volume of the AHC can be monitored by MRI and may be used to follow up the disease process.
This study investigated cerebral glucose metabolism in very early Alzheimer's disease, before a clinical diagnosis of probable Alzheimer's disease is possible, using [18F]fluorodeoxyglucose positron emission tomography. First, 66 patients with probable Alzheimer's disease with a spectrum of dementia severity (Mini-Mental State Examination score, 0-23) were recruited and studied. Cortical metabolic activity was analyzed topographically using three-dimensional stereotactic surface projections. Regression analysis was performed for each brain pixel to predict metabolic patterns of very early disease. Predictions were tested prospectively in a group of 8 patients who complained only of memory impairment without general cognitive decline (Mini-Mental State Examination score, 25 +/- 1) at the time of scanning but whose condition later progressed to probable Alzheimer's disease. Both results were compared to cerebral metabolic activity in 22 age-similar normal control subjects. Prediction and analysis of actual patients consistently indicated marked metabolic reduction (21-22%) in the posterior cingulate cortex and cinguloparietal transitional area in patients with very early Alzheimer's disease. Mean metabolic reduction in the posterior cingulate cortex was significantly greater than that in the lateral neocortices or parahippocampal cortex. The result suggests a functional importance for the posterior cingulate cortex in impairment of learning and memory, which is a feature of very early Alzheimer's disease.
In a prospective study of more than 200 cases of dementia and 119 controls, annual technetium-99m-hexamethyl-propylene amineoxime (99mTc-HMPAO) single-photon emission computed tomography (SPECT) and annual medial temporal lobe (MTL) oriented X-ray computed tomography (CT) have been used to evaluate the diagnostic potential of functional and structural neuroimaging in the differential diagnosis of dementia. Some subjects have had up to 7 annual evaluations. So far, of 151 who have died, 143 (95%) have come to necropsy. Histology is known for 118, of whom 80 had Alzheimer's disease (AD), 24 had other "non-AD" dementias, and 14 controls with no cognitive deficit in life also had no significant central nervous system pathology. To compare the findings in the dementias with the profile of structural and functional imaging in the cognitively normal elderly, scan data from 105 living, elderly controls without cognitive deficit have also been included in the analysis. All clinical diagnoses were according to National Institute of Neurological and Communicable Disease and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; DSM-III-R) criteria, and all histopathological diagnoses according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Early data from this cohort have suggested that the combination of both MTL atrophy seen on CT with parietotemporal hypoperfusion on SPECT may predict the pathology of AD. The diagnostic sensitivity, specificity, accuracy, and positive and negative predictive values of the NINCDS-ADRDA and DSM-III-R criteria could be assessed in this cohort against the gold standard of histopathology. The diagnostic potential of CT evidence of MTL atrophy alone, SPECT evidence of parietotemporal hypoperfusion alone, and the combination of both of these scan changes in the same individual could then be compared against the diagnostic accuracy of clinical operational criteria in the pathologically confirmed cases. Furthermore, all of these modalities could be compared with the diagnostic accuracy of apolipoprotein E4 (Apo E4) genotyping to predict AD in the histopathologically confirmed cohort. In this population, NINCDS "probable-AD" was 100% specific, 49% sensitive, and 66% accurate; "possible-AD" was only 61% specific, but 93% sensitive and 77% accurate; and the combination of both "probable-AD" and "possible-AD" was 61% specific, 96% sensitive, and 85% accurate. DSM-III-R criteria were 51% sensitive, 97% specific, and 66% accurate. In the same cases and including the 105 living, elderly controls, the diagnostic accuracy of the Oxford Project to Investigate Memory and Aging (OPTIMA) scanning criteria showed CT alone to be 85% sensitive, 78% specific, and 80% accurate; SPECT alone had 89% sensitivity, 80% specificity, and 83% accuracy; and the combination of the two was 80% sensitive, 93% specific, and 88% accurate. The Apo E4 genotype was 74% sensitive but yielded 40% false positives in the histologically confirmed series. The diagnostic accuracy afforded by this method of CT and SPECT used alone is better than that of any established clinical criteria and reveals that the combination of MTL atrophy and parietotemporal hypoperfusion is common in AD, much less common in other dementias, and rare in normal controls. In the NINCDS-ADRDA criteria "possible-AD" cases, the combination of CT and SPECT findings alone were better in all diagnostic indices than the presence of Apo E4 alone in predicting AD. The frequent occurrence of MTL atrophy in AD and also in other "non-AD" dementias later in the course of the disease suggests the concept of medial temporal lobe dementia. This could explain some of the overlap of clinical profiles in the dementias, particularly as the dementia progresses, making clinical differential diagnosis difficult. In this context, the use of SPECT can significantly e
To determine whether the hypometabolism observed in PET images of patients with Alzheimer's disease (AD) is due entirely to brain atrophy.
Reduced brain glucose metabolism in AD patients measured using PET has been reported by numerous authors. Actual glucose metabolic values in AD may be reduced artificially because of brain atrophy, which accentuates the partial volume effect (PVE) on data collected by PET.
Using segmented MR images, we corrected regional cerebral metabolic rates for glucose for PVEs to evaluate the effect of atrophy on uncorrected values for brain metabolism in AD patients and healthy control subjects.
Global glucose metabolism was reduced significantly before and after correction in AD patients compared with controls. Before PVE correction, glucose metabolic values in patients were lower than in control subjects in the inferior parietal, frontal, and lateral temporal cortex; in the posterior cingulate; and in the precuneus. These reductions remained significantly lower after PVE correction, although in the posterior cingulate the difference in metabolism between AD patients and control subjects lessened. Regional glucose metabolism of these areas with PVE correction was lower in moderately-severely demented patients than in mildly demented patients.
Reduced glucose metabolism measured by PET in AD is not simply an artifact due to an increase in CSF space induced by atrophy, but reflects a true metabolic reduction per gram of tissue.
Regional cerebral perfusion measured by single photon emission computed tomography (SPECT) was examined as a preclinical predictor of the development of Alzheimer's disease (AD).
Singular value decomposition was used to produce 20 SPECT factors (known as vectors) (n=152). Vector scores were then computed for four groups (n=136), differing in cognitive status: Group 1--normal controls at both baseline and follow-up; Group 2--subjects with "questionable" AD at both baseline and follow-up; Group 3--subjects with questionable AD at baseline who converted to AD on follow-up (Converters); Group 4--subjects with AD at baseline. All SPECT data in the analyses were gathered at baseline.
The four groups could be distinguished on the basis of their baseline SPECT data (p < or = 0.00005; hit rate=83%). Regional decreases in perfusion were most prominent among Converters in the hippocampal-amygdaloid complex, the posterior cingulate, the anterior thalamus, and the anterior cingulate. Inclusion of apolipoprotein E status did not significantly improve the discrimination.
SPECT data gathered and analyzed in this manner may be useful as one aspect of the preclinical prediction of AD. Three of the four brain regions important for discriminating Converters from normal controls involve a distributed brain network pertaining to memory, suggesting that this network may be selectively affected in the earliest stages of AD.
We investigated atrophic alterations in different regions of the corpus callosum in Alzheimer's disease (AD) and vascular dementia (VD) with respect to clinical changes. 32 patients with AD (NINCDS-ADRDA criteria), 17 patients with VD (NINDS-AIREN criteria) and 13 healthy control subjects were included. 3-D MRI sequences were acquired using a 1.5T MRI scanner. The size of the corpus callosum and its subdivisions was sampled on 5 mid-saggital slices using a personal computer-based software. Total callosal size was significantly reduced in AD but not in VD. Furthermore, the most rostral parts of the corpus callosum were significantly smaller in AD when compared to controls. Again, these changes were not found in patients with VD. Severity of dementia was significantly correlated with the size of the midbody of the corpus callosum in AD. Callosal atrophy in AD may reflect the severity and pattern of cortical neuronal damage occurring mostly in the inferior frontal, anterior parietal and midtemporal regions. Correlations between regional callosal atrophy and severity of dementia indicate that interhemispheric cortico-cortical disconnections may contribute to the dementia syndrome.
Image processing techniques were applied to interictal positron emission tomography (PET) and single-photon emission computed tomography (SPECT) brain images to aid in the localization of epileptogenic foci by calculating a functional image that represents the degree of coupling between perfusion and metabolism. Uncoupling of these two functions has been demonstrated to be a characteristic of epileptogenic tissue in temporal lobe epilepsy and has the potential to serve as a diagnostic measure for localization in other areas as well.
Interictal PET ((18)F-FDG) and interictal SPECT ((99m)Tc-HMPAO) scans were acquired from 11 epilepsy patients. The metabolism and perfusion images were three-dimensionally spatially registered, and a functional ratio-image was computed. These functional maps are overlaid onto a three-dimensional rendering of the same patient's magnetic resonance imaging anatomy.
In all patients, an average uniform perfusion-to-metabolism ratio showed approximately constant values throughout most of the whole brain. However, the epileptogenic area (confirmed on surgery) demonstrated an area of elevated perfusion/metabolism in the grey matter.
Although hypometabolism in the PET image was observed in most of these patients, the calculation of a functional ratio-image demonstrated localized foci that in some cases could not be observed on the PET image alone. The ratio-image also yields a quantitative measure of the uncoupling phenomenon.
A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimer's disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis.
Correlates of subjective memory impairment (SMI) were investigated using data from a community study of 1,204 individuals aged 65 or over in an urban and rural area of South Korea. SMI and depression were ascertained from the Geriatric Mental State Schedule and cognitive function from the Korean version of the Mini-Mental State Examination (MMSE-K). 686 participants had also completed the MMSE-K two years earlier. SMI was present in 22% of the sample and was associated with depression and lower MMSE-K scores. Depression and SMI were most strongly associated in the presence of cognitive impairment. SMI was weakly associated with previous cognitive decline and was not associated with APOE e4. SMI and cognitive impairment were most strongly associated in urban residents, particularly rural-to-urban migrants.
The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.