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Decreased cerebral blood flow velocity in apolipoprotein E ?4 allele carriers with mild cognitive impairment
European Journal of Neurology
Abstract
The aim of this study was to investigate the changes in cerebral blood flow velocity (CBFV) and its relation to apolipoprotein E (apoE) epsilon4 allele in mild cognitive impairment (MCI). Thirty MCI and 30 controls were assessed using Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination-Chinese version (CAMCOG-C), and then insonated in the anterior (ACA), middle (MCA) and basilar (BA) cerebral arteries using transcranial Doppler ultrasonography. Compared with controls, MCI showed significant decreases in the mean (V(m)), systolic (V(s)) and diastolic (V(d)) CBFV, bilaterally in MCA and ACA (P < 0.05-0.001), but not in BA. Compared with 17 apoE epsilon4 allele non-carriers, 13 carriers in MCI showed significant CBFV decreases, bilaterally in MCA (P < 0.05-0.001). Our findings, the decreased CBFV in apoE epsilon4 allele carriers with MCI, suggest that a large sample and longitudinal study in CBFV and cognitive changes may have the implications on early diagnosis of Alzheimer's disease.
... Findings of CBF at rest in MCI are inconclusive, likely due to the heterogeneity of the study population and relatively small sample size in previous studies [3]. In the present study, we found that mean CBFV measured in the MCA at rest was similar between amnestic MCI and CN subjects, consistent with some [26,27], but not other studies [28][29][30]. This inconsistency in CBFV at rest may be related to the severity of cognitive impairment of study participants. ...
... This inconsistency in CBFV at rest may be related to the severity of cognitive impairment of study participants. For example, Sun et al. (2007) and Roher et al. (2011) reported a lower CBFV in MCI patients with a group mean MMSE scores < 27 [29,30]. In contrast, similar CBFV was observed between MCI patients and normal subjects with group mean MMSE scores ≥ 29 [26]. ...
... This inconsistency in CBFV at rest may be related to the severity of cognitive impairment of study participants. For example, Sun et al. (2007) and Roher et al. (2011) reported a lower CBFV in MCI patients with a group mean MMSE scores < 27 [29,30]. In contrast, similar CBFV was observed between MCI patients and normal subjects with group mean MMSE scores ≥ 29 [26]. ...
Background
Cerebral blood flow (CBF) is sensitive to changes in arterial CO2, referred to as cerebral vasomotor reactivity (CVMR). Whether CVMR is altered in patients with amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer disease (AD), is unclear.
Objective
To determine whether CVMR is altered in aMCI and is associated with cognitive performance.
Methods
Fifty-three aMCI patients aged 55 to 80 and 22 cognitively normal subjects (CN) of similar age, sex, and education underwent measurements of CBF velocity (CBFV) with transcranial Doppler and end-tidal CO2 (EtCO2) with capnography during hypocapnia (hyperventilation) and hypercapnia (rebreathing). Arterial pressure (BP) was measured to calculate cerebrovascular conductance (CVCi) to normalize the effect of changes in BP on CVMR assessment. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and neuropsychological tests focused on memory (Logical Memory, California Verbal Learning Test) and executive function (Delis-Kaplan Executive Function Scale; DKEFS).
Results
At rest, CBFV and MMSE did not differ between groups. CVMR was reduced by 13% in CBFV% and 21% in CVCi% during hypocapnia and increased by 22% in CBFV% and 20% in CVCi% during hypercapnia in aMCI when compared to CN (all p < 0.05). Logical Memory recall scores were positively correlated with hypocapnia (r = 0.283, r = 0.322, p < 0.05) and negatively correlated with hypercapnic CVMR measured in CVCi% (r = –0.347, r = –0.446, p < 0.01). Similar correlations were observed in D-KEFS Trail Making scores.
Conclusion
Altered CVMR in aMCI and its associations with cognitive performance suggests the presence of cerebrovascular dysfunction in older adults who have high risks for AD.
... All studies lacked sample size calculations, and few demonstrated testing for validity and reliability ( Supplementary Figures 1 and 2). Twenty-two of the 26 studies were cross sectional [15,18,20,40,47,48,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69], and the remaining four studies were longitudinal [50][51][52]60] (two mixed design) [52,60]. Follow-up time in the longitudinal studies ranged from five weeks to two years [50][51][52]60]. ...
... Sample sizes were small for most studies (total sample size range: 15-127). The diagnostic classification system used for MCI varied between studies, five had no formal criteria [18,20,47,53,68], the majority used the Petersen criteria (n = 14) [40,48,51,52,54,[56][57][58][59][60][61][62]67], and fewer used the Mayo [50,55], Winbald [65], Jak [15,64,69], and Reisberg [66] criteria. Several studies had extensive exclusion of other neurodegenerative, psychiatric conditions [15, 48, 50-52, 57-60, 62, 63, 66, 67] and psychotropic medications [59,62,67]. ...
... All participants had an MMSE >24, or equivalent, except one study (mean MMSE 23.7) [54]. One study stratified participants by ApoE4 genotype [55]. The vessel insonated varied; seven measured solely the MCA [47,[51][52][53][54]57], two insonated the vertebral artery (VA) and internal carotid artery (ICA) [50,56], and four examined multiple vessels [18,48,55,68]. ...
Background: The incidence of dementia is projected to rise over the coming decades, but with no sensitive diagnostic tests available. Vascular pathology precedes the deposition of amyloid and is an attractive early target.
Objective: The aim of this review was to investigate the use of cerebral hemodynamics and oxygenation as a novel biomarker for mild cognitive impairment (MCI), focusing on transcranial Doppler ultrasonography (TCD) and near-infrared spectroscopy (NIRS).
Methods: 2,698 articles were identified from Medline, Embase, PsychINFO, and Web of Science databases. 306 articles were screened and quality assessed independently by two reviewers; 26 met the inclusion criteria. Meta-analyses were performed for each marker with two or more studies and limited heterogeneity.
Results: Eleven studies were TCD, 8 NIRS, 5 magnetic resonance imaging, and 2 positron/single photon emission tomography. Meta-analyses showed reduced tissue oxygenation index, cerebral blood flow and velocity, with higher pulsatility index, phase and cerebrovascular resistance in MCI compared to controls. The majority of studies found reduced CO2 reactivity in MCI, with mixed findings in neuroactivation studies.
Conclusion: Despite small sample sizes and heterogeneity, meta-analyses demonstrate clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at an early stage of cognitive decline. Further work is required to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia.
... The majority of studies, however, reported no significant difference in flow velocities between individuals with AD and VaD, respectively [22]. The other major cerebral arteries were studied less frequently and yielded ambiguous results [23][24][25]. ...
... In the context of this review, a comparison of healthy subjects and patients with MCI would be interesting but the available results are ambiguous, likely due to the insufficient sample size for detecting smaller differences than in AD [6,24,27]. ...
... Silvestrini[40] Correlation of changes in flow velocities and BHI with progression of cognitive impairment (MCA bilat., basal conditions/breath-holding), repeated after 12 month of donepezil (5 mg daily for 3 month, then 10 mg daily) MFV, PI, BHI (MCA) Lower MFV, higher PI and lower BHI in AD than in controlsSun[24] Comparison of flow velocities in MCI and controls, comparison of flow velocities in MCI ApoEε4 carriers and non-carriers (ACA, MCA bilat., BA) PSV, MFV, EDV (ACA, MCA, BA) Lower PSV, MFV and EDV in MCA and ACA bilat. in MCI than in controls; lower PSV, MFV, EDV in MCA bilat. (except of PSV in left MCA) in MCI ApoE ε4 carriers than non-carriers Vicenzini [17] Comparison of flow velocities, PI and CVR in AD, PSV, MFV, EDV, PI (MCA) Lower MFV, higher PI and lower CVR in AD and VaD compared to controls Viticchi [27] Comparison of IMT and BHI in AD and MCI, association of these parameters with the risk of conversion from MCI to AD (IMT in carotids, BHI in MCA bilat.) ...
Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by an increasing incidence. One of the pathologic processes that underlie this disorder is impairment of brain microvasculature. Transcranial ultrasound is a non-invasive examination of cerebral blood flow that can be employed as a simple and useful screening tool for assessing the vascular status of brain circulation in preclinical and clinical stages of AD. The objective of this review is to explore the utility of using a transcranial ultrasound to diagnose AD. With transcranial ultrasound, the most frequently studied parameters are cerebral blood flow velocities and pulsatility indices, cerebrovascular reserve capacity, and cerebral microembolization. On the basis of current knowledge, we recommend using as a transcranial Doppler sonography screening method of choice the assessment of cerebrovascular reserve capacity with breath-holding test.
... With increasing life expectancy, dementia is a global public health problem with no cure or effective medical treatment currently available [1]. A growing body of evidence suggests that the initiation and progression of dementia is a consequence of poor cerebral vascular function and hypoperfusion [2][3][4][5][6]. The maintenance of cerebral blood flow (CBF) is crucial for normal brain functioning. ...
... Apart from endothelial dysfunction, disturbances in CBF have also been associated with cognitive impairment. For instance, people suffering from MCI were shown to have a significantly decreased blood flow in the middle and anterior cerebral artery when compared to controls [6]. Moreover, the Rotterdam Study demonstrated that cerebral hypoperfusion precedes and possibly contributes to the onset of clinical dementia [4]. ...
Long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFA) may improve brain functions by acting on endothelial cells in the cerebrovasculature to facilitate vasodilatation and perfusion. The aim of this review is to explore this hypothesis by analyzing the effect of LCn-3 PUFA supplementation on systemic vasodilator and cognitive function and finding evidence to link LCn-3 PUFA intake, vasodilator function and cognition. Forty randomized controlled trials examining the effect of LCn-3 PUFA supplementation in humans on either endothelial vasodilator function or cognition were identified and pooled effects measured with a weighted analysis. Compared to placebo, LCn-3 PUFA tended to increase flow-mediated dilatation and significantly improved cognitive function. Emerging evidence links vasodilator dysfunction to cognitive impairment, but evidence that LCn-3 PUFA can improve cognition through enhancements of vasodilator function is still lacking. Further research is needed to determine: (1) whether LCn-3 PUFA can enhance dilatation of cerebral vessels; (2) if improvements in cerebrovascular responsiveness by LCn-3 PUFA are accompanied by cognitive benefits; and (3) the target population groups.
... The reproducibility of flow velocities measurement is good when done by an experienced examiner (McMahon et al., 2007). Many studies have found significantly lower flow velocities in AD compared to controls (Caamano et al., 1993;Roher et al., 2006Roher et al., , 2011Sun et al., 2007;Vicenzini et al., 2007;Claassen et al., 2009;Stefani et al., 2009;Gucuyener et al., 2010). The most often studied vessel was the middle cerebral artery (MCA) while other major intracranial arteries were studied less frequently. ...
... The most often decreased velocity in MCA in AD patients compared to healthy controls was the mean flow velocity (Roher et al., 2006(Roher et al., , 2011Vicenzini et al., 2007;Claassen et al., 2009;Stefani et al., 2009), although not all results support these findings (Ries et al., 1993). Decreases in peak systolic and end diastolic velocities varied in different arteries (Caamano et al., 1993;Sun et al., 2007;Gucuyener et al., 2010). According to a large longitudinal study (Ruitenberg et al., 2005), subjects with higher velocities in MCA ...
There has been a growing interest in vascular impairment associated with Alzheimer's disease (AD). This interest was stimulated by the findings of higher incidence of vascular risk factors in AD. Signs of vascular impairment were investigated notably in the field of imaging methods. Our aim was to explore ultrasonographic studies of extra- and intracranial vessels in patients with AD and mild cognitive impairment (MCI) and define implications for diagnosis, treatment, and prevention of the disease. The most frequently studied parameters with extracranial ultrasound are intima-media thickness in common carotid artery, carotid atherosclerosis, and total cerebral blood flow. The transcranial ultrasound concentrates mostly on flow velocities, pulsatility indices, cerebrovascular reserve capacity, and cerebral microembolization. Studies suggest that there is morphological and functional impairment of cerebral circulation in AD compared to healthy subjects. Ultrasound as a non-invasive method could be potentially useful in identifying individuals in a higher risk of progression of cognitive decline.
... Decreased MCA MFV was found strongly associated with cognitive impairment in patients with asymptomatic carotid stenosis and mild cognitive impairment. 19,20 It is basically consistent with our results. Apart from MFV, PI is also one of the important parameters of TCD, which reflects cerebrovascular resistance and compliance. ...
Purpose
This study aims to investigate the characteristics and influencing factors of cognitive impairment in patients with asymptomatic middle cerebral artery stenosis (aMCAS) and to construct a nomogram to predict the risk of cognitive impairment in patients with aMCAS.
Patients and Methods
We collected 54 patients with aMCAS and 35 healthy controls to investigate the impaired cognitive domains and pathogenesis in patients with aMCAS. All patients underwent a cranial MRI, CT perfusion, transcranial Doppler ultrasound, blood tests, and a comprehensive neuropsychological evaluation. According to the MoCA score, patients were divided into cognitively normal and cognitively impaired groups. To construct the nomogram, we conducted univariate and multivariate logistic regression analyses to identify factors that affect cognitive function. And the performance of nomogram was evaluated by ROC curves, calibration curves, decision curve analysis (DCA), and clinical impact curve (CIC).
Results
In 54 patients with aMCAS, 24 patients presented with cognitive normal, and 30 patients presented with cognitive impairment. The results of multivariate logistic regression suggested that perfusion decompensation, middle cerebral artery mean flow velocity, and LDL-cholesterol levels were independent influencing factors of cognitive impairment. In the following step, a nomogram was constructed. The AUC of the nomogram is 0.862. Calibrating curves show good agreement between nomogram predictions and actual observations, while DCA and CIC show great clinical usefulness.
Conclusion
Patients with aMCAS have cognitive impairment in multiple cognitive domains, and impaired executive function was observed during the perfusion compensation period. Furthermore, a nomogram was constructed and validated to predict the risk of cognitive impairment in patients with aMCAS, which can help clinicians to identify at an early stage and improve the management of patients.
... In this network, the PCC is a key integration node between the medial temporal lobe and medial prefrontal subsystems 66,67 . Previous studies reported in the DMN (including PCC) high glycolytic metabolism, enhancing abnormal amyloid deposition aggregation 68,69 . ApoE4, as a disrupted metabolic factor 10 , may alter the DMN resting-state activity and ultimately bringing atrophy in MCI ApoE4 Carriers, accelerating AD pathology early during the disease course. ...
The Apolipoprotein E isoform E4 (ApoE4) is consistently associated with an elevated risk of developing late-onset Alzheimer’s Disease (AD); however, less is known about the potential genetic modulation of the brain networks organization during prodromal stages like Mild Cognitive Impairment (MCI). To investigate this issue during this critical stage, we used a dataset with a cross-sectional sample of 253 MCI patients divided into ApoE4 - positive (‛Carriers’) and ApoE4 - negative (‘non-Carriers’). We estimated the cortical thickness (CT) from high-resolution T1-weighted structural magnetic images to calculate the correlation among anatomical regions across subjects and build the CT covariance networks ( CT-Nets ). The topological properties of CT-Nets were described through the graph theory approach. Specifically, our results showed a significant decrease in characteristic path length, clustering-index, local efficiency, global connectivity, modularity, and increased global efficiency for Carriers compared to non-Carriers. Overall, we found that ApoE4 in MCI shaped the topological organization of CT-Nets . Our results suggest that in the MCI stage, the ApoE4 disrupting the CT correlation between regions may be due to adaptive mechanisms to sustain the information transmission across distant brain regions to maintain the cognitive and behavioral abilities before the occurrence of the most severe symptoms.
... Amyloid plaques can further enhance microglial activation and induce secretion of proinflammatory cytokines, exacerbating the neuroinflammatory response [reviewed in more detail elsewhere (15)]. Furthermore, chronic systemic inflammation can also impair endothelium-mediated vasodilatation of cerebral vessels, resulting in a chronic state of hypoperfusion, which has been linked to the severity of cognitive impairment in the elderly (16,17). Thus, neuroinflammation can have farreaching deleterious consequences for neuronal, cerebrovascular, and consequently, cognitive function. ...
The rate of cognitive decline in the elderly is highly variable. One potential factor contributing to accelerated cognitive decline is chronic systemic inflammation, because it has been linked to cognitive impairment and increased dementia risk. Certain lifestyle factors, such as excess body weight and sedentary behavior, can exacerbate a proinflammatory state in older adults, resulting in chronic low-grade inflammation. Supplementing the diet with curcumin, an anti-inflammatory polyphenolic compound from the curry spice turmeric, is a potential approach to prevent accelerated cognitive decline by counteracting chronic inflammatory processes. Although the anti-inflammatory effects of curcumin are well established, the potential cognitive benefits of curcumin were discovered more recently. Several animal and epidemiologic studies on the effect of curcumin supplementation on cognition showed promising results; however, randomized controlled trials in humans are limited. In this review, we identified 5 randomized controlled trials, of which only 2 observed a beneficial effect of curcumin supplementation on cognition by improving working memory. By critically examining the methodologies of those studies, we identified some limitations, one of which is that none of the studies explored the possibility that anti-inflammatory mechanisms were mediating cognitive benefits (i.e., no study tested participants with low-grade inflammation or measured inflammatory biomarkers). Other factors influencing the likelihood of conclusive outcomes include choice of study population (cognitively unimpaired compared with impaired), study duration, curcumin dose and its bioavailability, and neurocognitive test battery. On the basis of these findings, we offer recommendations for future studies to examine the potential cognitive benefits of curcumin in humans, which include evaluating its effects on cerebral endothelial vasodilator function and boosting its cognitive effects by combining it with long-chain omega-3 (n-3) fatty acids.
... We found that flow velocities in cerebral arteries were lower in impaired participants than in controls, but these findings were not significant at basal conditions. Other studies revealed significant differences in flow velocities at basal conditions between AD patients and controls, but the results of these studies varied (significant differences were found in various vessels and various flow velocities) [24,25,34,[39][40][41][42]. However, we found significant differences in flow velocities in the MCA after the CO 2 challenge, which is, again, associated with pathological cerebrovascular reserve capacity. ...
Background
Cerebral microangiopathy in Alzheimer’s disease (AD) causes chronic hypoperfusion and probably accelerates neurodegenerative changes.
Objective
We hypothesize microvascular impairment could be present already in mild cognitive impairment (MCI) and can be revealed using transcranial color-coded sonography (TCCS) and the breath-holding maneuver.
Methods
Three groups of subjects (AD in the stage of dementia, MCI, and cognitively normal controls) with detailed neuropsychological testing and low cerebrovascular burden (no history of stroke, no intra- or extracranial artery stenoses, and no severe vascular lesions on brain MRI), underwent a TCCS assessment of peak systolic (PSV), mean flow (MFV), and end diastolic velocities (EDV) and resistance and pulsatility indices (RI, PI) in large intracranial vessels bilaterally. Cerebrovascular reserve capacity was assessed using the breath-holding index (BHI) in middle cerebral artery (MCA) bilaterally. The ultrasound parameters were compared between the groups, correlated with neuropsychological tests, and compared between amnestic and non-amnestic MCI subtypes.
Results
Fourteen AD (3 males, 67.9±11.1 years, MMSE 18.0±4.6), 24 MCI (13 males, 71.9±7.3 years, MMSE 28.0±1.6), and 24 risk factor-matched controls (14 males, 67.8±6.4 years, MMSE 29.1±1.2) were enrolled. Significant differences were found between AD and controls in MFV, EDV, RI, PI in right MCA after breath holding, in PSV, MFV, EDV in left MCA after breath holding, and in BHI on the left side. The left BHI correlated positively with verbal memory test.
Conclusion
Results show decreased cerebrovascular reserve capacity in AD as a sign of impaired cerebral hemodynamic status without severe underlying atherosclerosis. This can be identified using TCCS and BHI.
... Cognitive impairment is associated with reduced cerebral blood flow (CBF) and a reduced ability of cerebral arteries to dilate under dynamic conditions [5,6] and there is evidence to suggest that the loss of estrogen, rather than ageing per se, contributes to reduced cerebrovascular responsiveness (CVR) in post-menopausal women compared with pre-menopausal women and men [7]. Furthermore, women are more likely to suffer from depression following menopause [8], which has been associated with impaired CVR [9]. ...
We tested whether chronic supplementation with resveratrol (a phytoestrogen) could improve cerebrovascular function, cognition and mood in post-menopausal women. Eighty post-menopausal women aged 45–85 years were randomised to take trans-resveratrol or placebo for 14 weeks and the effects on cognitive performance, cerebral blood flow velocity and pulsatility index (a measure of arterial stiffness) in the middle cerebral artery (using transcranial Doppler ultrasound), and cerebrovascular responsiveness (CVR) to both cognitive testing and hypercapnia were assessed. Mood questionnaires were also administered. Compared to placebo, resveratrol elicited 17% increases in CVR to both hypercapnic (p = 0.010) and cognitive stimuli (p = 0.002). Significant improvements were observed in the performance of cognitive tasks in the domain of verbal memory (p = 0.041) and in overall cognitive performance (p = 0.020), which correlated with the increase in CVR (r = 0.327; p = 0.048). Mood tended to improve in multiple measures, although not significantly. These results indicate that regular consumption of a modest dose of resveratrol can enhance both cerebrovascular function and cognition in post-menopausal women, potentially reducing their heightened risk of accelerated cognitive decline and offering a promising therapeutic treatment for menopause-related cognitive decline.
... Another measure showing predictive value in AD is CBF velocity (CBFv), which may distinguish between normal controls, individuals at genetic risk, adults with MCI, and AD patients (Maalikjy Akkawi et al. 2003, 2005Sun et al. 2007;Claassen et al. 2009). Similarly, research looking at flow territory asymmetry, using vessel encoding ASL (VE-ASL), suggests that it is a promising predictor of cognitive decline, and should be the focus of further investigation (Donahue et al. 2014). ...
There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer's disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.
... To further evaluate the relationship between the network/nodal metrics and cognition, the CAMCOG-C score was entered into the analysis as an important variable. The CAMCOG-C score, a part of the CAMDEX [35], has a high test-retest reliability to evaluate the general level of cognitive function as well as the subtype cognition, as characterized by its subitems assessing orientation, attention, praxis, and so on [36]. In the present study, we found that the whole network clustering coefficient was positively correlated with the CAMCOG-C total scores in DCG. ...
To investigate the topological properties of the functional connectivity and their relationships with cognition impairment in subcortical vascular cognitive impairment (SVCI) patients, resting-state fMRI and graph theory approaches were employed in 23 SVCI patients and 20 healthy controls. Functional connectivity between 90 brain regions was estimated using bivariate correlation analysis and thresholded to construct a set of undirected graphs. Moreover, all of them were subjected to a battery of cognitive assessment, and the correlations between graph metrics and cognitive performance were further analyzed. Our results are as follows: functional brain networks of both SVCI patients and controls showed small-world attributes over a range of thresholds(0.15≤sparsity≤0.40). However, global topological organization of the functional brain networks in SVCI was significantly disrupted, as indicated by reduced global and local efficiency, clustering coefficients and increased characteristic path lengths relative to normal subjects. The decreased activity areas in SVCI predominantly targeted in the frontal-temporal lobes, while subcortical regions showed increased topological properties, which are suspected to compensate for the inefficiency of the functional network. We also demonstrated that altered brain network properties in SVCI are closely correlated with general cognitive and praxis dysfunction. The disruption of whole-brain topological organization of the functional connectome provides insight into the functional changes in the human brain in SVCI.
... Moreover, there was a significant decline in olfactory identification in MCI subjects bearing the ApoE ε4 allele (Wang et al., 2002). The ApoE 4 carriers with MCI also had significantly reduced cerebral blood flow velocity (Sun et al., 2007). ...
Elderly females, particularly those carrying the apolipoprotein E (ApoE)-ε4 allele, have a higher risk of developing Alzheimer's disease (AD). However, the underlying mechanism for this increased susceptibility remains unclear. In this study, we investigated the effects of the ApoE genotype and gender on the proteome of synaptosomes. We isolated synaptosomes and used label-free quantitative proteomics, to report, for the first time, that the synaptosomal proteomic profiles in the cortex of female human-ApoE4 mice exhibited significantly reduced expression of proteins related to energy metabolism, which was accompanied by increased levels of oxidative stress. In addition, we also first demonstrated that the proteomic response in synaptic termini was more susceptible than that in the soma to the adverse effects induced by genders and genotypes. This suggests that synaptic mitochondria might be 'older' than mitochondria in the soma of neurons; therefore, they might contain increased cumulative damage from oxidative stress. Furthermore, female human-ApoE4 mice had much lower oestrogen levels in the cortex and treatment with oestrogen protected ApoE3 stable transfected C6 neurons from oxidative stress. Overall, this study reveals complex ApoE- and gender-dependent effects on synaptic function and also provides a basis for future studies of candidates based on specific pathways involved in the pathogenesis of AD. The lack of oestrogen-mediated protection regulated by the ApoE genotype led to synaptic mitochondrial dysfunction and increased oxidative stress, which might make older females more susceptible to AD.
... Supporting evidence for a primary role of CBF in mental health is suggested by the pathophysiology of neurological disorders. Impaired cerebral blood flow has been implicated in mild cognitive impairment [26], dementias including AD [27][28][29], ADHD [30], depression [31], and schizophrenia [32,33]. BBB dysfunction has also been associated with several central nervous system (CNS) pathologies and in many of these cases cooperation between astrocytes and endothelium is implicated. ...
Since the pivotal role of long chain omega-3 (n-3) polyunsaturated fatty acids (PUFA) in brain structure and development became apparent in the 1970s, these lipids have been investigated in relation to a range of psychiatric disorders, with some positive and some conflicting evidence to support their use as a supplementary treatment for various symptoms. A number of mechanisms of action have been proposed to account for their potential benefits, largely based on their structural role in brain development and purported influences on central neurotransmission. Theories on the pathogenesis of mental health and psychiatric illness have traditionally fo-cused on the role of neurotransmitters, although there is also ample evidence that psychiatric disorders are associated with impaired cerebral blood flow (CBF) or impairments in blood-brain barrier (BBB) function. Associations between cardiovascular and psychiatric pathologies are further indicative of a possible underlying vascular component to psychiatric illness. We hy-pothesise that treatment with vasoactive nutrients that can improve cerebral perfusion may help to improve a variety of mental disorders. In presenting our hypothesis, we provide an overview of cerebral vascular function, focusing specifically on the role of the endothelium in CBF and BBB integrity, and review evidence for associations between impaired CBF/endothelial function and psychiatric illness. Then, as an example of a potential treatment, we review the influence of n-3 PUFA on endothelial func-tion, drawing on evidence of anti-inflammatory, anti-aggregatory and vasodilatory roles in blood flow and vascular permeability. We hypothesise that n-3 PUFA may act on the blood side of the BBB as well as on central neural pathways to influence cerebral functions. In the former * Dr Sinn is supported by an Australian Research Council Linkage Fellowship for the project 'Cognitive and behavioural benefits of omega-3 fatty acids across the lifespan'.
... Mozolic et al. [9] recently showed that an enhanced ability to concentrate during a visual and auditory attention task was linked to an improvement in resting cerebral blood flow in healthy older adults. Indeed, cerebral blood flow is reduced in those with mild cognitive impairment [10]. However the association between enhanced cerebral perfusion and improved cognitive performance has yet to be established, especially in healthy older adults with normal cognition. ...
... Mozolic et al. [9] recently showed that an enhanced ability to concentrate during a visual and auditory attention task was linked to an improvement in resting cerebral blood flow in healthy older adults. Indeed, cerebral blood flow is reduced in those with mild cognitive impairment [10]. However the association between enhanced cerebral perfusion and improved cognitive performance has yet to be established, especially in healthy older adults with normal cognition. ...
Preliminary evaluation of a wild green oat extract (WGOE) (Neuravena(®) ELFA(®)955, Frutarom, Switzerland) revealed an acute cognitive benefit of supplementation. This study investigated whether regular daily WGOE supplementation would result in sustained cognitive improvements.
A 12-week randomised, double-blind, placebo-controlled cross-over trial of WGOE supplementation (1500 mg/day) versus placebo was undertaken in 37 healthy adults aged 67 ± 0.8 years (mean ± SEM). Cognitive assessments included the Stroop colour-word test, letter cancellation, the rule-shift task, a computerised multi-tasking test battery and the trail-making task. All assessments were conducted in Week 12 and repeated in Week 24 whilst subjects were fasted and at least 18 h after taking the last dose of supplement.
Chronic WGOE supplementation did not affect any measures of cognition.
It appears that the cognitive benefit of acute WGOE supplementation does not persist with chronic treatment in older adults with normal cognition. It remains to be seen whether sustained effects of WGOE supplementation may be more evident in those with mild cognitive impairment.
Background/Objectives: Cardiovascular disease (CVD) and Alzheimer’s disease (AD) are two diseases highly prevalent in the aging population and often co-occur. The exact relationship between the two diseases is uncertain, though epidemiological studies have demonstrated that CVDs appear to increase the risk of AD and vice versa. This scoping review aims to examine the current identified overlapping genetics between CVDs and AD at the individual gene level and at the shared pathway level. Methods: Following PRISMA-ScR guidelines for a scoping review, we searched the PubMed and Scopus databases from 1990 to October 2024 for articles that involved (1) CVDs, (2) AD, and (3) used statistical methods to parse genetic relationships. Results: Our search yielded 2918 articles, of which 274 articles passed screening and were organized into two main sections: (1) evidence of shared genetic risk; and (2) shared mechanisms. The genes APOE, PSEN1, and PSEN2 reportedly have wide effects across the AD and CVD spectrum, affecting both cardiac and brain tissues. Mechanistically, changes in three main pathways (lipid metabolism, blood pressure regulation, and the breakdown of the blood–brain barrier (BBB)) contribute to subclinical and etiological changes that promote both AD and CVD progression. However, genetic studies continue to be limited by the availability of longitudinal data and lack of cohorts that are representative of diverse populations. Conclusions: Highly penetrant familial genes simultaneously increase the risk of CVDs and AD. However, in most cases, sets of dysregulated genes within larger-scale mechanisms, like changes in lipid metabolism, blood pressure regulation, and BBB breakdown, increase the risk of both AD and CVDs and contribute to disease progression.
Objectives
Hemodynamic parameters measured by the Transcranial Doppler Ultrasound (TCD) are related to cognitive impairment in many cross-sectional studies, but the longitudinal evidence is scarce. In this study, we aim to verify the association between flow velocity of Middle Cerebral Artery (MCA) and the longitudinal cognitive decline in community dwelling older adults.
Materials and methods
Participants were administered TCD examination at the baseline. The Peak Systolic Velocity (PSV), Mean Flow Velocity (MFV), and Pulsatility Index (PI) of MCA segments on left middle (LmMCA), left proximal (LpMCA), right middle (RmMCA), and right proximal (RpMCA) were obtained. Mini-mental state examination (MMSE) were conducted at both baseline and follow-up.
Results
One hundred and thirteen participants without dementia were followed up for 6.3 years in average. The mean annual rate of decline in the MMSE score was 0.15 (min to max: −1.0 to 1.2). LpMCA PSV (β = −0.0034, r = −0.231, P = 0.022) and LpMCA MFV (β = −0.0049, r = −0.217, P = 0.031) were inversely associated with annual rate of decline in the MMSE score after adjusting for age, gender, education year, APOE ε4, obesity, hypertension, diabetes mellitus, stroke, and coronary heart disease.
Conclusions
Blood flow velocity of left proximal MCA was inversely related to global cognitive decline. Cerebral blood flow velocity may impact the cognitive function.
The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer's disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.
Objective: To investigate the cognitive impairment characteristics in Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) as well as their related risk factors. Methods: In all of the participants, a battery of neuropsychological tests were selected to identify the cognitive deficits; the 2 cognitive screening tests utilized in this study were the MMSE and the CAMCOG-C; the severity of disease was measured using the Hoehn-Yahr; the motor portion of the UPDRS and Webster scale were used to evaluate motor function and PD-MCI were classified according to modified Petersen's criteria. Results: Of the 89 PD cases, 56 (63%) were cognitively normal (PDCOGNL), 20 (22%) had MCI and 13 (15%) met criteria for PD dementia (PDD). The cognitive domain abnormal in PD-MCI was orientation, language, memory, attention, praxis, thinking and perception. The PDCOGNL group had no significant differences in age and PD onset versus the PD-MCI group, but had significant difference in the years of education (PD-MCI: 4.4 ± 4.3, PDCOGNL: 7.1 ± 4.9; q = 3.270, P < 0.05); PD-MCI also had no significant differences for all of them versus the PDD, but the PDD group had significant differences for them (q = -4.913, -4.997, 4.740, all P < 0.01) compared with the PDCOGNL group; there were no significant differences among 3 groups in years of PD duration. Hoehn-Yahr and Webster scale, UPDRS-motor score had negative correlation with PD cognitive function. Conclusions: A stage of clinical cognitive impairment in PD can be defined between PDCOGNL and PDD that characterized as PD-MCI. There are multiple domains impaired in PD-MCI. The risk factors of PD cognitive impairment include the elder, later onset and lower education level. There are negative correlation between the severity of disease, motor function and PD cognitive function.
This chapter reviews age-related changes in the cerebral microvasculature, their clinical consequences, and potential preventive and therapeutic approaches that are under investigation. The consequences of large vessel atherosclerosis, such as coronary artery disease, stroke, and renal failure, have received the greatest attention over the past 50 years, it is now becoming clear that alterations in the microvasculature, particularly small vessels of the brain, can have equally important clinical consequences. Advanced imaging techniques are now identifying abnormalities in the brain that were initially thought to be “covert” strokes (not associated with acute stroke symptoms) or “incidental” hyperintensities, “consistent with age,” and of no major significance. However, these findings are rapidly gaining importance as significant clinical entities, with profound effects on cognition, mobility, affect, and continence. Aging and the accumulation of vascular risk factors are associated with cerebral endothelial dysfunction that may impair the ability of cerebral microvessels to meet the metabolic demands of various neuronal networks in the brain. The mismatch between blood supply and metabolic demand may lead to the accumulation of ischemic damage in the watershed regions of the brain. Watershed regions are areas of the brain that receive a dual blood supply from the most distal branches of two large cerebral arteries and are particularly vulnerable to ischemia during hypoperfusion. If pathogenic mechanism of cerebral microvascular disease is verified in longitudinal studies, future efforts to reduce cardiovascular risk factors and improve cerebral perfusion may help reduce the burden of falls and dementia in the elderly population. Promising approaches to improving cerebral perfusion include HIF-1 activation, flavonoids, and inhibitors of the renin–angiotensin system.
To address the possible role of brain regional metabolic differences between different types of mild cognitive impairment (MCI).
Brain regional metabolites in patients with amnestic mild cognitive impairment (A-MCI) and vascular mild cognitive impairment (V-MCI) were measured via proton magnetic resonance spectroscopy ((1)H MRS) technique. Twenty-eight patients with A-MCI, 24 patients with V-MCI and 34 normal controls (NC) were tested by a battery of neuropsychological screens. All the subjects underwent the single voxel (1)H MRS with the regions of interest (ROIs) located in the left frontal lobe, left basal ganglia and left hippocampus.
The A-MCI showed lower NAA/Cr ratio in the left hippocampus. There was a significant correlation between recent memory score and the NAA/Cr ratio. In V-MCI, NAA/Cr ratio in the left frontal lobe was positively correlated with the cognitive score evaluated with Cambridge Cognitive Examination-Chinese version (CAMCOG-C) and its subscores of orientation, praxi, language and language comprehension.
This study indicated that there are differences in metabolism related to brain regions between A-MCI and V-MCI, thus it may be concluded that (1)H MRS may be a useful tool to differentiate A-MCI and V-MCI.
Copyright © 2015 Elsevier B.V. All rights reserved.
ApoE forms a lipid-protein complex with HDL-cholesterols (HDL-C) and remnant lipoproteins and is an important regulator of cholesterol and lipid clearance, transport and distribution. In the CNS, ApoE is strictly bound to HDL. Unlike ApoE2 or ApoE3, the ApoE4 isoform is associated with both coronary artery disease and Alzheimer's disease. HDL-C levels may possess a U-shaped association with vascular diseases and HDL-C size might reflect an alteration in function. Inflammation plays a key role in coronary artery disease and Alzheimer's disease. Elevated inflammatory markers such as C-reactive protein and serum amyloid A are associated with both diseases. Serum amyloid A, similar to ApoE, binds to HDL-C and may alter the lipoproteins size and function. Familial hypercholesterolemia (FH) is a genetic disorder resulting in elevated plasma levels of LDL-cholesterol (LDL-C), xanthomas and premature coronary artery disease. FH patient's plasma contains decreased levels of HDL-C with increased levels of ApoE4 and ApoE-bound HDL. LDL-apheresis therapy lowers LDL-C and is designated for FH patients resistant to pharmacotherapy. LDL-apheresis also lowers inflammatory HDL-C, ApoE4, and a host of inflammatory markers such as C-reactive protein and serum amyloid A. LDL-apheresis, adjunct to reducing cholesterol, may provide additional benefit to patients with cardiovascular and cerebrovascular diseases.
Alteration in cerebrovascular hemodynamics has reported in both ageing and dementia. However, it is still unclear whether this alteration follows similar pattern in ageing and in different dementia pathologies. The aim of this meta-analysis was to investigate changes in cerebral blood flow velocity and pulsatility index in two most common forms of dementia; Alzheimer's disease and vascular dementia, using transcranial Doppler studies.
A literature search was conducted in Pubmed, EMBASE and Web of Science. After initial screening of 304 articles and removing duplicates, a total of 53 articles, published between 1980 and 2010, were reviewed. Finally 12 articles were included in the meta-analysis. For each study, effect sizes (ES) indicating the standardized mean differences of the hemodynamic measures between two groups were calculated. Using random effect models, pooled estimates of ES were measured.
Patients with Alzheimer's disease (ES=-1.09, 95% CI -1.77 to -0.44, p=0.004) and vascular dementia (ES=-1.62, 95% CI -2.26 to -0.98, p<0.001) had significantly lower cerebral blood flow velocity compared with healthy aged-matched controls. In addition, pulsatility index was significantly higher in both Alzheimer's disease (ES=0.5, 95% CI 0.28-0.72, p<0.001) and vascular dementia patients (ES=2.34, 95% CI 1.39-3.29, p<0.001). Patients with Alzheimer's disease had lower pulsatility index (ES=-1.22, 95% CI -1.98 to -0.46, p=0.002) compared to subjects with vascular type of dementia.
Patients with Alzheimer's disease and vascular dementia have a pronounced disturbance in their cerebrovascular hemodynamics. The severity of disturbances in cerebral hemodynamics is significantly lower in Alzheimer's disease compared to vascular dementia.
The contribution of early microvascular and autonomic derangements to the pathogenesis of mild cognitive impairment (MCI) is unclear. Aim of this study is to evaluate cerebrovascular reactivity (CVR) and cardiac autonomic function in patients with MCI by means of transcranial Doppler (TCD).
Fifteen patients with MCI and 28 controls underwent carotid ultrasound and TCD evaluation, including assessment of mean flow velocity (MFV) in the middle cerebral artery at baseline, after CO(2) inhalation and after hyperpnoea. End-tidal CO(2) , mean arterial blood pressure (MAP), heart rate (HR), and respiratory rate were monitored throughout the procedure, and CVR was calculated.
MAP, end-tidal CO(2) , and MFV variations during hypercapnia and hyperventilation showed no between-group differences. CVR was similar in controls and MCI (2.30 vs 2,39, respectively, P = 0.767). HR significantly increased in hypercapnia (+9.4%, P < 0.0001) and hyperventilation (+18.7%, P < 0.0001) in controls, while in MCI it significantly increased in hyperventilation (+10.4%, P = 0.002), but not in hypercapnia (+1.1%, P = 0.635).
This study demonstrates that patients with MCI have a normal CVR, but they exhibit signs of autonomic dysfunction after CO(2) challenge. Should this finding be confirmed in larger studies, HR response to CO(2) challenge could become a marker of MCI.
Nearly twice as many participants are represented in the current literature than were available at the time of the last major meta-analytic neurocognitive examination of apolipoprotein E (ApoE) epsilon allele combinations [Small, B.J., Rosnick, C.B., Fratiglioni, L., Backman, L., 2004. Apolipoprotein E and cognitive performance: a meta-analysis. Psychol. Aging 19, 592-600]. The meta-analysis in the current study sought to specifically examine (1) small effects and (2) possible moderating variables associated with ApoE allele combinations that may have been undiscoverable in previous examinations of smaller data sets. A total of 77 studies, representing 40,942 cognitively healthy adults were identified for inclusion in the current meta-analysis (random effects design). Results were congruent with the previous meta-analytic findings indicating that carriers of ApoE allele 4 (ɛ4) perform significantly worse on measures of episodic memory, executive functioning, and overall global cognitive ability. In addition, the current analysis revealed a small effect suggesting that ApoE allele 4 adversely impacts perceptual speed. In contrast to earlier studies, the results also indicate that increases in age result in significantly larger differences between ApoE ɛ4 carriers and ApoE non-ɛ4 carriers on measures of episodic memory and global cognitive ability. ApoE ɛ4 exerts broad, but specific, adverse small effects on a range of neurocognitive functions in cognitively healthy adults.
Apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD) and has also been implicated in cardiovascular disease, cognitive decline and cognitive changes in healthy ageing. The aim of this paper is to systematically review and critically assess the association between the APOE genotype and structural/functional cerebral changes as evidenced by brain imaging studies. A second aim is to determine whether these observed associations between APOE and the brain reflect changes which are consistent with the progression of AD neurodegenerative changes described in Braak stages. A search of Pubmed, Psycinfo, and Web of Science databases identified 64 articles available for qualitative review. The review found that presence of the APOE epsilon4 allele is associated with (1) hippocampal, amygdalar and entorhinal cortex atrophy, (2) increased brain atrophy, (3) increased white matter hyperintensity volumes and (4) altered cerebral blood flow and glucose metabolism patterns. It is possible that there are critical age ranges when these effects are evident and that the APOE epsilon2 genotype might present a risk. We conclude that structural brain change is associated with the APOE genotype and that it is more salient in younger ageing individuals.
The intention of this study was to examine the relation of clinical variables and cognitive dysfunction to cerebrovascular blood flow in a sample of patients with Alzheimer's disease without any sign or symptom of cardiovascular or cerebrovascular disease. The patients met DSM-III-R criteria for dementia of Alzheimer type. Blood flow velocities in the anterior, middle (MCA) and posterior cerebral arteries were recorded using transcranial Doppler sonography. Several psychometric tests including the Mini-Mental State Examination (MMSE) were performed. The patients' age correlated significantly with the systolic flow velocity in the left MCA (r = -0.57) explaining 24% of the total variance; there was a reduction of the mean flow velocity of 0.7 +/- 0.2 mm/s for every additional year. The MMSE correlated significantly with the systolic flow velocity in the left MCA (r = 0.62) explaining 29% of the total variance. The correlations of flow velocities with age indicate that even in very old patients there is a progressive reduction of cerebral blood flow velocities. The independent negative correlations of flow velocities with cognitive dysfunction indicate that there are progressive cerebrovascular flow reductions in the course of Alzheimer's disease. Both facts should be taken into account when Alzheimer patients are compared with other samples.
The differentiation between the Alzheimer and multi-infarct types of dementia may still be equivocal considering clinical criteria, neuropsychological tests, and imaging techniques. Cerebral microangiopathic alterations underlying multi-infarct dementia should allow the characterization of dementia subgroups.
Patients with a diagnosis of multi-infarct dementia (n = 17; mean age, 69.1 +/- 8.5 years) or Alzheimer dementia (n = 24, mean age, 65.8 +/- 9.0 years) according to standard testing criteria, clinical findings, and neuroimaging techniques (computed tomography and magnetic resonance imaging) were investigated prospectively by transcranial Doppler sonography and compared with a normal reference group (n = 64; mean age, 61.0 +/- 11.1 years). Transcranial Doppler sonography allows an indirect evaluation of peripheral flow resistance in the microcirculatory bed by quantifying pulsatility characteristics, as reflected in the effective pulsatility range (time-averaged mean blood flow velocity minus the peak-systolic to end-diastolic amplitude, in centimeters per second).
A total of 204 vessels were investigated in 105 subjects. Mean and diastolic blood flow velocities as well as the effective pulsatility range were significantly lower in the multi-infarct dementia group compared with the Alzheimer and the normal reference groups (p < 0.001). By using receiver operating characteristic analysis, a cutoff point for effective pulsatility range values of -5 cm/sec gives a side-dependent sensitivity of 90.48-95.24% and a specificity of 64.71-70.59% in diagnosing Alzheimer-type dementia; the corresponding sensitivity and specificity for a value of -2 cm/sec are 82.35-88.24% and 80.95-90.48%, respectively.
Pulsatility changes as reflected by the effective pulsatility range are a noninvasive additional criterion in the differential diagnosis of dementia.
Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APO epsilon 2, APO epsilon 3, and APO epsilon 4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (ChAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that > 80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.
Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.
To characterize clinically subjects with MCI cross-sectionally and longitudinally.
A prospective, longitudinal inception cohort.
General community clinic.
A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.
The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, respectively.
The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.
Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
To examine the relation of midlife raised blood pressure and serum cholesterol concentrations to Alzheimer's disease in later life.
Prospective, population based study.
Populations of Kuopio and Joensuu, eastern Finland.
Participants were derived from random, population based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average of 21 years' follow up, a total of 1449 (73%) participants aged 65-79 took part in the re-examination in 1998.
Midlife blood pressure and cholesterol concentrations and development of Alzheimer's disease in later life.
People with raised systolic blood pressure (>/=160 mm Hg) or high serum cholesterol concentration (>/=6.5 mmol/l) in midlife had a significantly higher risk of Alzheimer's disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than those with normal systolic blood pressure (odds ratio 2.3, 95% confidence interval 1.0 to 5.5) or serum cholesterol (odds ratio 2.1, 1.0 to 4.4). Participants with both of these risk factors in midlife had a significantly higher risk of developing Alzheimer's disease than those with either of the risk factors alone (odds ratio 3.5, 1.6 to 7.9). Diastolic blood pressure in midlife had no significant effect on the risk of Alzheimer's disease.
Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increase the risk of Alzheimer's disease in later life.
To evaluate the impact of midlife elevated serum cholesterol levels and blood pressure on the subsequent development of mild cognitive impairment (MCI) and to investigate the prevalence of MCI in elderly Finnish population, applying the MCI criteria devised by the Mayo Clinic Alzheimer's Disease Research Center.
MCI has been considered as a predictor of AD. Vascular risk factors may be important in the development of cognitive impairment and AD. However, the role of vascular risk factors in MCI and the prevalence of MCI still remain virtually unknown.
Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1,449 subjects aged 65 to 79 years were reexamined in 1998.
Eighty-two subjects, 6.1% of the population (average age, 72 years) met the criteria for MCI. Midlife elevated serum cholesterol level (> or =6.5 mmol/L) was a significant risk factor for MCI (OR, 1.9; 95% CI, 1.2 to 3.0, adjusted for age and body mass index); the effect of systolic blood pressure approached significance.
Data point to a role for midlife vascular risk factors in the development of MCI in late life.
Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex. Related observations with in vivo imaging have enabled the prediction of dementia from MCI. Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change. The objective of this MRI-guided 2-[(18)F]fluoro-2-deoxy-d-glucose/positron-emission tomography (FDG/PET) study was to examine the hypothesis that among normal elderly subjects, EC METglu reductions predict decline and the involvement of the Hip and neocortex. In a 3-year longitudinal study of 48 healthy normal elderly, 12 individuals (mean age 72) demonstrated cognitive decline (11 to MCI and 1 to Alzheimer's disease). Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender. At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI. Among those who declined, the baseline EC predicted longitudinal memory and temporal neocortex metabolic reductions. At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip. Among those subjects who declined, apolipoprotein E E4 carriers showed marked longitudinal temporal neocortex reductions. In summary, these data suggest that an EC stage of brain involvement can be detected in normal elderly that predicts future cognitive and brain metabolism reductions. Progressive E4-related hypometabolism may underlie the known increased susceptibility for dementia. Further study is required to estimate individual risks and to determine the physiologic basis for METglu changes detected while cognition is normal.
The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.
Single photon emission computer tomography (SPECT) applied early in the course of Alzheimer's disease (AD) may identify regions with impaired brain function. Moreover, it may be relevant to characterize SPECT perfusion patterns in patients with mild cognitive impairment (MCI), in particular the subgroup of MCI patients with isolated amnesia, as these patients have been demonstrated to convert to AD in more than half of the cases within 3 years. The primary aim of the present study was to characterize the regional cerebral blood flow (CBF) in patients with neuropsychologically verified isolated amnesia. We examined 32 patients (11 men/21 women) with isolated amnesia according to strict neuropsychological criteria and 15 healthy volunteers (11 men/4 women). All subjects had an SPECT-99mTc-d,l-HMPAO perfusion study and neuropsychological assessments. Cranial MRI or CT was performed in all subjects. Semiquantitative (cerebellar relative) flow values were calculated and statistically compared. Patients with isolated amnesia had significant hypoperfusion in several cortical regions of interest compared to control subjects, most prominently in the left temporal cortex. Additionally, there was a trend towards globally reduced CBF in the patients, although this was not significant. These findings may indicate the presence of a progressive degenerative illness affecting multiple brain regions at its early or preclinical stage.
Recent ultrastructural studies demonstrate characteristic and extensive angioarchitectural distortions of cerebral capillaries in Alzheimer’s brains. Alzheimer’s disease subjects additionally show reduced cerebral blood flow (CBF), glucose metabolism and oxygen utilization which appear inversely proportional to the disease severity. These findings led us to develop a hypothetical model which appears consistent with the pathogenesis and progression of AD. During ageing, brain capillaries (site of the blood-brain barrier) may undergo progressive degeneration caused by amyloid deposits, thickened basement membrane, cerebral atrophy, reduced vessel elasticity, or genetic predispostion. When these structural abnormalities of the brain microvasculature begin to interfere with basic laws of fluid dynamics, haemorheological compromise will result in cerebral capillary resistance, high blood viscosity, abnormal flow patterns, and changes in shear stress and shear rate in vessel walls. The net effect is chronic ‘disturbed’ blood flow to the brain that impairs the delivery of essential nutrients, particularly oxygen and glucose, to cerebral neurons. As ischaemic-sensitive neurons lower their oxidative phosphorylation and ATP production to subfunctional levelsthey release a diffusible glial mitogen that directly stimulates reactive astrocytosis. These reactive glia differ significantly from normal glia because they proliferate mostly in response to brain injury and can spread to unaffected tissue. It has been suggested that amyloid precursor protein (APP) may be expressed from reactive glia following neuronal injury thus providing the nidus of plaque formation. As brain tissue space is invaded by reactive glia and microglia\, neuronal cytoskeletal damage can result in neurofibrillary tangles. Evolving microvascular insufficiency could also alter the availability of proteases responsible for the removal of APP and the products of cell injury involved in plaque formation. The linear outcome of this process is slow and progressive neuronal damage, transmission failure and brain tissue death. [Neurol Res 1993; 15: 146-153]
Background
Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.Objective
To characterize clinically subjects with MCI cross-sectionally and longitudinally.Design
A prospective, longitudinal inception cohort.Setting
General community clinic.Participants
A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.Main Outcome Measures
The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively.Results
The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.Conclusions
Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
Objective
To examine the relation of midlife raised blood pressure and serum cholesterol concentrations to Alzheimer's disease in later life.
Design
Prospective, population based study.
Setting
Populations of Kuopio and Joensuu, eastern Finland.
Participants
Participants were derived from random, population based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average of 21 years' follow up, a total of 1449 (73%) participants aged 65–79 took part in the re-examination in 1998.
Main outcome measures
Midlife blood pressure and cholesterol concentrations and development of Alzheimer's disease in later life.
Results
People with raised systolic blood pressure (≥160 mm Hg) or high serum cholesterol concentration (≥6.5 mmol/l) in midlife had a significantly higher risk of Alzheimer's disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than those with normal systolic blood pressure (odds ratio 2.3, 95% confidence interval 1.0 to 5.5) or serum cholesterol (odds ratio 2.1, 1.0 to 4.4). Participants with both of these risk factors in midlife had a significantly higher risk of developing Alzheimer's disease than those with either of the risk factors alone (odds ratio 3.5, 1.6 to 7.9). Diastolic blood pressure in midlife had no significant effect on the risk of Alzheimer's disease.
Conclusion
Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increase the risk of Alzheimer's disease in later life.
What is already known on this topic
What is already known on this topic
Vascular risk factors may play an important part as risk factors for Alzheimer's disease No population based studies have evaluated prospectively the impact of both midlife blood pressure and cholesterol concentration in both men and women on the subsequent development of Alzheimer's disease
What this study adds
What this study adds
Raised systolic blood pressure and high serum cholesterol concentration, and in particular the combination of these risks, in midlife increased the risk of Alzheimer's disease in later life Raised systolic blood pressure and hypercholesterolaemia may have a role in the pathogenesis of Alzheimer's disease; more emphasis should be placed on identification and appropriate treatment of these conditions
Transcranial Doppler sonography examination of 23 patients with Alzheimer's disease (AD) showed significantly slower blood flow velocities, bilaterally, in the middle cerebral arteries (MCAs) than in 10 healthy controls. The asymmetries of velocities in MCA were positively correlated with asymmetries of cognitive impairment, but not with global severity or duration of disease. Patients with prevalent left hemispheric neuropsychological dysfunction showed significantly slower blood flow in the left MCA, while the opposite pattern was observed in patients with prevalent right hemisphere dysfunction. The possibility that these findings are an expression of the reduction of cerebral blood flow and metabolism shown in AD by emission tomography studies is discussed.Copyright © 1992 S. Karger AG, Basel
Primary degenerative dementia of the Alzheimer type and multiinfarct dementia exhibit differences in cerebrovascular blood flow velocity profiles, which were investigated by transcranial Doppler sonography. The pulsatility indices, as angle-independent parameters of peripheral vascular resistence, measured in middle cerebral and basilar arteries of patients with multiinfarct dementia were significantly increased (p less than 0.005) compared with cases of primary degenerative dementia of the Alzheimer type and with healthy age-matched controls.
A new interview schedule for the diagnosis and measurement of dementia in the elderly is described. The schedule named the Cambridge Mental Disorders of the Elderly Examination (CAMDEX), consists of three main sections: A structured clinical interview with the patient to obtain systematic information about the present state, past history and family history; a range of objective cognitive tests which constitute a mini-neuropsychological battery; a structured interview with a relative or other informant to obtain independent information about the respondent's present state, past history and family history. The CAMDEX is acceptable to patients, has a high inter-rater reliability and the cognitive section has been shown to have high sensitivity and specificity.
In this report the authors describe a noninvasive transcranial method of determining the flow velocities in the basal cerebral arteries. Placement of the probe of a range-gated ultrasound Doppler instrument in the temporal area just above the zygomatic arch allowed the velocities in the middle cerebral artery (MCA) to be determined from the Doppler signals. The flow velocities in the proximal anterior (ACA) and posterior (PCA) cerebral arteries were also recorded at steady state and during test compression of the common carotid arteries. An investigation of 50 healthy subjects by this transcranial Doppler method revealed that the velocity in the MCA, ACA, and PCA was 62 +/- 12, 51 +/0 12, and 44 +/- 11 cm/sec, respectively. This method is of particular value for the detection of vasospasm following subarachnoid hemorrhage and for evaluating the cerebral circulation in occlusive disease of the carotid and vertebral arteries.
A new Geriatric Depression Scale (GDS) designed specifically for rating depression in the elderly was tested for reliability and validity and compared with the Hamilton Rating Scale for Depression (HRS-D) and the Zung Self-Rating Depression Scale (SDS). In constructing the GDS a 100-item questionnaire was administered to normal and severely depressed subjects. The 30 questions most highly correlated with the total scores were then selected and readministered to new groups of elderly subjects. These subjects were classified as normal, mildly depressed or severely depressed on the basis of Research Diagnostic Criteria (RDC) for depression. The GDS, HRS-D and SDS were all found to be internally consistent measures, and each of the scales was correlated with the subject's number of RDC symptoms. However, the GDS and the HRS-D were significantly better correlated with RDC symptoms than was the SDS. The authors suggest that the GDS represents a reliable and valid self-rating depression screening scale for elderly populations.
In a previous transcranial Doppler (TCD) study, we demonstrated a decrease in blood flow velocity in the proximal tract of the middle cerebral artery (MCA) in patients with Alzheimer's disease (AD). In these patients there was also an asymmetry in blood flow velocity which positively correlated with the cognitive asymmetry often seen in the early phase of AD. In this study we found a correlation between the absolute values and asymmetry indexes of MCA blood flow velocity with adjusted metabolic values and asymmetry indexes of the relative cortical frontotemporoparietal (FTP) areas, evaluated by FDG-PET, and with neuropsychological asymmetry indexes. Patients with prevalent visuospatial deficits (right hemisphere dysfunction) showed significant decreases in right MCA blood flow velocity and right FTP cortical glucose hypometabolism, whereas in patients with prevalent language deficits (left hemisphere dysfunction), these signs were observed on the other side. In AD patients, the decrease of blood flow velocity in MCA might be due to reduced metabolic demands in the temporoparietal cortical areas primarily affected by AD.
Recent ultrastructural studies demonstrate characteristic and extensive angio-architectural distortions of cerebral capillaries in Alzheimer's brains. Alzheimer's disease subjects additionally show reduced cerebral blood flow (CBF), glucose metabolism and oxygen utilization which appear inversely proportional to the disease severity. These findings led us to develop a hypothetical model which appears consistent with the pathogenesis and progression of AD. During ageing, brain capillaries (site of the blood-brain barrier) may undergo progressive degeneration caused by amyloid deposits, thickened basement membrane, cerebral atrophy, reduced vessel elasticity, or genetic predisposition. When these structural abnormalities of the brain microvasculature begin to interfere with basic laws of fluid dynamics, haemorheological compromise will result in cerebral capillary resistance, high blood viscosity, abnormal flow patterns, and changes in shear stress and shear rate in vessel walls. The net effect is chronic 'disturbed' blood flow to the brain that impairs the delivery of essential nutrients, particularly oxygen and glucose, to cerebral neurons. As ischaemic-sensitive neurons lower their oxidative phosphorylation and ATP production to subfunctional levels, they release a diffusible glial mitogen that directly stimulates reactive astrocytosis. These reactive glia differ significantly from normal glia because they proliferate mostly in response to brain injury and can spread to unaffected tissue. It has been suggested that amyloid precursor protein (APP) may be expressed from reactive glia following neuronal injury thus providing the nidus of plaque formation. As brain tissue space is invaded by reactive glia and microglia, neuronal cytoskeletal damage can result in neurofibrillary tangles.(ABSTRACT TRUNCATED AT 250 WORDS)
Inconsistencies within results of case-control studies on Alzheimer's disease risk factors led to a search of the literature for a potential cofactor. Reduced cerebral blood flow was selected and literature was surveyed for evidence of a cerebral blood flow linkage with the more than 40 putative risks. Alcohol abuse, depression, head trauma, underactivity, old age, sleep disturbance, glucose utilization, Down's syndrome, and Parkinson's disease are risk factors where an association with reduced cerebral blood flow is documented. Studies were cited showing that improved cerebral blood flow is associated with factors thought to be helpful in Alzheimer's disease, such as education or occupational attainment, exercise, headache, smoking, and arthritis/anti-inflammatory drugs to the extent that aspirin is used. Sugar consumption is identified as a potential risk factor with glucose management in Alzheimer's disease also shown to involve reduced cerebral blood flow. An hypothesis is developed showing how compromised regional cerebral blood flow could fit as a cofactor for genetic, autoimmune, and neurotoxic aspects of Alzheimer's disease.
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.
The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.
We used MRI volume sampling with coregistered and atrophy corrected FDG-PET scans to test three hypotheses: 1) hippocampal formation measures are superior to temporal neocortical measures in the discrimination of normal (NL) and mild cognitive impairment (MCI); 2) neocortical measures are most useful in the separation of Alzheimer disease (AD) from NL or MCI; 3) measures of PET glucose metabolism (MRglu) have greater diagnostic sensitivity than MRI volume. Three groups of age, education, and gender matched NL, MCI, and AD subjects were studied. The results supported the hypotheses: 1) entorhinal cortex MRglu and hippocampal volume were most accurate in classifying NL and MCI; 2) both imaging modalities identified the temporal neocortex as best separating MCI and AD, whereas widespread changes accurately classified NL and AD; 3) In most between group comparisons regional MRglu measures were diagnostically superior to volume measures. These cross-sectional data show that in MCI hippocampal formation changes exist without significant neocortical changes. Neocortical changes best characterize AD. In both MCI and AD, metabolism reductions exceed volume losses.
We investigated retrieval and encoding of episodic memory in normal aging and patients with mild cognitive impairment (MCI). There was significant decline in the function of orientation, language and praxis besides memory impairment in the MCI group. Impairment of encoding and retrieval of episodic memory was observed in the MCI group. Encoding of episodic memory is vulnerable to be impaired in the MCI group.
To investigate olfactory identification and apolipoprotein E epsilon 4 allele in patients with mild cognitive impairment (MCI), we used Cross-Cultural Smell Identification Test (CC-SIT) from University of Pennsylvania to assess olfactory identification performance and polymerase chain reaction (PCR) to detect apolipoprotein E epsilon 4 (ApoE epsilon 4) allele in 28 patients with MCI and the 30 age-matched control subjects in present study. The Mann-Whitney U test demonstrated that the MCI group performed significantly worse on CC-SIT than the normal aging group (P<0.01). For MCI patients olfaction scores correlated positively with CAMCOG-C (r=0.61, P<0.01), but not with age, gender or years of education. In normal subjects, the CC-SIT score showed no significant associations with age, gender, years of education, or CAMCOG-C. As the least common allele in Chinese, epsilon 4 was found in 13.3% of controls and in 35.8% of MCI in this study. ApoE epsilon 4 was significantly higher in MCI group than normal group (chi(2)=4.65, P<0.01). There was a significant effect of allele status on odor identification: subjects with epsilon 4 allele were not able to identify as many odors as the subjects without epsilon 4 allele (P<0.01). These results suggested that the decreased olfactory identification in MCI may be a marker for the early diagnosis of Alzheimer's disease, and ApoE genotype may be part of the basis of olfactory identification decline.
1. The amyloid B-peptide (AB) is involved in the mechanisms of Alzheimer dementia. This paper reviews experimental evidence indicating that AB exerts profound effects on the regulation of the cerebral circulation. 2. Thus, AB compromises the ability of cerebral endothelial cells to produce vascular relaxing factors, impairs the ability of cerebral blood vessels to maintain adequate flow during hypotension, and attenuates the increases in CBF evoked by enhanced brain activity. 3. Studies in transgenic mice overexpressing the amyloid precursor protein suggest that these cerebrovascular alterations disrupt the delicate balance between the brain's energy requirements and cerebral blood supply, rendering the brain more vulnerable to ischemic injury. 4. The findings support the recently emerged notion that vascular factors play a pathogenic role in the early stages of Alzheimer dementia.
To investigate whether the combination of fluoro-2-deoxy-d-glucose (FDG) PET measures with the APOE genotype would improve prediction of the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).
After 1 year, 8 of 37 patients with MCI converted to AD (22%). Differences in baseline regional glucose metabolic rate (rCMRglc) across groups were assessed on a voxel-based basis using a two-factor analysis of variance with outcome (converters [n = 8] vs nonconverters [n = 29]) and APOE genotype (E4 carriers [E4+] [n = 16] vs noncarriers [E4-] [n = 21]) as grouping factors. Results were considered significant at p < 0.05, corrected for multiple comparisons.
All converters showed reduced rCMRglc in the inferior parietal cortex (IPC) as compared with the nonconverters. Hypometabolism in AD-typical regions, that is, temporoparietal and posterior cingulate cortex, was found for the E4+ as compared with the E4- patients, with the E4+/converters (n = 5) having additional rCMRglc reductions within frontal areas, such as the anterior cingulate (ACC) and inferior frontal (IFC) cortex. For the whole MCI sample, IPC rCMRglc predicted conversion to AD with 84% overall diagnostic accuracy (p = 0.003). Moreover, ACC and IFC rCMRglc improved prediction for the E4+ group, yielding 100% sensitivity, 90% specificity, and 94% accuracy (p < 0.0005), thus leading to an excellent discrimination.
Fluoro-2-deoxy-d-glucose-PET measures may improve prediction of the conversion to Alzheimer disease, especially in combination with the APOE genotype.
The association of decreased cerebral blood flow with the development of Alzheimer’s disease (AD) has been a recent target of interest. By using neuroimaging techniques, growing attention has been devoted to the identification of preclinical AD.
In this study, color duplex sonography of cervical arteries was used to measure mean cerebral blood flow (CBF) on 55 amnestic Mild Cognitive Impairment (MCI) patients. Two years after enrolment, excluding patients who progressed to dementia other than AD, two subgroups were identified, patients who developed AD (MCI converters) and patients with preserved cognitive and functional level (MCI non–converters). Examining the mean difference of CBF measured at baseline in the two subgroups obtained, a significant difference was noticed (MCI converters 539.3 ± 114.3 vs MCI non converters 636.0 ± 143.9, p < 0.05). MCI patients with CBF higher than median value (558 ml/min) had lower risk of developing AD (specificity 72.2%, sensitivity 68.4%) within a two year follow–up. Ultrasonography of the cervical arteries is a simple, non invasive and widespread technique useful in detecting CBF decline during the MCI stage, thus identifying patients who later will convert to AD.
Possession of one or more copies of the apolipoprotein E (APOE) epsilon4 allele is a known risk factor for Alzheimer's disease (AD), but it is uncertain whether the epsilon4 allele is associated with disease incidence among persons with mild cognitive impairment (MCI). We addressed this issue with data from the Religious Orders Study. Participants were 181 older Catholic clergy members who met criteria for MCI based on a uniform structured clinical evaluation; 56 (30.9%) had at least one epsilon4 allele. Clinical evaluations, which included clinical classification of dementia and AD, were repeated annually. During a mean of 5.7 years of observation, 79 persons (43.6%) developed AD. In a proportional hazards model that controlled for age, sex, and education, possession of an epsilon4 allele was associated with a 93% increase in the risk of developing Alzheimer's disease (95% CI; 1.02, 2.63). There was a marginally significant reduction in the effect of epsilon4 in older compared to younger participants (p=.053). The results suggest that possession of an epsilon4 allele does increase risk of AD in persons with MCI.
To facilitate image analysis, most recent 2-[18F]fluoro-2-deoxy-d-glucose PET (FDG-PET) studies of glucose metabolism (MRglc) have used automated voxel-based analysis (VBA) procedures but paradoxically none reports hippocampus MRglc reductions in mild cognitive impairment (MCI) or Alzheimer disease (AD). Only a few studies, those using regions of interest (ROIs), report hippocampal reductions. The authors created an automated and anatomically valid mask technique to sample the hippocampus on PET (HipMask).
Hippocampal ROIs drawn on the MRI of 48 subjects (20 healthy elderly [NL], 16 MCI, and 12 AD) were used to develop the HipMask. The HipMask technique was applied in an FDG-PET study of NL (n = 11), MCI (n = 13), and AD (n = 12), and compared to both MRI-guided ROIs and VBA methods.
HipMask and ROI hippocampal sampling produced significant and equivalent MRglc reductions for contrasts between MCI and AD relative to NL. The VBA showed typical cortical effects but failed to show hippocampal MRglc reductions in either clinical group. Hippocampal MRglc was the only discriminator of NL vs MCI (78% accuracy) and added to the cortical MRglc in classifying NL vs AD and MCI vs AD.
The new HipMask technique provides accurate and rapid assessment of the hippocampus on PET without the use of regions of interest. Hippocampal glucose metabolism reductions are found in both mild cognitive impairment and Alzheimer disease and contribute to their diagnostic classification. These results suggest re-examination of prior voxel-based analysis 2-[18F]fluoro-2-deoxy-d-glucose PET studies that failed to report hippocampal effects.
Patients with mild cognitive impairment (MCI) represent a risk population for progressing to dementia of the Alzheimer type (DAT). However, clinical criteria do not ensure reliable individual prognosis in these patients. The objective of this longitudinal, prospective study was to examine the value of (18)F-FDG PET of cerebral glucose metabolism and of genetic susceptibility, as defined by an APOEepsilon4-positive genotype, with regard to the early diagnosis of DAT in patients with MCI.
In 30 patients with the diagnosis of MCI (16 female, 14 male; age, 70 +/- 8 y), baseline and follow-up examinations (mean observation period, 16 mo) were performed. In all patients, the APOE genotype was assessed and cerebral glucose metabolism was evaluated at baseline using cranial (18)F-FDG PET. Individual PET data were screened for findings suggestive of Alzheimer's disease (AD), with the help of an automated computer program. After stereotactical normalization of the PET images, this program performs an observer-independent statistical comparison with an age-matched reference database (n = 22).
In 43% of all MCI subjects, a PET scan suggestive of AD pathology according to our predefined criteria was observed at baseline (PET+); 57% of all MCI patients were carriers of the APOE epsilon4 allele (e4+). In 40% of all patients, progression of symptoms within the observation period justified the clinical diagnosis of probable DAT at the time of follow-up reevaluation. Statistical evaluation revealed the best results for PET with regard to early diagnosis of DAT in MCI patients (sensitivity, 92%; specificity, 89%). Classification according to the APOE genotype was significantly less successful (sensitivity, 75%; specificity, 56%). However, a combination of both diagnostic tests allowed early diagnosis with either very high specificity (PET+ AND e4+: sensitivity, 67%; specificity, 100%) or very high sensitivity (PET+ OR e4+: sensitivity, 100%; specificity, 44%).
(18)F-FDG PET of cerebral glucose metabolism is a valuable diagnostic tool for the prediction of clinical outcome in individual MCI patients. Results are superior to the exclusive assessment of the APOE genotype. A combination of both functional imaging and genotyping may allow an early high-risk or low-risk stratification of patients with either very high sensitivity or very high specificity. This may be valuable, for example, for patient selection in scientific studies.
Neuroimaging techniques such as PET and SPECT demonstrated a consistent reduction of cerebral blood flow (CBF) in Alzheimer's disease (AD). The aim of the study was to assess the potential role of ultrasonography for CBF measurement in AD patients and whether the CBF volume correlates positively with disease severity. Fifty patients who met the diagnostic criteria of probable AD (NINDS-ADRDA) were compared to 50 age-matched healthy elderly volunteers. The extracranial internal carotid arteries (ICAs) and the vertebral arteries (VAs) of the patients and controls were examined. Angle-corrected time-averaged flow velocity (TAV) and the diameter of the vessel were measured. Intravascular flow volumes were calculated as the product of TAV and the cross-sectional area of the circular vessel. CBF volume was calculated as the sum of flow volumes in the ICAs and VAs of both sides. All subjects underwent the MMSE. The mean global CBF (474.87 +/- 94.085 vs. 744.26 +/- 94.082 ml/min; p < 0.0001) was lower in AD patients than in healthy volunteers. A significant decline in global flow volumes (r = 0.48; p < 0.0007) with the degree of cognitive impairment was also present. The ability of ultrasonography to characterize flow decreases makes such a technique an attractive tool for the study of AD, for the evaluation of pharmacological therapies and, possibly, for early diagnosis.
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