TGF‐β1 Pathway as a New Target for Neuroprotection in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 37 million people worldwide. Current drugs for AD are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of ß‐amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. The identification of the molecular determinants underlying AD pathogenesis is a fundamental step to design new disease‐modifying drugs. Recently, a specific impairment of transforming‐growth‐factor‐β1 (TGF‐β1) signaling pathway has been demonstrated in AD brain. The deficiency of TGF‐β1 signaling has been shown to increase both Aβ accumulation and Aβ‐induced neurodegeneration in AD models. The loss of function of TGF‐ß1 pathway seems also to contribute to tau pathology and neurofibrillary tangle formation. Growing evidence suggests a neuroprotective role for TGF‐β1 against Aβ toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF‐β1 levels in the central nervous system (CNS), and might be considered as new neuroprotective tools against Aβ‐induced neurodegeneration. In the present review, we examine the evidence for a neuroprotective role of TGF‐β1 in AD, and discuss the TGF‐β1 signaling pathway as a new pharmacological target for the treatment of AD.     

TGF‐β2 and TGF‐β3 from cultured β‐amyloid‐treated or 3xTg‐AD‐derived astrocytes may mediate astrocyte–neuron communication

Astrocytes participate in the development and resolution of neuroinflammation in numerous ways, including the release of cytokines and growth factors. Among many, astrocytes release transforming growth factors beta (TGF‐β) TGF‐β1, TGF‐β2 and TGF‐β3. TGF‐β1 is the most studied isoform, while production and release of TGF‐β2 and TGF‐β3 by astrocytes have been poorly characterized. Here, we report that purified cultures of hippocampal astrocytes produce mainly TGF‐β3 followed by TGF‐β2 and TGF‐β1. Furthermore, astrocytes release principally the active form of TGF‐β3 over the other two. Changes in release of TGF‐β were sensitive to the calcineurin (CaN) inhibitor FK506. Starvation had no effect on TGF‐β1 and TGF‐β3 while TGF‐β2 mRNA was significantly up‐regulated in a CaN‐dependent manner. We further investigated production and release of astroglial TGF‐β in Alzheimer's disease‐related conditions. Oligomeric β‐amyloid (Aβ) down‐regulated TGF‐β1, while up‐regulating TGF‐β2 and TGF‐β3, in a CaN‐dependent manner. In cultured hippocampal astrocytes from 3xTg‐AD mice, TGF‐β2 and TGF‐β3, but not TGF‐β1, were up‐regulated, and this was CaN‐independent. In hippocampal tissues from symptomatic 3xTg‐AD mice, TGF‐β2 was up‐regulated with respect to control mice. Finally, treatment with recombinant TGF‐βs showed that TGF‐β2 and TGF‐β3 significantly reduced PSD95 protein in cultured hippocampal neurons, and this effect was paralleled by conditioned media from Aβ‐treated astrocytes or from astrocytes from 3xTg‐AD mice. Taken together, our data suggest that TGF‐β2 and TGF‐β3 are produced by astrocytes in a CaN‐dependent manner and should be investigated further in the context of astrocyte‐mediated neurodegeneration.     

Differences in risk factors for dementia with neurodegenerative traits and for vascular dementia

In 229 patients with dementia and in 144 control subjects, polymorphisms of apolipoprotein E (ApoE), low-density-lipoprotein (LDL)-receptor-related protein, alpha(2)-macroglobulin, interleukin (IL) 1beta, angiotensin-converting enzyme and of methylene tetrahydrofolate reductase genes were investigated. In plasma, antibodies against Chlamydia pneumoniae and lipids were determined. Dementia was classified as probable Alzheimer's disease (AD), probable dementia of vascular origin (VaD) and mixed dementia (MD). An association of the disease with ApoE and IL-1beta polymorphism and increased levels of LDL cholesterol were observed in AD and in MD but not in VaD.     

β‐Catenin expression in human neural cell lines following exposure to cytokines and growth factors

β‐Catenin acts as a key mediator of the Wnt/Wingless signaling pathway involved in cell proliferation, differentiation and survival. Recent studies have shown that an unstable interaction between β‐catenin and the mutant presenilin‐1 induces neuronal apoptosis, and that β‐catenin levels are decreased in the brains of patients with Alzheimer’s disease (AD). Since activated microglia and astrocytes play a role in the process of neuronal degeneration in AD, the cytokine/growth factor‐regulated expression of β‐catenin in human neural cell lines, including NTera2 teratocarcinoma‐derived differentiated neurons (NTera2‐N), IMR‐32 neuroblastoma, SKN‐SH neuroblastoma and U‐373MG astrocytoma, was studied quantitatively following exposure to epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), brain‐derived neurotrophic factor (BDNF), tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐1β, IL‐6, interferon (IFN)‐γ, transforming growth factor (TGF)‐β1, dibutyryl cyclic adenosine 3′,5′‐cyclic monophosphate (cAMP) (dbcAMP) or phorbol 12‐myristate 13‐acetate (PMA). β‐Catenin mRNA expressed constitutively in all of these cell lines was unaffected by treatment with any factors examined. In contrast, β‐catenin protein levels were reduced markedly in NTera2‐N cells by exposure to dbcAMP, EGF or bFGF, and in U‐373MG cells by treatment with dbcAMP or PMA, but were unaffected in any cell lines by BDNF, TNF‐α, IL‐1β, IL‐6, IFN‐γ or TGF‐β1. These results indicate that β‐catenin is expressed constitutively in human neural cells and downregulated at a protein level by a set of growth factors in a cell type‐specific manner.     

Endothelin‐converting enzyme‐1 in Alzheimer's disease and vascular dementia

J. C. Palmer, P. G. Kehoe and S. Love (2010) Neuropathology and Applied Neurobiology 36, 487–497
Endothelin‐converting enzyme‐1 in Alzheimer's disease and vascular dementia Aims: Alzheimer's disease (AD) is believed to be caused by the accumulation of amyloid beta (Aβ) peptide within the brain. Endothelin‐converting enzyme‐1 and 2 (ECE‐1 and ECE‐2) are expressed in endothelial cells and neurones, respectively, and both cleave ‘big endothelin’ to produce the vasoconstrictor endothelin‐1 (ET‐1). ECE‐1 and ECE‐2 also degrade Aβ. AD patients have regionally reduced microvascular blood flow in the brain, with impaired endothelium‐dependent relaxation and cerebrovascular autoregulation, and abnormal production of ET‐1 has been demonstrated in mice overexpressing amyloid precursor protein. We recently found ECE‐2 mRNA and protein to be elevated in the brain in AD. In vitro, expression of ECE‐2 was upregulated by Aβ. Our aims for this study were to examine expression of ECE‐1 (which has 57% homology with ECE‐2) in temporal cortex from patients with AD, vascular dementia (VaD) and controls. Methods: We examined the distribution of ECE‐1 with immunohistochemistry, and measured ECE‐1 mRNA by real‐time polymerase chain reaction (PCR). ECE‐1 protein levels were measured by western blot, and results analysed before and after adjustment for factor VIII‐related antigen. Results: We showed ECE‐1 to be in vascular endothelial cells. We did not find significant differences in ECE‐1 mRNA or protein levels (either full‐length ECE‐1 or the soluble spliced variant, ECE‐1sv) in AD or VaD compared with controls. Conclusions: Our findings suggest that any disease‐specific contribution of ECE‐1 to the accumulation of Aβ or reduction in local microvascular blood flow in AD or VaD is probably small, with abnormal production of ET‐1 being more likely to reflect Aβ‐mediated upregulation of ECE‐2.     

Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of beta-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature-vascular or degenerative-dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development.     

Serum BDNF, TNF-α and IL-1β levels in dementia patients

Neurotrophins such as the brain-derived neurotrophic factor (BDNF) are reportedly related to the pathogenesis of Alzheimer's disease (AD). Several studies have revealed an alteration in BDNF expression in the postmortem brains of AD patients. BDNF has great potential as a therapeutic agent because of its ability to cross the blood-brain barrier and due to its wide in vivo distribution. However, little is known about in vivo BDNF in dementia patients. Moreover, the immunological function of neurotrophins such as BDNF has received great interest. Therefore, we investigated the serum levels of BDNF and cytokines such as TNF-alpha and IL-1beta in dementia patients by the enzyme-linked immunosorbent assay (ELISA). The following subjects were included in this study: 60 AD patients, 60 vascular dementia (VaD) patients and 33 healthy controls. AD and VaD patients were matched for age, gender and severity of dementia. Serum BDNF levels in AD patients were significantly lower than those in VaD patients and controls. TNF-alpha and IL-1beta levels showed no significant difference among the three groups. In the dementia groups, neither the TNF-alpha nor the IL-1beta levels correlated with the BDNF levels. Our results suggest that BDNF may play a pathological role in some cases of AD.     

Alpha rhythms in mild dements during visual delayed choice reaction time tasks: a MEG study

Can simple delayed response tasks affect latency and amplitude of magnetoencephalographic midline alpha rhythms (6-12 Hz) in early dementia? We recruited 15 mild Alzheimer's disease (AD) and 10 vascular dementia (VaD) patients (paired mini mental state exam of 17-24). The control groups comprised 18 young and 22 elderly normal subjects. In the first task, a simple "cue" stimulus (one bit) was memorized along a brief delay period (3.5-5.5s) up to a "go" stimulus triggering (right or left) button press. In the second task, the "cue" stimulus remained available along the delay period. Event-related reduction in power of the alpha rhythms indexed the cortical activation (event-related desynchronization, ERD) for the trials associated with correct behavioral responses. Behavioral performances to both tasks were lower in the AD and VaD patients than in the normal subjects. In particular, just four AD and five VaD patients executed a sufficient amount of correct responses for the alpha ERD analysis, so they were included in a unique group. In both tasks, the alpha ERD peak was later in latency in the demented and normal elderly subjects than in the normal young subjects. Furthermore, the alpha ERD peak was stronger in amplitude in the demented patients than in the normal subjects. These results suggest that simple delayed response tasks during physiological recordings are quite difficult for patients even at an early dementia stage. Such difficulty may induce the abnormal amount of the related cortical activation in dementia as revealed by the alpha ERD.     

Prevalence of Alzheimer's disease with diabetes in the Japanese population

Background:  The aim of the present study was to estimate the prevalence of impaired cognitive function and Alzheimer's disease (AD) in diabetic subjects from Japan.
Methods:  In the present study, 386 Japanese diabetic subjects aged more than 50 years were initially screened with the 'brief screening test' for AD, and were diagnosed with AD and vascular dementia (VaD) according to the criteria of the NINCDS-ADRDA and the NINDS-AIREN. We compared the prevalence of dementia in diabetic patients with that in ordinary subjects, and analyzed the association of the status of diabetes with dementia including AD and VaD.
Results:  Forty-six (11.9%) patients were diagnosed with dementia, including 13 (3.4%) patients with AD and nine (2.3%) patients with VaD. Of the 221 subjects aged more than 65 years, 39 (17.6%) patients had dementia, including 13 (5.9%) patients with AD and eight (3.6%) patients with VaD. Compared with ordinary subjects, the prevalence of dementia in the present study was more frequent than the prevalence of dementia for the general population in almost each age group examined. There was also a greater prevalence of AD and VaD in subjects aged over 65 years in the present study. In the present study, AD subjects had significantly higher levels of fasting plasma glucose (FPG; 247.5 ± 116.3 mg/dL; P  < 0.05) and glycosylated hemoglobin (HbA1c; 8.8 ± 1.9%; P  < 0.01) compared with non-demented subjects. In AD patients, the odds ratios of FPG and HbA1c were also significantly higher (1.02 and 2.07, respectively; both P  < 0.01).
Conclusion:  The present study shows that diabetes can be associated with impaired cognitive function, particularly AD, in Japanese subjects.     

CSF levels of β‐amyloid 1‐42, tau and phosphorylated tau protein in CADASIL

Background and purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be considered a useful model of pure subcortical vascular dementia (SVD) because it occurs in young adults, unlikely to have concomitant age‐ and Alzheimer’s disease (AD)‐related pathology. In patients with CADASIL we evaluated the cerebrospinal fluid (CSF) levels of β‐amyloid 1‐42 (Aβ42), total tau protein (t‐tau) and phosphorylated tau protein (p‐tau), which are well‐accepted biomarkers of AD. Methods: The CSF Aβ42, t‐tau and p‐tau levels were determined with Innotest β‐amyloid 1‐42, Innotest hTAU‐Ag and Innotest Phospho‐tau 181p sandwich enzyme‐linked immunoassay, in 10 CADASIL patients and 17 healthy age‐matched subjects. A case–control statistical analysis was carried out. Results: CSF Aβ42 levels were significantly lower in CADASIL patients than in controls, whereas CSF t‐tau and p‐tau levels did not differ between the two groups. Conclusions: The pattern found in CADASIL patients is similar to that reported in those with sporadic SVD, suggesting that decreased CSF Aβ42 might be related to the subcortical vascular lesions in the white matter.     

Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle‐only dementia): The Hisayama study

Senile dementia of the neurofibrillary tangle type (SD‐NFT) is characterized by numerous neurofibrillary tangles (NFT) in the hippocampal region and the absence or minimal presence of senile plaques throughout the brain. We analyzed 207 demented subjects and 68 non‐demented subjects autopsied in the Hisayama study to investigate the clinicopathological aspects of SD‐NFT in the general Japanese population. The prevalence of SD‐NFT in the consecutive autopsy cases was 8/207 (3.9%), comprising three men and five women. The average age at onset and death was 83.8 ± 6.8 (mean ± SD; standard deviation) and 88.1 ± 7.6 years, respectively. A mild memory disturbance preceded a decrease in the ability to undertake the activities of daily living and the diagnosis of dementia. Focal cerebral symptoms, such as aphasia and paralysis, did not appear during the disease course of any subject. Gross examination of the brains showed moderate to severe diffuse cerebral atrophy with brain weight loss (mean ± SD; standard deviation: 1118.1 ± 124.0 g). Histologically, there were abundant NFT and neuropil threads predominantly in or limited to the limbic cortex. The density of NFT in the CA1/subiculum in SD‐NFT was much higher than the densities in the other hippocampal regions. The average density of NFT in CA1 in SD‐NFT subjects was 115.4 per 100× field (range 23–247), that in Alzheimer disease (AD) subjects was 80.1 (range 1–227), and that in non‐demented elderly subjects was 37.2 (range 0–203). Although many previous papers have reported that the densities of NFT in the limbic system in SD‐NFT were significantly higher than those in AD, there was considerable overlap of NFT densities in CA1 among the non‐demented elderly, AD subjects and SD‐NFT subjects.     

Neuropsychiatric symptoms and functional status in Alzheimer's disease and vascular dementia patients

Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). In this study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimer's Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients.     

Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: Possible implications for diagnosis and treatment

Degeneration of the locus ceruleus (LC) and decreased cortical levels of norepinephrine are common findings in Alzheimer’s disease (AD), but their significance is unknown. Because the noradrenergic system is accessible to pharmacological intervention, the role of LC degeneration and noradrenergic dysfunction in the pathogenesis and clinical manifestations of AD needs clarification. Hypothetically, loss of noradrenergic innervation could cause microvascular dysfunction and manifest as ischemia. The objectives of this study were to develop a scale for assessment of LC degeneration and to determine whether degeneration of the LC correlates quantitatively with either duration of clinical dementia, overall severity of AD pathology or with measures of ischemic non‐focal white matter disease (WMD) in AD. This report is a pathological follow‐up of a clinical longitudinal dementia study of 66 consecutive cases of AD without admixture of vascular dementia (VaD) from the Lund Longitudinal Dementia Study, neuropathologically diagnosed between 1990 and 1999. Ten cases of VaD were included for comparative purposes. No correlation between degree of LC degeneration and duration of dementia, AD or WMD severity was found. LC degeneration was significantly more severe in the AD group than in the VaD group. Even though LC degeneration was not associated with WMD or the severity of AD pathology in this AD material, we suggest that clinical studies on the consequences of noradrenergic dysfunction are warranted. Treatment augmenting noradrenergic signaling is available and safe. The marked difference in the level of LC degeneration between AD and VaD cases suggests that LC degeneration could be used as a diagnostic marker of AD.     

Impaired glutamate recycling and GluN2B‐mediated neuronal calcium overload in mice lacking TGF‐β1 in the CNS

Transforming growth factor β1 (TGF‐β1) is a pleiotropic cytokine expressed throughout the CNS. Previous studies demonstrated that TGF‐β1 contributes to maintain neuronal survival, but mechanistically this effect is not well understood. We generated a CNS‐specific TGF‐β1‐deficient mouse model to investigate the functional consequences of TGF‐β1‐deficiency in the adult mouse brain. We found that depletion of TGF‐β1 in the CNS resulted in a loss of the astrocyte glutamate transporter (GluT) proteins GLT‐1 (EAAT2) and GLAST (EAAT1) and decreased glutamate uptake in the mouse hippocampus. Treatment with TGF‐β1 induced the expression of GLAST and GLT‐1 in cultured astrocytes and enhanced astroglial glutamate uptake. Similar to GLT‐1‐deficient mice, CNS‐TGF‐β1‐deficient mice had reduced brain weight and neuronal loss in the CA1 hippocampal region. CNS‐TGF‐β1‐deficient mice showed GluN2B‐dependent aberrant synaptic plasticity in the CA1 area of the hippocampus similar to the glutamate transport inhibitor DL‐TBOA and these mice were highly sensitive to excitotoxic injury. In addition, hippocampal neurons from TGF‐β1‐deficient mice had elevated GluN2B‐mediated calcium signals in response to extrasynaptic glutamate receptor stimulation, whereas cells treated with TGF‐β1 exhibited reduced GluN2B‐mediated calcium signals. In summary, our study demonstrates a previously unrecognized function of TGF‐β1 in the CNS to control extracellular glutamate homeostasis and GluN2B‐mediated calcium responses in the mouse hippocampus.     

Rate of progression of mild cognitive impairment to dementia – meta‐analysis of 41 robust inception cohort studies

Objective: To quantify the risk of developing dementia in those with mild cognitive impairment (MCI). Method: Meta‐analysis of inception cohort studies. Results: Forty‐one robust cohort studies were identified. To avoid heterogeneity clinical studies, population studies and clinical trials were analysed separately. Using Mayo defined MCI at baseline and adjusting for sample size, the cumulative proportion who progressed to dementia, to Alzheimer’s disease (AD) and to vascular dementia (VaD) was 39.2%, 33.6% and 6.2%, respectively in specialist settings and 21.9%, 28.9% and 5.2%, respectively in population studies. The adjusted annual conversion rate (ACR) from Mayo defined MCI to dementia, AD and VaD was 9.6%, 8.1% and 1.9%, respectively in specialist clinical settings and 4.9%, 6.8% and 1.6% in community studies. Figures from non‐Mayo defined MCI and clinical trials are also reported. Conclusion: The ACR is approximately 5–10% and most people with MCI will not progress to dementia even after 10 years of follow‐up.     

Relation between plasma homocysteine and Alzheimer's disease

OBJECTIVE: Several studies have shown that plasma total homocysteine (tHcy) concentration is elevated in Alzheimer's disease (AD). However, it is not clear whether elevated plasma tHcy is a primary cause or a consequence of AD. METHOD: To elucidate this question, we have analysed plasma homocysteine and its determinants in patients with early (EOAD)- and late-onset AD (LOAD) and compared the findings with those in vascular dementia (VaD) and age- and sex-matched control subjects. RESULTS: One of the main findings in the present study is that in EOAD there is no change in the levels of either plasma tHcy or its determinants compared with an age- and sex-matched control group. The fact that plasma tHcy concentration is normal in EOAD thus indicates that elevated plasma tHcy is not the primary cause of the disease. Another main finding is that patients with mixed dementia (AD and VaD) and patients with VaD showed significantly increased plasma tHcy concentration compared with controls and that plasma tHCy concentration in patients with LOAD and a history of additional cardiovascular disease was elevated compared both with AD patients without such a history and with the controls. Thus, there is an association between elevated plasma tHcy and vascular disease. A third main finding is that patients with AD who were followed up for several years showed a clinical deterioration of dementia and an elevation of plasma tHcy concentration. This finding likewise supports the notion that elevated plasma tHcy is not the primary cause of the disease. CONCLUSIONS: The findings suggest that elevated plasma tHcy is not the primary cause of the disease. Furthermore, the findings indicate that elevated plasma tHcy might be a reflection of concomitant vascular disease in AD patients.     

CT brain findings in clinical dementia investigation--underestimation of mixed dementia

Dementia has been found to display a more heterogeneous clinical picture than previously recognized. We investigated brain changes on computed tomography (CT) in a clinical dementia population consisting of 67 cases with Alzheimer's disease (AD), 13 with mixed dementia (AD and vascular dementia, VaD), 71 with VaD, and 12 cases that were not demented. Temporal cortical atrophy and atrophy around the temporal horns were more common in patients with mixed dementia compared to patients with VaD and the non-demented, respectively. Frontal white matter changes were present in 64% of AD, in 85% of mixed dementia and in 79% of VaD cases, but there were no differences between the dementia groups. Lacunes were present in almost 40% of AD cases and in 80 and 85% of VaD and mixed dementia cases, respectively. Only 14% of the VaD cases had large infarcts on the CT. We conclude that large infarcts were rare, even in VaD cases. The increased incidence of white matter changes and lacunes in AD patients strongly indicates an underestimation of the mixed dementia diagnosis. More distinct criteria for this diagnostic category are warranted.     

Mitochondrial fission proteins in peripheral blood lymphocytes are potential biomarkers for Alzheimer’s disease

Background and purpose: Expression of the mitochondrial fission proteins dynamin‐related protein 1 (Drp1), S‐nitrosylated Drp1 (SNO‐Drp1), and Fis1 has been found to be altered in brain tissues and skin fibroblasts from patients with Alzheimer’s disease (AD). The aim of this study was to determine whether these proteins are also changed in peripheral blood lymphocytes (PBL) of AD patients and whether these changes are specific and sensitive enough for AD diagnosis. Methods: Western blot analysis and enzyme‐linked immunosorbent assay (ELISA) were employed to quantify relative levels of Drp1, SNO‐Drp1, and Fis1 in PBL obtained from 91 controls, 82 AD, 26 mild cognitive impairment (MCI), 12 Parkinson’s disease (PD), and 36 vascular dementia (VaD) patients. Logistic regression and receiver operating characteristic (ROC) curve analysis were used to measure diagnostic accuracy of these proteins. Results: Compared with controls, SNO‐Drp1 and Fis1 levels were remarkably increased in PBL of AD and MCI patients, and Drp1 was significantly decreased in AD, MCI, and PD. None of these proteins were changed in VaD patients. Disease severity or duration had no major effects on levels of these proteins in AD PBL. ROC curve analysis showed that the specificity and sensitivity were 81% and 73% for Drp1, 84% and 82% for SNO‐Drp1, and 89% and 80% for Fis1 in identifying AD patients from control subjects. Conclusions: Altered mitochondrial fission proteins Drp1, SNO‐Drp1, and Fis1 in PBL were relatively sensitive and specific in identifying AD patients and could be serving as a biomarker in the procedure of diagnosis.     

18FDG PET in vascular dementia: differentiation from Alzheimer's disease using voxel-based multivariate analysis.

The brain metabolic pattern of vascular dementia (VaD) remains poorly characterized. Univariate voxel-based analysis ignores the functional correlations among structures and may lack sensitivity and specificity. Here, we applied a novel voxel-based multivariate technique to a large ((18)F)2-fluoro-2-deoxy-D-glucose positron emission tomography data set. The sample consisted of 153 subjects, one-third each being probable subcortical VaD, probable Alzheimer disease (AD) (matched for Mini-Mental-State examination (MMSE) and age), and normal controls (NCs). We first applied principal component (PC) analysis and removed PCs significantly correlated to age. The remainders were used as feature vectors in a canonical variate analysis to generate canonical variates (CVs), that is, linear combinations of PC-scores. The first two CVs efficiently separated the groups. CV(1) separated VaD from AD with 100% accuracy, whereas CV(2) separated NC from demented subjects with 72% sensitivity and 96% specificity. Images depicting CV(1) and CV(2) showed that lower metabolism differentiating VaD from AD mainly concerned the deep gray nuclei, cerebellum, primary cortices, middle temporal gyrus, and anterior cingulate gyrus, whereas lower metabolism in AD versus VaD concerned mainly the hippocampal region and orbitofrontal, posterior cingulate, and posterior parietal cortices. The hypometabolic pattern common to VaD and AD mainly concerned the posterior parietal, precuneus, posterior cingulate, prefrontal, and anterior hippocampal regions, and linearly correlated with the MMSE. This study shows the potential of voxel-based multivariate methods to highlight independent functional networks in dementing diseases. By maximizing the separation between groups, this method extracted a metabolic pattern that efficiently differentiated VaD and AD.