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Posts Tagged ‘Mild cognitive impairment’


Alzheimer Disease Developments – Spring 2015

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Cognitive Stimulation Modulates Platelet Total Phospholipases A2 Activity in Subjects with Mild Cognitive Impairment

 

JNK: A Putative Link Between Insulin Signaling and VGLUT1 in Alzheimer’s Disease

Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive ImpairmentOpenly Available
Oulhaj, Abderrahim | Jernerén, Fredrik | Refsum, Helga | Smith, A. David | de Jager, Celeste A.

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic EncephalopathyOpenly Available
Stern, Robert A. | Tripodis, Yorghos | Baugh, Christine M. | Fritts, Nathan G. | Martin, Brett M. | Chaisson, Christine | Cantu, Robert C. | Joyce, James A. | Shah, Sahil | Ikezu, Tsuneya | Zhang, Jing | Gercel-Taylor, Cicek | Taylor, Douglas D

AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate KineticsOpenly Available
Eketjäll, Susanna | Janson, Juliette | Kaspersson, Karin | Bogstedt, Anna | Jeppsson, Fredrik | Fälting, Johanna | Haeberlein, Samantha Budd | Kugler, Alan R. | Alexander, Robert C. | Cebers, Gvido

Predictive Value of Cerebrospinal Fluid Visinin-Like Protein-1 Levels for Alzheimer’s Disease Early Detection and Differential Diagnosis in Patients with Mild Cognitive Impairment
Babić Leko, Mirjana | Borovečki, Fran | Dejanović, Nenad | Hof, Patrick R. | Šimić, Goran

Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study
Chatterjee, Pratishtha | Lim, Wei L.F. | Shui, Guanghou | Gupta, Veer B. | James, Ian | …… | Wenk, Marcus R. | Bateman, Randall J. | Morris, John C. | Martins, Ralph N.

Cognitive reserve in ageing and Alzheimer’s disease / Stern Y / Lancet Neurol. 2012 Nov; 11(11):1006-12. PMID: 23079557.

A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline/ Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, et al. / Nature. 2012 Aug 2; 488(7409):96-9. PMID: 22801501.

 Propagation of tau pathology in a model of early Alzheimer’s disease / de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, et al. / Neuron. 2012 Feb 23; 73(4):685-97. PMID: 22365544.

Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years/ Braak H, Thal DR, Ghebremedhin E, Del Tredici K / J Neuropathol Exp Neurol. 2011 Nov; 70(11):960-9. PMID: 22002422.

Neuroinflammation in Alzheimer’s disease and mild cognitive impairment: a field in its infancy / McGeer EG, McGeer PL / J Alzheimers Dis. 2010; 19(1):355-61. PMID: 20061650.

Metallothioneins in Prion- and Amyloid-Related Diseases

MICROGLIA

Microglia are the immune cells of the CNS and account for approximately 10% of the CNS cellpopulation, with regional variation in density [27, 28]. During embryonic development, microglia originate from yolk sac progenitor cells that migrate into the developing CNS during early embryogenesis [29,30].Following construction of the blood-brain barrier (BBB), microglia are renewed by local turnover [31]. In the healthy brain, microglia actively support neurons through the release of insulin-like growth factor 1, nerve growth factor, ciliary neurotrophic factor, and brain-derived neurotrophic factor (BDNF) [32–34]. Microglia also provide indirect support to neurons by clearance of debris to maintain the extracellular environment, and phagocytosis of apoptotic cells to facilitate neurogenesis [35, 36]. In the adult brain, microglia coordinate much of their activity with astrocytes and activate in response to similar stimuli [37, 38]. Dysfunctional signaling between microglia and astrocytes often results in chronic inflammation, a characteristic of many neurodegenerative diseases [39, 40].

Historically, it has been thought that microglia ‘rest’ when not responding to inflammatory stimuli or damage [41, 42]. However, this notion is being increasingly recognized as inaccurate [43]. When not involved in active inflammatory signaling, microglia constantly patrol the neuropil by extension and retraction of their finely branched processes [44]. Microglial activation is often broadly classified into two states; pro-inflammatory (M1) or anti-inflammatory (M2) [36, 45], based on similar phenotypes in peripheral macrophages [46]. M1 activated microglia are characterized by increased expression of pro-inflammatory mediators and cytokines, including inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-1β, often under the control of the transcription factor nuclear factor-κB [45]. Pro-inflammatory microglia rapidly retract their processes and adopt an amoeboid morphology and often migrate closer to the site of injury [47]. Anti-inflammatory M2 activation of microglia, often referred to as alternative activation, represents the other side of microglial behavior. Anti-inflammatory activation is characterized by increased expression of cytokines including arginase 1 and interleukin-10, and is associated with increased ramification of processes [45]. The polarization of microglia into M1 or M2 throughout the brain is well characterized, especially in neurodegenerative diseases [48]. In the AD brain, microglia expressing markers of M1 activation are typically localized to brain regions such as the hippocampus that are most heavily affected in the disease [49]. However, it is important to note that M1 and M2 classifications of microglia may over-simplify microglial phenotypes and may only represent the extremes of microglial activation [50]. It has been more recently proposed that microglia likely occupy a continuum between these phenotypes [39, 51].

Do microglia have multiple roles in AD?

Classical pro-inflammatory activation of microglia has long been associated with AD [39, 49]. Samples taken from late-stage AD brains contain characteristic signs of inflammation, including amoeboid morphology of microglia, high levels of pro-inflammatory cytokines in the cerebrospinal fluid, and evidence of neuronal damage due to chronic exposure to pro-inflammatory cytokines and oxidative stress [52, 53]. The cause of this inflammation may be in response to direct toxicity of Aβ to neurons resulting in activation of nearby microglia and astrocytes [53, 54]. However, Aβ may also induce inflammatory activation of microglia and astrocytes. Activated immune cells are typically present surrounding amyloid plaques [55–57], with such peri-plaque cells exhibiting strong evidence of pro-inflammatory activation [56, 58–60]. The presence of undigested Aβ particles within these activated microglia may suggest that the Aβ peptide itself is a pro-inflammatory signal for microglia [61–64]. In vitro experiments provide supporting evidence for the in vivo studies, with Aβ promoting pro-inflammatory microglial activation [65, 66], and also acting as a potent chemotactic signal [67].

However, it is important to note that although widespread inflammation is characteristic of late-stage AD, it remains unclear what role inflammation could play in early stages of the disease. Some evidence suggests that reducing inflammation through the long-term use of some non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of AD [68]. However, these findings have not yet been verified in clinical trials [69, 70]. Little is understood about how NSAIDs and related compounds affect the delicate balance of pro- versus anti-inflammatory microglial activity within the brain. Although there is considerable evidence to suggest that chronic inflammation may contribute to pathology in the later stages of AD, it is important to note that inflammation normally only represents a small aspect of microglial function. The non-inflammatory functions of microglia may play a more important role in early disease; specifically, microglial functions relating to maintenance of the CNS.

Phagocytosis: A vital role of microglia that may be lost in AD    

SYNAPTIC PRUNING: MICROGLIA CAN REGULATE NETWORK ACTIVITY

Recently, a new function has been proposed for microglia. A number of studies have provided evidence that microglia prune synapses throughout life. Microglia are known to remove extraneous synapses during development to ensure that only meaningful connections remain [43]. It was, however, thought that differentiated astrocytes performed the majority of synaptic pruning in the adult brain [91]. The discovery that microglial processes are constantly active within the brain and are often positioned near synapses raised the question of whether microglial synaptic pruning continued throughout life [44, 47, 92–94]. This question was answered in 2014 in a study that demonstrated that microglia do prune synapses into adulthood, and that this activity is important for normal brain function [95]. These findings supported those found a year earlier in a study reporting that ablation of microglia from brain slices increases synapse density and results in abnormal firing of hippocampalneurons [96].

Altered microglial behavior may underlie altered neuronal firing in AD  

Altered neuronal activity is an early phenomenon in AD

The cause of DMN hypoactivity in AD is not yet clear; however studies performed in cohorts that are genetically predisposed to AD suggest that DMN hypoactivity is preceded by a period of hyperactivity and increased functional connectivity [123, 136], often manifesting as an absence of normal DMN deactivation during external tasks [137–140]. DMN hyperactivity may interfere with hippocampal memory encoding, leading to the memory deficits that are present in mild cognitive impairment [141, 142]. It has been proposed that hippocampal hyperexcitability in AD may develop as a protective mechanism against increased input from the DMN [142–144]. As AD progresses, the initial hyperexcitability of the DMN and hippocampus may result in hypoactivity due to exhaustion of compensatory mechanisms [123, 136]. Evidence from both transgenic AD mice and longitudinal human studies supports an exhaustion model of hyperactivation leading to later hypoactivation [143, 145–147]. Interestingly, a number of studies report a lower incidence of AD among those who regularly practice meditation which specifically ‘calms’ the DMN [148].

Our understanding of AD as a disease is changing. Historically considered to be primarily a disease of neuronal degeneration, this neurocentric view has widened to encompass non-neuronal cells such as astrocytes into our understanding of the disease process and pathogenesis. A proposed model for microglia in AD is shown in Fig. 2. Microglia perform a wide range of functions in the CNS and although this includes induction of an inflammatory reaction in response to damage, they also have critical roles for maintaining normal function in the brain. Recent evidence shows that microglia regulate neuronal activity through synaptic pruning throughout life as an extension on their normal phagocytosis behavior. The discovery of a large number of AD risk genes associated with reduced immune cell function suggests that perturbed microglial phagocytosis could lead to AD. In our model, altered microglial phagocytosis of synapses results in network dysfunction and onset of AD, occurring downstream of Aβ.

The immune system and microglia represent a novel target for intervention in AD. Importantly, a large number of anti-inflammatory drugs are already in use for other conditions. What is important to know at this stage is exactly how to best target immune cell function. The studies outlined here provide evidence that an indiscriminate dampening down of all microglial activity may result in a worse outcome for individuals by suppressing normal microglial regulatory functions. We currently do not know whether future microglial-based therapies should focus on reducing chronic inflammation or conversely, whether they should be aimed at boosting microglial phagocytosis. It is also likely that future treatment strategies may use a combination of approaches to target Aβ, immune cell phagocytosis and network activity. An increasing view in the AD field is that any drug or therapy needs to be provided very early in the disease process to maximize its beneficial effects. Although we are currently unable to effectively target those at risk of AD at such an early stage, advances in neuroimaging for subtle changes in network activity, or in assays for immune cell function, may provide new avenues for identification of early damage and risk of disease.

REFERENCES

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Glenner GG , Wong CW ((1984) ) Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120: , 885–890.

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Goldgaber D , Lerman MI , McBride OW , Saffiotti U , Gajdusek DC ((1987) ) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 235: , 877–880.

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Kang J , Lemaire HG , Unterbeck A , Salbaum JM , Masters CL , Grzeschik KH , Multhaup G , Beyreuther K , Muller-Hill B ((1987) ) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325: , 733–736.

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Robakis NK , Ramakrishna N , Wolfe G , Wisniewski HM ((1987) ) Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci U S A 84: , 4190–4194.

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Levy E , Carman MD , Fernandez-Madrid IJ , Power MD , Lieberburg I , van Duinen SG , Bots GT , Luyendijk W , Frangione B ((1990) ) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248: , 1124–1126.

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Levy-Lahad E , Wasco W , Poorkaj P , Romano DM , Oshima J , Pettingell WH , Yu CE , Jondro PD , Schmidt SD , Wang K , et al ((1995) ) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269: , 973–977.

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Rogaev EI , Sherrington R , Rogaeva EA , Levesque G , Ikeda M , Liang Y , Chi H , Lin C , Holman K , Tsuda T , et al ((1995) ) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376: , 775–778.

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Sherrington R , Rogaev EI , Liang Y , Rogaeva EA , Levesque G , Ikeda M , Chi H , Lin C , Li G , Holman K , Tsuda T , Mar L , Foncin JF , Bruni AC , Montesi MP , Sorbi S , Rainero I , Pinessi L , Nee L , Chumakov I , Pollen D , Brookes A , Sanseau P , Polinsky RJ , Wasco W , Da Silva HA , Haines JL , Perkicak-Vance MA , Tanzi RE , Roses AD , Fraser PE , Rommens JM , St George-Hyslop PH ((1995) ) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375: , 754–760.

 

Late-Onset Metachromatic Leukodystrophy with Early Onset Dementia Associated with a Novel Missense Mutation in the Arylsulfatase A Gene

Microbes and Alzheimer’s DiseaseOpenly Available
Itzhaki, Ruth F. | Lathe, Richard | Balin, Brian J. | Ball, Melvyn J. | Bearer, Elaine L. | Braak, Heiko | Bullido, Maria J. | Carter, Chris | Clerici, Mario | Cosby, S. Louise | Del Tredici, Kelly | Field, Hugh | Fulop, Tamas | Grassi, Claudio | Griffin, W. Sue T. | Haas, Jürgen | Hudson, Alan P. | Kamer, Angela R. | Kell, Douglas B. | Licastro, Federico | Letenneur, Luc | Lövheim, Hugo | Mancuso, Roberta | Miklossy, Judith | Otth, Carola | Palamara, Anna Teresa | Perry, George | Preston, Christopher | Pretorius, Etheresia | Strandberg, Timo | Tabet, Naji | Taylor-Robinson, Simon D. | Whittum-Hudson, Judith A.

Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health StudyOpenly Available
Raji, Cyrus A. | Merrill, David A. | Eyre, Harris | Mallam, Sravya | Torosyan, Nare | Erickson, Kirk I. | Lopez, Oscar L. | Becker, James T. | Carmichael, Owen T. | Gach, H. Michael | Thompson, Paul M. | Longstreth Jr., W.T. | Kuller, Lewis H.

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic EncephalopathyOpenly Available
Stern, Robert A. | Tripodis, Yorghos | Baugh, Christine M. | Fritts, Nathan G. | Martin, Brett M. | Chaisson, Christine | Cantu, Robert C. | Joyce, James A. | Shah, Sahil | Ikezu, Tsuneya | Zhang, Jing | Gercel-Taylor, Cicek | Taylor, Douglas D.

Unraveling Alzheimer’s: Making Sense of the Relationship between Diabetes and Alzheimer’s Disease1Openly Available
Schilling, Melissa A.

Pain Assessment in Elderly with Behavioral and Psychological Symptoms of DementiaOpenly Available
Malara, Alba | De Biase, Giuseppe Andrea | Bettarini, Francesco | Ceravolo, Francesco | Di Cello, Serena | Garo, Michele | Praino, Francesco | Settembrini, Vincenzo | Sgrò, Giovanni | Spadea, Fausto | Rispoli, Vincenzo

Editor’s Choice from Volume 50, Number 4 / 2016

Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials
Kennedy, Richard E. | Cutter, Gary R. | Wang, Guoqiao | Schneider, Lon S.

Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model
Bourgade, Karine | Le Page, Aurélie | Bocti, Christian | Witkowski, Jacek M. | Dupuis, Gilles | Frost, Eric H. | Fülöp, Tamás

Association Between Serum Ceruloplasmin Specific Activity and Risk of Alzheimer’s Disease
Siotto, Mariacristina | Simonelli, Ilaria | Pasqualetti, Patrizio | Mariani, Stefania | Caprara, Deborah | Bucossi, Serena | Ventriglia, Mariacarla | Molinario, Rossana | Antenucci, Mirca | Rongioletti, Mauro | Rossini, Paolo Maria | Squitti, Rosanna

Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex
Ashby, Emma L. | Miners, James S. | Kehoe , Patrick G. | Love, Seth

AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate KineticsOpenly Available
Eketjäll, Susanna | Janson, Juliette | Kaspersson, Karin | Bogstedt, Anna | Jeppsson, Fredrik | Fälting, Johannad | Haeberlein, Samantha Budd | Kugler, Alan R. | Alexander, Robert C. | Cebers, Gvido

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Curated by: Dr. Venkat S. Karra, Ph.D.

A human brain showing frontotemporal lobar deg...

The number of patients with dementia have been increasing exponentially with the aging of society.  The development of AD research has clarified that the pathogenesis of AD is initiated by amyloidosis with secondary tauopathy and provided a strategy for investigating drugs that may improve or cure AD.

Mild cognitive impairment (MCI) as a prodromal stage of AD and the pathogenesis of Dementia with Lewy bodies (DLB) and Frontotemporal lobar degeneration (FTLD) as a non-AD type dementia have also been elucidated. Currently, a consortium study by the Alzheimer Disease Neuroimaging initiative (ADNI) is being performed to establish global clinical evidence regarding a neuropsychiatric test battery, CSF biomarkers, neuroimaging including MRI, FDG-PET, and amyloid PET to predict progression from MCI to AD and to promote studies of basic therapy for AD [1].

Several new biomarkers such as Aβ oligomer, α-synuclein, and TDP-43 are now under investigation for further determination of their usefulness to detect AD and other non-AD type dementia.

Cerebrospinal Fluid Aβ40, Aβ42, Tau, and Phosphorylated Tau biomarkers have been used for a clinical diagnosis of AD, discrimination from the Vascular dementia (VaD) and non-AD type dementia, exclusion of treatable dementia and MCI, prediction of AD onset and evaluation of the clinical trials of an anti-Aβ antibody, Aβ vaccine therapy, and secretase inhibitors [2–4].

In the current study Schoonenboom et al., [10] conducted a large cohort of patients with different types of dementia to determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels behave in CSF.

Aβ is produced mainly in the nerve cells of the brain, and it is secreted about 12 hours later into the CSF, then excreted through the blood-brain barrier 24 hours later into blood (Aβ clearance), and finally degraded in the reticuloendothelial system. Aβ levels are regulated in strict equilibrium among the brain, CSF, and blood [6, 7]. Aβ levels are high while awake and low while a sleep suggesting the presence of a daily change in the CSF Aβ amounts and it is because Aβ amounts in CSF are controlled by orexin and thus collection of CSF by lumbar puncture early in morning in a fasting state is recommended [5].

In AD brains, Aβ42 forms insoluble amyloids and accumulates as insoluble amyloid fibrils in the brain. The reason Aβ42 levels are decreased in the CSF of AD patients is considered to be caused by deterioration of physiologic Aβ clearance into the CSF in AD brains [2, 3]. CSF total tau levels increase slightly with aging. However, CSF tau levels show a 3-fold greater increase in AD patients than in normal controls [8].

It is thought that the rise in CSF total tau is related to degeneration of axons and neurons and to severe destructive disease of the nervous system. Several diseases show slightly increased tau levels such as VaD, multiple sclerosis, AIDS dementia, head injury, and tauopathy. However, CSF tau levels show significant increases in Creutzfeldt-Jakob disease (CJD) and meningoencephalitis [8].

These biomarkers can be measured with an Amyloid ELISA Kit (Wako), which is commercially available and used worldwide. The ELISA kit was developed in Japan by Suzuki et al. and shows extremely high sensitivity and reproducibility [9]. INNOTEST β-AMYLOID1-42 (Innogenetics), for Aβ42 is used widely in Europe and America.

Several assay kits for total tau and phosphorylated tau are also used for the measurement of CSF tau. Currently, total tau is measured using INNOTEST hTau Ag (Innogenetics). There are 3 ELISA systems for measurement of phosphorylated tau that recognize the special phosphorylation sites at Ser199 (Mitsubishi Chemical Corp.), Thr181 (Innogenetics) and Thr231 (Applied NeuroSolutions Inc.), and phosphorylated tau levels are increased in CSF of AD on assays using these kits. Of these 3 kits, INNOTEST PHOSPHO-TAU (181) (Innogenetics) is commercially available and used widely. Recently, INNO-BIA AlzBio3 by Innogenetics has been able to measure Aβ1-42, total tau, and P-tau181P simultaneously in 75 μL of CSF, which is a very small amount of CSF.

In the current study researchers used the following strategy to collect Baseline CSF and Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA:

Types of patients with Alzheimer disease (AD) = 512 patients
Types of patients with other types of dementia (OD) = 272 patients
Types of patients with a psychiatric disorder (PSY) = 135 patients
Types of patients with subjective memory complaints (SMC) = 275 patients
Autopsy was obtained in a subgroup of about 17 patients.

The study suggested that CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis, whereas in DLB, FTLD, VaD, and CBD, a substantial group exhibited a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

The study found a correct classification of patients with AD (92%) and patients with OD (66%)  when CSF Aβ42 and p-tau were combined.
Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%.

Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau.

CSF AD biomarker profile was seen in

47% of patients with dementia with Lewy bodies (DLB),

38% in corticobasal degeneration (CBD), and

30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD).

PSY and SMC patients had normal CSF biomarkers in 91% and 88%.

Older patients are more likely to have a CSF AD profile.

Concordance between clinical and neuropathologic diagnosis was 85%.

CSF markers reflected neuropathology in 94%.

The study concluded that CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

References:

1. R. C. Petersen, P. S. Aisen, L. A. Beckett et al., “Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization,” Neurology, vol. 74, no. 3, pp. 201–209, 2010.

2. M. Shoji and M. Kanai, “Cerebrospinal fluid Aβ40 and Aβ42: natural course and clinical usefulness,” Journal of Alzheimer’s Disease, vol. 3, no. 3, pp. 313–321, 2001.

3. M. Shoji, M. Kanai, E. Matsubara et al., “The levels of cerebrospinal fluid Aβ40 and Aβ42(43) are regulated age-dependently,” Neurobiology of Aging, vol. 22, no. 2, pp. 209–215, 2001.

4. M. Kanai, E. Matsubara, K. Isoe et al., “Longitudinal study of cerebrospinal fluid levels of tau, Aβ1-40, and Aβ1-42(43) in Alzheimer’s disease: a study in Japan,” Annals of Neurology, vol. 44, no. 1, pp. 17–26, 1998.

5. J. E. Kang, M. M. Lim, R. J. Bateman et al., “Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle,” Science, vol. 326, no. 5955, pp. 1005–1007, 2009.

6. M. Shoji, T. E. Golde, J. Ghiso et al., “Production of the Alzheimer amyloid β protein by normal proteolytic processing,” Science, vol. 258, no. 5079, pp. 126–129, 1992.

7. R. J. Bateman, E. R. Siemers, K. G. Mawuenyega et al., “A γ-secretase inhibitor decreases amyloid-β production in the central nervous system,” Annals of Neurology, vol. 66, no. 1, pp. 48–54, 2009.

8. M. Shoji, E. Matsubara, T. Murakami et al., “Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group,” Neurobiology of Aging, vol. 23, no. 3, pp. 363–370, 2002.

9. N. Suzuki, T. T. Cheung, X. D. Cai et al., “An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP) mutants,” Science, vol. 264, no. 5163, pp. 1336–1340, 1994.

Source:

10. N.S.M. Schoonenboom et al., Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort

For further insight read the following excellent review article by M. Shoji

Biomarkers of Dementia

Special thanks to Wikipedia for excellent relevant pictures and keyword links.

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