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Alzheimer's Disease
[edit]Cause
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Genetics
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The genetic heritability of Alzheimer's disease (and memory components thereof), based on reviews of twin and family studies, range from 49% to 79%.[1][2] Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65.[3] This form of the disease is known as early onset familial Alzheimer's disease. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2.[4] Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques.[5] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—e.g., Aβ40—without increasing Aβ42 levels.[5][6] This suggests that presenilin mutations can cause disease even if they lower the total amount of Aβ produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its fragments other than Aβ. There exist variants of the APP gene which are protective.[7]
Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD, in which environmental and genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE).[8][9] Between 40 and 80% of people with AD possess at least one APOEε4 allele.[9] The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes.[3] Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, certain Nigerian populations do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.[10][11] Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield,[3][4] More recent genome-wide association studies (GWAS) have found 19 areas in genes that appear to affect the risk.[12] These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SlC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP.[12]
Mutations in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer's disease.[13][14] A suggested mechanism of action is that when TREM2 is mutated, white blood cells in the brain are no longer able to control the amount of beta amyloid present.
Cholinergic hypothesis
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Amyloid hypothesis
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In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease.[15][16] Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age.[17][18] Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Whilst apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.[19] Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.[20]
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.[21] Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication.[22] One receptor for Aβ oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.[23]
In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by ageing-related processes in later life to cause the neuronal withering of Alzheimer's disease.[24] N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21).[24] DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.
Tau hypothesis
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![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/51/TANGLES_HIGH.jpg/300px-TANGLES_HIGH.jpg)
The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade.[16] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.[25] When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.[26] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.[27]
Sleep Disruption
[edit]A more recent explanation of Alzheimer's pathology postulates that sleep disruption can lead to or exacerbate already existing Alzheimer's Disease. Around 40% of Alzheimer's patients suffer from sleep disruption and it is the most common cause of institutionalization.[28][29] In general, sleep fragmentation has been found to correlate with the incidence of the disease[30] and there are various explanations for this hypothesis.
Slow wave sleep (SWS) is an important part of Non-rapid eye movement sleep that is implicated in facilitating memory consolidation. The amount of SWS is correlated with next day memory recall in healthy and Alzheimer's disease patients.[31] During SWS, mammals express two well defined oscillatory patterns, hippocampal ripples and cortical spindles. In Alzheimer's disease, patients show a decrease in time spent in SWS and a decreased ratio of SWS to REM sleep. Patients also show a reduction in fast spindles and overall spindle density, two measures which are associated with accuracy on memory recall tasks.[32] A reduction of SWS may lead to a breakdown of memory consolidation between the hippocampus and neocortex.[33]
Sleep disruption also adds a new dimension to the Amyloid hypothesis. In healthy patients, Aβ levels increase with wakefulness, but decrease during rest. In patients with Alzheimer's disease, there is less variability in Aβ, which remains high at night. This correlates with sleep disruption and increased wakefulness, which may lead to an overall increase in Aβ production.[34] Sleep disruption, therefore, could contribute to the build of Aβ proposed by the Amyloid hypothesis.
Another possible cause of sleep disruption is deregulation of hypocretin, melanin-concentrating hormone (MCH) and melatonin, three neuropeptides important in sleep and wakefulness. A deficiency in hypocretin is associated with sleeping disorders such as narcolepsy. Patients with Alzheimer's have decreased levels of hypocretin and hypocretin-1 neurons.[35] Low levels of hypocretin-1 has also been shown to correlate with increased sleep fragmentation in Alzheimer's.[36] If hypocretin levels are deregulated in Alzheimer's disease, then this could lead to poor sleep quality and therefore increased memory impairment.
MCH is correlated with Aβ levels and tau proteins associated with Alzheimer's. The levels of MCH in cerebral spinal fluid negatively correlate with memory. It has been suggested that misfolded tau protein tangles result in the hypersecretion of MCH, leading to daytime sleepiness and memory impairment.[37]
A potential treatment for Alzheimer's disease currently being tested is prolonged-release melatonin supplements. Melatonin improved sleep in Alzheimer's patients with and without insomnia, and it not only stopped memory decline, but improved performance after only 12 weeks. [38]
Other hypotheses
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Sleep and Memory
[edit]Methods of measuring memory
[edit]Behavioral measures
[edit]- A self-ordered pointing task is a task of memory where a participant is presented with a number of images (or words) which are arranged on a display. Several trials are presented, each with a different arrangement and containing some of the previous words or images. The task for the participant is to point to a word or image they had not previously pointed to in other trials.[39]
- In a recency discrimination task participants are shown two trials of image presentation and then a third trial containing a mixture of images from the first and second trial. Their task is to determine whether the image was from the most recent presentation or the previous one.[39]
- In a route retrieval task spatial learning occurs where a participant virtual tours a particular place (such as a town or maze). Participants are asked to virtually tour the same thing at a later time while brain imaging is used to measure activity.[40]
- A paired word associative task consists of two phases. During the first phase (acquisition), the responses of the paired-associate task are learned and become recallable. In the second phase (associative phase), the subject learns to pair each response to a separate stimulus. For example a visual cue would provide information as to what words must be recalled after the stimulus and words are removed.[41]
- In a mirror tracing task participants are asked to trace several figures as fast and as accurately as possible which they can only see in a mirror. Speed is recorded as well as how much they deviate from the original image (accuracy).[41]
- In the Morris water maze task rats are used to test their spatial learning in two kinds of conditions: spatial and nonspatial. In the spatial condition, a platform is hidden by using murky water and in the nonspatial condition, the platform is visible. The spatial condition the rat must rely on their spatial memory to find the platform whereas the nonspatial condition is used for comparison purposes.[42]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/b/bc/MorrisWaterMaze.jpg/180px-MorrisWaterMaze.jpg)
- The serial reaction time task (SRT task) is a task whereby subjects face a computer screen where several markers are displayed that are spatially related to relevant markers on their keyboard. The subjects are asked to react as fast and accurately as possible to the appearance of a stimulus below one of the markers. Subjects can be trained on the task with either explicit instructions (e.g. there are colour sequences presented which must be learned) or implicit ones (e.g. the experimentor does not mention colour sequences, thus leaving the subjects to believe that they are taking place in a speed test). When this task is used in sleep studies, after a time delay, subjects are tested for retention.[43]
- In a block tapping task participants are asked to type a sequence of five numbers with their dominant or non-dominant hand (specified in experiment), for an allotted period of time, followed by a rest period. A number of these trials occur and the computer records the number of sequences completed to assess speed and the error rate to assess accuracy.[44]
- A finger tapping test is commonly used when a pure motor task is needed. A finger tapping test requires subjects to continuously press four keys (typically numerical keys) on a keypad with their nondominant hand in a sequence, such as 4-3-1-2-4, for a given amount of time. Testing is done by determining the number of errors made.[45]
Neural imaging measures
[edit]Neuroimaging can be classified into two categories, both used in varying situations depending on what type of information is needed. Structural imaging deals predominately with the structure of the brain (computed tomography) while functional imaging deals more heavily with metabolic processes in regards to anatomical functioning (positron emission tomography, functional magnetic resonance imaging). In recent years, the relationship between sleep and memory processes had been aided by the development of such neuroimaging techniques.[46]
Positron emission tomography (PET) is used in viewing a functional processes of the brain (or other body parts). A Positron-emitting radionuclide is injected into the blood stream and emits gamma rays which are detected by an imaging scanner. Computer analysis then allows for a 3-dimensional reconstruction of the brain region or body part of interest.
Functional magnetic resonance imaging (fMRI) is a type of brain imaging that measures the change of oxygen in the blood due to the activity of neurons. The resulting data can be visualized as a picture of the brain with colored representations of activation.
Molecular measures
[edit]Although this may be seen as similar to neuroimaging techniques, molecular measures help to enhance areas of activation that would otherwise be indecipherable to neuroimaging. One such technique that aids in both the temporal and visual resolution of fMRI is the blood-oxygen-level dependent (BOLD) response. Changes in the BOLD response can be seen when there is differing levels of activation in suspected areas of functioning. Energy is supplied to the brain in the form glucose and oxygen (which is transferred by hemoglobin). The blood supply is consistently regulated so that areas of activation receive higher amounts of energy compared to areas that are less activated.[47] In positron emission tomography, the use of radionuclides (isotopes with short half lives) facilitates visual resolution. These radionuclides are attached to glucose, water and ammonia so that easy absorption into the activated brain areas is accomplished. Once these radioactive tracers are injected into the bloodstream, the efficiency and location of chemical processes can be observed using PET.[48]
Methods of measuring sleep
[edit]Electrophysiological measures
[edit]The main method of measuring sleep in humans is polysomnography (PSG). For this method, participants often must come into a lab where researchers can use PSG to measure things such as total sleep time, sleep efficiency, wake after sleep onset, and sleep fragmentation. PSG can monitor various body functions including brain activity (electroencephalography), eye movement (electrooculography), muscle movement (electromyography), and heart rhythm (electrocardiography).
Electroencephalography (EEG) is a procedure that records electrical activity along the scalp. This procedure cannot record activity from individual neurons, but instead measures the overall average electrical activity in the brain.
Electrooculography (EOG) measures the difference in electrical potential between the front and the back of the eye. This does not measure a response to individual visual stimuli, but instead measures general eye movement.
Electromyography (EMG) is used to records the electrical activity of skeletal muscles. A device called an electromyograph measures the electrical potential of muscle cells to monitor muscle movement.
Electrocardiography (ECG or EKG) measures the electrical depolarization of the heart muscles using various electrodes placed near the chest and limbs. This measure of depolarization can be used to monitor heart rhythm.
Behavioural measures
[edit]Actigraphy is a common and minimally invasive way to measure sleep architecture. Actigraphy has only one method of recording, movement. This movement can be analyzed using different actigraphic programs. As such, an actigraph can often be worn similarly to a watch, or around the waist as a belt. Because it is minimally invase and relatively inexpensive, this method allows for recordings outside of a lab setting and for many days at a time. But, actigraphy often over estimates sleep time (de Souza 2003 and Kanady 2011).
Alternative sleep schedules
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Sleep and Aging
[edit]Sleep often becomes deregulated in the elderly and can lead to or exacerbate preexisting memory decline.
Healthy older adults
[edit]The positive correlation between sleep and memory breaks down with aging. In general, older adults suffer from decreased sleep efficiency.[49] The amount of time and density of REM sleep and SWS decreases with age.[50][51][52] Consequently, it is common that the elderly receive no increase in memory after a period of rest.[53]
To combat this, donepezil has been tested in healthy elderly patients where it was shown to increase time spent in REM sleep and improve next day memory recall.[54]
Alzheimer's disease
[edit]Patients with Alzheimer's disease experience more sleep disruption than the healthy elderly. Studies have shown that in patients with Alzheimer's disease, there is a decrease in fast spindles. It has also been reported that spindle density the night before a memory test correlate positively with accuracy on an immediate recall task.[50] A positive correlation between time spent in SWS and next day autobiographical memory recall has also been reported in Alzheimer's patients.[55]
- ^ Wilson RS, Barral S, Lee JH, Leurgans SE, Foroud TM, Sweet RA, Graff-Radford N, Bird TD, Mayeux R, Bennett DA. Heritability of different forms of memory in the Late Onset Alzheimer's Disease Family Study.. J Alzheimers Dis.. 2011;23(2):249–55. doi:10.3233/JAD-2010-101515. PMID 20930268.
- ^ Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63(2):168–74. doi:10.1001/archpsyc.63.2.168. PMID 16461860.
- ^ a b c Blennow K, de Leon MJ, Zetterberg H. Alzheimer's Disease. Lancet. 2006;368(9533):387–403. doi:10.1016/S0140-6736(06)69113-7. PMID 16876668.
- ^ a b Waring SC, Rosenberg RN. Genome-wide association studies in Alzheimer disease. Archives of Neurology. 2008;65(3):329–34. doi:10.1001/archneur.65.3.329. PMID 18332245.
- ^ a b Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature. 1999;399(6738 Suppl):A23–31. doi:10.1038/19866. PMID 10392577. Cite error: The named reference "pmid8938131" was defined multiple times with different content (see the help page).
- ^ Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK. FAD mutants unable to increase neurotoxic Aβ 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. Journal of Neurochemistry. 2007;101(3):674–81. doi:10.1111/j.1471-4159.2006.04391.x. PMID 17254019.
- ^ Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.. Nature. 2 August 2012;488(7409):96–9. doi:10.1038/nature11283. PMID 22801501.
- ^ Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(5):1977–81. doi:10.1073/pnas.90.5.1977. PMID 8446617.
- ^ a b Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(15):5644–51. doi:10.1073/pnas.0600549103. PMID 16567625.
- ^ Hall K, Murrell J, Ogunniyi A, Deeg M, Baiyewu O, Gao S, Gureje O, Dickens J, Evans R, Smith-Gamble V, Unverzagt FW, Shen J, Hendrie H. Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba. Neurology. 2006;66(2):223–227. doi:10.1212/01.wnl.0000194507.39504.17. PMID 16434658.
- ^ Gureje O, Ogunniyi A, Baiyewu O, Price B, Unverzagt FW, Evans RM, Smith-Gamble V, Lane KA, Gao S, Hall KS, Hendrie HC, Murrell JR. APOE ε4 is not associated with Alzheimer's disease in elderly Nigerians. Annals of Neurology. 2006;59(1):182–185. doi:10.1002/ana.20694. PMID 16278853.
- ^ a b Lambert, JC (Dec 2013). "Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease". Nature Genetics. 45 (12): 1452–8. doi:10.1038/ng.2802. PMC 3896259. PMID 24162737.
- ^ Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K. Variant of TREM2 associated with the risk of Alzheimer's disease. The New England Journal of Medicine. 2012;368(2):107–16. doi:10.1056/NEJMoa1211103. PMID 23150908.
- ^ Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J. TREM2 variants in Alzheimer's disease. The New England Journal of Medicine. 2012;368(2):117–27. doi:10.1056/NEJMoa1211851. PMID 23150934.
- ^ Hardy J, Allsop D. Amyloid Deposition as the Central Event in the Aetiology of Alzheimer's Disease. Trends in Pharmacological Sciences. 1991;12(10):383–88. doi:10.1016/0165-6147(91)90609-V. PMID 1763432.
- ^ a b Mudher A, Lovestone S. Alzheimer's disease-do tauists and baptists finally shake hands?. Trends in Neurosciences. 2002;25(1):22–26. doi:10.1016/S0166-2236(00)02031-2. PMID 11801334.
- ^ Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E. Alpha- and Beta-secretase Activity as a Function of Age and Beta-amyloid in Down Syndrome and Normal Brain. Neurobiology of Aging. 2007;28(10):1493–1506. doi:10.1016/j.neurobiolaging.2006.06.023. PMID 16904243.
- ^ Lott IT, Head E. Alzheimer Disease and Down Syndrome: Factors in Pathogenesis. Neurobiology of Aging. 2005;26(3):383–89. doi:10.1016/j.neurobiolaging.2004.08.005. PMID 15639317.
- ^ Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K. Apolipoprotein E, Dementia, and Cortical Deposition of Beta-amyloid Protein. The New England Journal of Medicine. 1995;333(19):1242–47. doi:10.1056/NEJM199511093331902. PMID 7566000.
- ^ Transgenic mice:
- Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F. Alzheimer-type Neuropathology in Transgenic Mice Overexpressing V717F Beta-amyloid Precursor Protein. Nature. 1995;373(6514):523–27. doi:10.1038/373523a0. PMID 7845465.
- Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. Comparison of Neurodegenerative Pathology in Transgenic Mice Overexpressing V717F Beta-amyloid Precursor Protein and Alzheimer's Disease. The Journal of Neuroscience. 1996;16(18):5795–811. PMID 8795633.
- Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative Memory Deficits, Abeta Elevation, and Amyloid Plaques in Transgenic Mice. Science. 1996;274(5284):99–102. doi:10.1126/science.274.5284.99. PMID 8810256.
- Lalonde R, Dumont M, Staufenbiel M, Sturchler-Pierrat C, Strazielle C. Spatial Learning, Exploration, Anxiety, and Motor Coordination in Female APP23 Transgenic Mice with the Swedish Mutation. Brain Research. 2002;956(1):36–44. doi:10.1016/S0006-8993(02)03476-5. PMID 12426044.
- ^ Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term Effects of Abeta42 Immunisation in Alzheimer's Disease: Follow-up of a Randomised, Placebo-controlled Phase I Trial. Lancet. 2008;372(9634):216–23. doi:10.1016/S0140-6736(08)61075-2. PMID 18640458.
- ^ Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. Aß Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease. The Journal of Neuroscience. 2007;27(4):796–807. doi:10.1523/JNEUROSCI.3501-06.2007. PMID 17251419.
- ^ Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers. Nature. 2009;457(7233):1128–32. doi:10.1038/nature07761. PMID 19242475.
- ^ a b Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP Binds DR6 to Cause Axon Pruning and Neuron Death via Distinct Caspases. Nature. 19 February 2009;457(7232):981–989. doi:10.1038/nature07767. PMID 19225519.
- ^ Goedert M, Spillantini MG, Crowther RA. Tau Proteins and Neurofibrillary Degeneration. Brain Pathology (Zurich, Switzerland). 1991;1(4):279–86. doi:10.1111/j.1750-3639.1991.tb00671.x. PMID 1669718.
- ^ Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I. Tau Pathology in Alzheimer Disease and Other Tauopathies. Biochimica Et Biophysica Acta. 2005;1739(2–3):198–210. doi:10.1016/j.bbadis.2004.09.008. PMID 15615638.
- ^ Chun W, Johnson GV. The Role of Tau Phosphorylation and Cleavage in Neuronal Cell Death. Frontiers in Bioscience: A Journal and Virtual Library. 2007;12:733–56. doi:10.2741/2097. PMID 17127334.
- ^ Carpenter B, Stauss M, Patterson M. Sleep Disturbances in Community-Dwelling Patients with Alzheimer's Disease. Clin Gerontol. 1996;16(2):35–49. doi:10.1300/J018v16n02_04.
- ^ Tractenberg R, Singer C, Cummings J, Thai L. The Sleep Disorders Inventory: an instrument for studies of sleep disturbance in persons with Alzheimer's disease. J Sleep Res. 2003;12(4):331–337. doi:10.1046/j.0962-1105.2003.00374.x. PMID 14633245.
- ^ Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA. Sleep fragmentation and the risk of incident Alzheimer's disease and cognitive decline in older persons. SLEEP. 2013;36(7):1027–1032. doi:10.5665/sleep.2802. PMID 23814339.
- ^ Rauchs G, Piolino P, Bertran F, de La Sayette V, Viader F, Eustache F, Desgranges B. Retrieval of recent autobiographical memories is associated with slow-wave sleep in early AD. Front Behav. 2013;7(114):1–11. doi:10.3389/fnbeh.2013.00114. PMID 24065896.
- ^ Rauchs G, Schabus M, Parapatics S, Bertran F, Clochon P, Hot P, Denise P, Desgranges B, Eustache F, Gruber G, Anderer P. Is there a link between sleep changes and memory in Alzheimer’s disease?. NeuroReport. 2008;19(11):1159–1162. doi:10.1097/WNR.0b013e32830867c4. PMID 18596620.
- ^ Siapas A, Wilson A. Coordinated Interactions between Hippocampal Ripples and Cortical Spindles during Slow-Wave Sleep. Neuron. 1998;21(5):1123–1128. doi:10.1016/S0896-6273(00)80629-7. PMID 9856467.
- ^ Huang Y, Potter R, Sigurdson W, Santacruz A, Shih S, Ju YE, Kasten T, Morris JC, Mintun M, Duntley S, Bateman RJ. Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system. Arch Neurol. 2012;69(1):51–58. doi:10.1001/archneurol.2011.235. PMID 21911660.
- ^ Fronczek R, van Geest S, Frölich M, Overeem S, Roelandse FW, Lammers GJ, Swaab DF. Hypocretin (orexin) loss in Alzheimer’s disease. Neurobiol Aging. 2012;33:1642–1650. doi:10.1016/j.neurobiolaging.2011.03.014. PMID 21546124.
- ^ Friedman LF, Zeitzer JM, Lin L, Hoff D, Mignot E, Peskind ER, Yesavage JA. In Alzheimer disease, increased wake fragmentation found in those with lower hypocretin-1. Neurology. 2012;68:793–794. doi:10.1212/01.wnl.0000256731.57544.f9. PMID 17339595.
- ^ Schmidt FM, Kratzsch J, Gertz HJ, Tittmann M, Jahn I, Pietsch UC, Kaisers UX, Thiery J, Hegerl U, Schönknecht P. Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer's disease. PLoS One. 2013;8(5):1–6. doi:10.1371/annotation/7a79c40c-c1c2-41eb-a894-614c12e8c056. PMID 23667582.
- ^ Wade AG, Farmer M, Harari G, Fund N, Laudon M, Nir T, Frydman-Marom A, Zisapel N. Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer's disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 2014;9:947–961. doi:10.2147/CIA.S65625. PMID 24971004.
- ^ a b Gillin, J. Christian; Drummond, Sean P. A.; Brown, Gregory G.; Stricker, John L.; Wong, Eric C.; Buxton, Richard B. (2000). "Altered brain response to verbal learning following sleep deprivation". Nature. 403 (6770): 655–7. Bibcode:2000Natur.403..655D. doi:10.1038/35001068. PMID 10688201.
- ^ Cite error: The named reference
spatial memories
was invoked but never defined (see the help page). - ^ a b Gais, Steffen; Born, Jan (2004). "Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation". Proceedings of the National Academy of Sciences. 101 (7): 2140. Bibcode:2004PNAS..101.2140G. doi:10.1073/pnas.0305404101. JSTOR 3371408.
- ^ Cite error: The named reference
brain research
was invoked but never defined (see the help page). - ^ Robertson, Edwin M.; Pascual-Leone, Alvaro; Press, Daniel Z. (2004). "Awareness Modifies the Skill-Learning Benefits of Sleep". Current Biology. 14 (3): 208–12. doi:10.1016/j.cub.2004.01.027. PMID 14761652.
- ^ Cite error: The named reference
walker
was invoked but never defined (see the help page). - ^ Walker, Matthew P.; Brakefield, Tiffany; Morgan, Alexandra; Hobson, J.Allan; Stickgold, Robert (2002). "Practice with Sleep Makes Perfect". Neuron. 35 (1): 205–11. doi:10.1016/S0896-6273(02)00746-8. PMID 12123620.
- ^ Maquet, Pierre; Laureys, Steven; Peigneux, Philippe; Fuchs, Sonia; Petiau, Christophe; Phillips, Christophe; Aerts, Joel; Del Fiore, Guy; et al. (2000). "Experience-dependent changes in cerebral activation during human REM sleep". Nature Neuroscience. 3 (8): 831–6. doi:10.1038/77744. PMID 10903578.
- ^ Siesjo, Bo K. (1978). Brain Energy Metabolism. New York: Wiley. p. 612. ISBN 0-471-99515-0.
- ^ Rennie, Michael J. (2007). "An introduction to the use of tracers in nutrition and metabolism". Proceedings of the Nutrition Society. 58 (4): 935–44. doi:10.1017/S002966519900124X. PMID 10817161.
- ^ Morin, Charles; Gramling, Sandy (1989). "Sleep patterns and aging: Comparison of older adults with and without insomnia complaints". Psychology and Aging. 4 (3): 290–294. doi:10.1037/0882-7974.4.3.290. PMID 2803622.
- ^ a b Rauchs, Géraldine; Schabus, Manuel; Parapatics, Silvia; Bertran, Francoise; Clochon, Patrice; Hot, Pascal; Denise, Pierre; Desgranges, Beatrice; Eustache, Francis; Gruber, Georg; Anderer, Peter (2008). "Is there a link between sleep changes and memory in Alzheimer's disease?". Learning and Memory. 19 (11): 1159–1162. doi:10.1097/WNR.0b013e32830867c4. PMID 18596620.
- ^ Petit, Dominique; Gagnon, Jean-François; Fantini, Maria; Ferini-Strambi, Luigi; Montplaisir, Jacques (2004). "Sleep and quantitative EEG in neurodegenerative disorders". Journal of Psychosomatic Research. 56 (5): 487–496. doi:10.1016/j.jpsychores.2004.02.001. PMID 15172204.
- ^ Darchia, Nato; Campbell, Ian; Feinberg, Irwin (2003). "Rapid eye movement density is reduced in the normal elderly". Sleep. 26 (8): 973–977. PMID 14746377.
- ^ Scullin, Michael (2013). "Sleep, Memory, and Aging: The Link Between Slow-Wave Sleep and Episodic Memory Changes from Younger to Older Adults". Psychology and Aging. 28 (1): 105–114. doi:10.1037/a0028830. PMC 3532961. PMID 22708533.
- ^ Schredl, M; Weber, B; Leins, M; Heuser, I (2001). "Donepezil-induced REM sleep augmentation enhances memory performance in elderly, healthy persons". Experimental Gerontology. 36 (2): 353–361. PMID 11226748.
- ^ Rauchs, G; Piolino, P; Bertran, F; de La Sayette, V; Viader, F; Eustache, F; Desgranges, B (2013). "Retrieval of recent autobiographical memories is associated with slow-wave sleep in early AD". Frontiers in Behavioral Neuroscience. 7 (114): 1–11. doi:10.3389/fnbeh.2013.00114. PMID 24065896.
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