Module 5: Discussion Board replies

Reply to the 2 peer post


Post 1

Compare and contrast current disease-modifying treatments with symptomatic treatments of Alzheimer’s disease. For this discussion, be sure to specify what the treatments are, their targets, and at what stage of the disease process they are used (if applicable).

The disease modifying treatments are new and under investigative research. Immunotherapies aim to reduce Aβ plaque deposition in the brain, which is the hallmark pathological feature of AD. These treatments are typically initiated in the early stages of the disease to prevent further accumulation of Aβ and potentially slow disease progression (Jacobson, 2014).

Symptomatic treatments do not alter the progression of disease. Cholinesterase inhibitors include drugs such as donepezil, rivastigmine, and galantamine. These drugs increase acetylcholine levels in the brain, thereby improving cognitive function and managing symptoms like memory loss and confusion. These medications are typically used across all stages of AD to alleviate cognitive symptoms (Jacobson, 2014).

NMDA Receptor Antagonists include memantine. This drug regulates glutamate activity in the brain, helping to manage symptoms like agitation and aggression. It is indicated in moderate to severe stages of AD (Stahl, 2021).

Non-pharmacological approaches, including cognitive stimulation therapy, reality orientation therapy, and caregiver support, are essential for managing behavioral and psychological symptoms throughout the disease progression.

Discuss the three stages of Alzheimer’s disease; make sure to include neurodegeneration in your discussion.

Alzheimer’s disease typically progresses through three stages. The early stage is or presymptomatic stage characterized by subtle memory lapses, difficulty concentrating, and mild cognitive impairment. At this stage, amyloid beta accumulates in the brain silently (Stahl, 2021).

The middle stage (Moderate Alzheimer’s Disease) is when cognitive decline becomes more pronounced, with individuals experiencing significant memory loss, language difficulties, and behavioral changes. Neurodegeneration in Alzheimer’s disease involves the progressive loss of neurons and synapses, accompanied by the accumulation of abnormal protein aggregates such as amyloid beta plaques and tau tangles. This neuronal loss disrupts neural circuits and neurotransmitter systems, contributing to cognitive decline and functional impairment (Stahl, 2021).

The third and final stage is late stage (Severe Alzheimer’s Disease). This is characterized by severe cognitive deficits, profound memory loss, disorientation, and loss of motor function. Neurodegeneration affects widespread regions of the brain, leading to global cognitive decline and loss of independence (Stahl, 2021).

García-Martín (2023) discusses the prevalence of neuropsychiatric symptoms associated with AD. Depression caused more distress in the early stages. Irritability, disinhibition, agitation, and aberrant motor activity, all of which are symptoms of hyperactivity, caused greater distress in cases of mild and moderate dementia. Psychotic symptoms (delusions, hallucinations, and sleep disorders) caused greater distress in advanced stages. Apathy remained more stable throughout all phases of dementia.

Discuss the sleep wake cycle and histamine’s role in it.

The sleep-wake cycle, also known as the circadian rhythm, is regulated by a complex interplay of neurotransmitters and neurochemicals in the brain, including histamine. Histamine, primarily synthesized in the hypothalamus, promotes wakefulness and alertness by acting on histamine receptors, particularly H1 and H3 receptors (Stahl, 2021).

Histaminergic neurons of the hypothalamus project widely throughout the brain, promoting wakefulness and maintaining attention during the waking state. Conversely, histaminergic activity decreases during sleep, allowing other sleep-promoting neurotransmitters such as GABA and melatonin to dominate. It is also the site of action for some drugs that when blocked causes sedation, drowsiness, and sleep. Histamine’s role in the sleep-wake cycle is crucial for maintaining optimal arousal levels and promoting wakefulness during the day. Dysregulation of histaminergic signaling has been associated with sleep disorders such as insomnia and excessive daytime sleepiness (Stahl, 2021).


García-Martín, V., de Hoyos-Alonso, M. C., Delgado-Puebla, R., Ariza-Cardiel, G., & Del Cura-González, I. (2023). Burden in caregivers of primary care patients with dementia: influence of neuropsychiatric symptoms according to disease stage (NeDEM project). BMC Geriatrics, 23(1), 525. to an external site.

Jacobson, S. (2014). Clinical manual of geriatric psychopharmacology (2nd ed.). American Psychiatric Association.

Stahl, S. M. (2021). Stahl’s essential psychopharmacology: Neuroscientific basic and practical applications (5th edition). Cambridge University Press.

Post 2:

Compare and contrast current disease-modifying treatments with symptomatic treatments of Alzheimer’s disease. For this discussion, be sure to specify what the treatments are, their targets, and at what stage of the disease process they are used (if applicable).

Disease-modifying treatment strategies that could reverse or halt the course of Alzheimer disease (AD) by interfering with amyloid-beta accumulation and intracellular neurofibrillary tangle formation are still under extensive research (Yiannopoulou & Papgeorgiou, 2020). Unfortunately, many of these treatments have failed in the past 30 years (Stahl, 2021). The current treatments available for AD are symptomatic treatments that improve suffering but do not stop neurodegeneration (Stahl, 2021). Instead, the symptomatic treatment approach targets neurotransmitters in different brain circuits that hypothetically regulate different dementia symptoms (Stahl, 2021).

Acetylcholinesterase inhibitiors (AChEIs) target the degeneration of cholinergic neurons, thought to be responsible for memory disturbance and cognitive decline as MCI progress to dementia in AD (Stahl, 2021). Acetylcholinesterase inhibition increases acetylcholine levels and hypothetically restores some of the lost function of degenerated cholinergic neurons (Stahl, 2021). The AChEIs that are approved for the treatment of AD include Donepezil, Rivastigmine, and Galantamine (Stahl, 2021). They have been proven clinically useful in delaying cognitive decline in AD, at least during the first year of treatment (Yiannopoulou & Papageorgiou, 2020). Further decline occurs, but discontinuation results in rapid decline (Yiannopoulou & Papageorgiou, 2020). Initiation of AChEI treatment is recommended as soon as possible after diagnosis, and is approved for mild, moderate, and severe AD (Yiannopoulou & Papageorgiou, 2020).

Another treatment for the memory disturbance and cognitive decline of AD is the low-to-moderate affinity, noncompetitive NMDA receptor antagonist memantine (Yiannopoulou & Papageorgiou, 2020).  Memantine targets excess glutamate release because of neurodegeneration of glutamatergic circuits as patients transition from MCI to AD (Stahl, 2021). It’s hypothesized that neurotoxic amyloid-beta plaques and neurofibrillary tangles cause a steady leak of glutamate, interfering with glutamate neurotransmission, and therefore with memory and learning (Stahl. 2021). This glutamate release is thought to worsen as AD progresses, eventually killing off dendrites and full neurons through excitotoxic cell death (Stahl, 2021). Memantine binds to open NMDA receptor-operated calcium channels, blocking ion flux and reducing abnormal activation of glutamate neurotransmission (Yiannopoulou & Papageorgiou, 2020). This theoretically improves memory, slows the rate of neuronal death, and delays associated cognitive decline that causes AD progression (Stahl, 2021). Memantine is approved for moderate and severe AD, either as monotherapy or in combination with AChEI (Yiannopoulou & Papageorgiou, 2020).

Behavioral and psychological symptoms of dementia are treated with antipsychotics and antidepressants (cite). Selective serotonin reuptake inhibitors are preferred for depression and anxiety in AD (Yiannopoulou & Papageorgiou, 2020). Antipsychotics are only recommended when there is a significant safety risk for the patient or caregivers (Yiannopoulou & Papageorgiou, 2020). There are a couple novel treatments that aim to address psychosis and agitation in AD including primavenserin, a 5HT2A antagonist for dementia-related psychosis, and brexiprazole, a serotonin-dopamine-norepinephrine antagonist/partial agonist (Stahl, 2021).

There are multiple drugs under research for AD that target either disease modification or symptoms (Yiannopoulou & Papageorgiou, 2020).  There have been many recent failures of anti-amyloid agents for disease modifying therapy, and it’s thought that these therapies are started too late in disease development, are at incorrect doses, and are due to inadequate understanding of the pathophysiology of AD (Yiannopoulou & Papageorgiou, 2020). Still, current research remains focused both on disease modifying treatments that can halt disease progression as well as symptomatic treatments to reduce suffering (Yiannopoulou & Papageorgiou, 2020).

Discuss the three stages of Alzheimer’s disease; make sure to include neurodegeneration in your discussion.

The presymptomatic stage of Alzheimer’s Disease (AD), or asymptomatic amyloidosis, is characterized by the silent process of amyloid-beta accumulation in the brain (Stahl, 2021). PET scans and radioactive neuroimaging tracers can detect amyloid-beta plaques in the brain and therefore are considered to have presymptomatic AD (Stahl, 2021). Low levels of amyloid-beta may also be detected in cerebrospinal fluid (CSF) at this stage of illness (Stahl. 2021).

The second stage of AD is referred to as prodromal AD, predementia AD, or mild cognitive impairment (MCI) due to AD (Stahl, 2021). This stage is characterized by clinical symptoms of MDI and signs of neurodegeneration (Stahl, 2021). Neurodegeneration is identified by the presence of elevated tau protein levels in CSF, the presence of neurofilament light (NfL) on CSF or plasma, and by atrophy on MRI (Stahl, 2021). Tau proteins normally bind and stabilize microtubules within axonal projections allowing transportation of neurotransmitters to the synapse, but when hyperphosphorylated, tau is no longer able to bind, so microtubules become destabilized resulting in synaptic dysfunction (Stahl, 2021). Hyperphosphorylated tau also results in paired helical filaments which accumulate neurofibrillary tangles (NFTs), a hallmark of AD (Stahl, 2021). In this stage, tau levels progressively rise in CSF (Stahl, 2021). Neurodegeneration is visible on MRI or FDG PET (Stahl, 2021).

Dementia is the final stage of AD (Stahl, 2021). In this stage, full-blown dementia is clinically evident, and a large accumulation of brain amyloid-beta can be seen on PET imaging (Stahl, 2021). Neuronal loss may be detected on MRI or FDG PET (Stahl, 2021). Changes on MRI include hippocampal atrophy, ventricular enlargement, and loss of cortical thickness (Stahl, 2021).

Discuss the sleep wake cycle and histamines role in it.

The sleep wake cycle includes two opposing drivers including the homeostatic sleep drive and the circadian wake drive (Stahl, 2021). The circadian wake drive occurs with the input of light, melatonin, and activity to the suprachiasmatic nucleus of the hypothalamus, stimulating the release of orexin and stabilizing wakefulness (Stahl, 2021). The homeostatic sleep drive depends on the increasing accumulation of adenosine the longer one is awake, and the decrease of adenosine with sleep (Stahl, 2021). As adenosine accumulates, the ventrolateral preoptic nucleus is disinhibited, and GABA is released in the tuberomammillary nucleus to inhibit wakefulness (Stahl, 2021). As the day goes on, the homeostatic sleep drive increases, and the circadian wake drive decreases, until a tipping point is reached (Stahl, 2021). Sleep is then regulated by the ultradian sleep cycle including multiple phases of progressively deep sleep and rapid eye movement (Stahl, 2021).

Histamine is a key neurotransmitter which regulates wakefulness (Stahl, 2021). It’s release is in circadian rhythm with wake behavior (Mochizuki, 2021). When postsynaptic histamine 1 (H1) receptors are activated by histamine, a G-protein-linked second messenger activates phosphatidylinositol which then triggers the transcription factor cFOS, resulting in normal alertness, wakefulness, and pro-cognitive actions (Stahl, 2021). When H1 receptors are blocked in the brain, such as by antihistamines, the wake-promoting actions of histamine are blocked and the result is sedation, drowsiness, or sleep (Stahl, 2021). H3 receptors are presynaptic, and when histamine binds to these receptors it turns off further histamine release (Stahl, 2021). Blocking these receptors results in wakefulness, and is a potential novel approach to pro-cognitive, wake-promoting drugs (Stahl, 2021).


Mochizuki, T. (2021). Histamine as an Alert Signal in the Brain. In: Yanai, K., Passani, M.B. (eds) The Functional Roles of Histamine Receptors. Current Topics in Behavioral Neurosciences, vol 59. Springer, Cham.

Stahl, S. (2021). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications. Cambridge University Press. doi: 10.1017/9781108975292

Yiannopoulou, K. G., & Papageorgiou, S. G. (2020). Current and Future Treatments in Alzheimer Disease: An Update. Journal of central nervous system disease12, 1179573520907397.


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