Purpose : To introduce Alzheimer’s disease and the discovery of senile plaques and neurofibrillary tangles Key Points : Frau Auguste D. was brought by her husband to Alois Alzheimer at a German mental asylum. The husband complained that she had changed drastically over the last few years, that she had become insanely jealous, had severe memory loss, fits of screaming, and hallucinations. He no longer recognized the woman he was married to. Upon her death, Alois Alzheimer examined her brain and observed abundant senile plaques and strange neurofibrillary formations in the cerebral cortex, which he determined were responsible for her dementia. As we now know, senile plaques, made up of insoluble amyloid beta fragments, and neurofibrillary tangles of hyperphosphorylated tau are the hallmarks of Alzheimer’s disease.
Purpose : To show the prevalence, diagnosis, and treatment of AD across the 3 stages of the disease Key Points : There is a significant number of patients in the moderate and severe stages of AD. Until now, these patients have been treated primarily with acetylcholinesterase inhibitor therapies, which are indicated for mild to moderate stages of the disease. Based on current understanding of the neuropathology of AD, much more cellular content and signaling remain intact late in the disease. This provides an opportunity to develop therapies that can benefit patients with moderate to severe AD.
Cholinergic neurons manufacture choline acetyltransferase (ChAT), which catalyzes the formation of acetylcholine (ACh) from acetyl-coenzyme A (acetyl-CoA) and choline. ACh is then released from the presynaptic neuron into the synaptic cleft, where it binds to cholinergic receptors on the postsynaptic neuron or is broken down by acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) into choline and acetate. Choline is then taken up by the presynaptic neuron and recycled for the synthesis of ACh.1,2 Two classes of cholinergic receptors are recognized: muscarinic (stimulatory) and nicotinic (inhibitory). Numerous types of muscarinic and nicotinic receptors have been identified. Muscarinic receptors are found mainly on the autonomic nervous system end organs such as cardiac tissue, smooth muscle, and exocrine glands. Nicotinic receptors are found in the central nervous system, adrenal medulla, autonomic ganglia, and the neuromuscular junction.1 AChE, the primary cholinesterase in the brain, is located in the synaptic space (soluble form) and in the synaptic membranes (membrane-bound form) of the neurons of the cholinergic system. BuChE, the other type of cholinesterase, is produced by glial cells.2 References: 1. Mycek MJ, Gertner SB, Perper MM. Cholinergic agonists. In: Harvey RA, Champe PC, eds. Pharmacology: Lippincott's Illustrated Reviews. Philadelphia, Pa: J. B. Lippincott Company; 1992:35-44. 2. Wright CI et al. Neuroglial cholinesterases in the normal brain and in Alzheimer's disease: relationship to plaques, tangles, and patterns of selective vulnerability. Ann Neurol. 1993;34:373-384.
There are number of different dementias of which AD is the most common form. Due to the lack of acceptable biological markers, the diagnosis of dementia is primarily clinical. The diagnostic guidelines and criteria are included in the National Institute of Neurological and Communicative Disorders and Stroke—the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA), American Academy of Neurology (AAN), Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the International Classification of Diseases (ICD-10) of the World Health Organization (1992), and the Mini-Mental State Examination (MMSE). Accurate diagnosis of dementia that could account for the progressive memory and other cognitive deficits may be often difficult. The first step in the differential diagnosis of dementia is to exclude any reversible dementias, in which the conditions are reversed after proper treatment, ie, vitamin B 12 , folic acid, or thiamine deficiency, hypothyroidism, or any other systemic causes of symptoms except organic brain syndromes, ie, AIDS-related or alcohol-induced. The other, nonreversible dementias are characterized by similar symptom presentation but are differentiated based on etiology. A common characteristic seen among many of these disorders is the cholinergic deficit with the exception of progressive supranuclear palsy, frontal lobe dementia, and Pick’s disease. In addition, many patients may have multiple etiologies that may explain their dementia, ie, mixed dementia, AD with Lewy bodies.
Treatment of Alzheimer’s Disease and Related Dementias Diana R. Kerwin, M.D. Assistant Professor Department of Medicine,Division of Geriatrics Neurobehavior Clinic-CNADC Northwestern University Feinberg School of Medicine Chicago, IL CME 2010
Prevalence and Treatment Rates 0 200 400 600 800 1000 1200 1400 1600 1800 2000 Mild Moderate Severe Number of Patients (thousands) Prevalence 1 Diagnosed 2 Treated with AChEI 3 Sources: 1. Hebert LE, Scherr PA, Bienias J, et al. Arch Neurol. 2003;60:1119-1122. 2. Datamonitor AD Treatment Algorithms. 2002. 3. Market Measures. 2003.
Alzheimer’s Disease: Course, Prevention, Treatment Strategies Disease Progression No Disease No Symptoms Early Brain Changes No Symptoms AD Brain Changes Mild Symptoms Mild, Moderate, or Severe Impairment Normal AD Pre- symptomatic AD Mild Cognitive Impairment Clinical State Brain Pathologic State “ Prevention” Studies
Normal Cholinergic Function AChE Acetyl CoA Choline ACh Presynaptic neuron Synaptic cleft Postsynaptic neuron Acetate Choline Choline + + ACh AChE ChAT MR NR MR NR ACh ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor. Adapted from Adem, 1992. Glial cell BuChE BuChE
The Amyloid Hypothesis Amyloid Production and Accumulation Oxidation, Excitotoxicity, Inflammation, Tau Hyperphosphorylation Cognitive and Behavioral Deterioration Neurotoxicity Cummings JL. New Engl J Med. 2004; 351:56-67.
Published Cholinesterase Use Guidelines ACP-AAFP(2008) Trial of AChI in AD Weak recommendation ACOVE-3 (2007) AChIs shown to slow progression (AD, VaD, LBD) Document discussion AAGP (2006) Supports efficacy Recommends consideration of AChIs in mild-moderate AD AGS (2006) AChIs use in mild-moderate AD Standard practice AAN (2001) **Update pending** Does not support use AChI Small treatment effect size
MMSE Scores Correlate With Functional Ability Adapted with permission from Galasko et al. Eur J Neurol. 1998;5:S9-S17. Keep Appointments Telephone Obtain Meal/Snack Travel Alone Use Home Appliance Find Belongings Select Clothes Dress Groom Maintain Hobby Dispose Litter Clear Table Walk Eat Activities of Daily Living 25 20 15 10 5 0 MMSE Score Progressive Loss of Function Loss of Optimal (Independent) Performance 25% 75%
ACOVE-3 QI Dementia Guidelines AChI discussion -AD, VaD and dLB AChIs slow progression of cognitive and functional decline Stroke prophylaxis -VaD, mixed dementia *AAGP 2006 Antihypertensives Lipid-lowering aspirin Caregiver support Patient safety Diagnosis, prognosis, behaviors, home safety, community resources Delay NH placement
Links between Pathology of AD and Vascular Risk
Several previous studies have found an increased risk of AD associated classic VRFs
At least 1/3 of patients with AD have some vascular pathology
Vascular pathology appears to lower the threshold of the clinical symptoms