Alzheimer's Disease¶
Chapter 442 | Harrison's 22e · Part 13 – Neurologic Disorders
Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition
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[PAGE 3475] Alzheimer’s Disease 3475 CHAPTER 442 tricyclics, such as amitriptyline, or anticonvulsants, such as topira- mate or valproate, are most often tried. This phenotype can be seen in 442 Alzheimer’s Disease combination with migraine and the TACs, in which cases treatment of the primary headache disorder is often effective for the nummular Gil D. Rabinovici, Peter A. Ljubenkov, headache as well. William W. Seeley, Bruce L. Miller Hypnic Headache This headache syndrome typically begins a few hours after sleep onset. The headaches last from 15–30 min and are typically moderately severe and generalized, although they may ALZHEIMER’S DISEASE be unilateral and can be throbbing. Patients may report falling back Approximately 55 million people across the world are living with to sleep only to be awakened by a further attack a few hours later; up dementia. Alzheimer’s disease (AD) is the most common cause of to three repetitions of this pattern occur through the night. Daytime dementia, contributing to an estimated 60–70% of all cases. Total U.S. naps can also precipitate head pain. Most patients are female, and the health care costs related to dementia care are estimated at $360 billion onset is usually after age 60 years. Headaches are typically bilateral but in 2024, translating into an average of ~$25,000 per patient. Further- may be unilateral. Photophobia, phonophobia, and nausea are usually more, the emotional toll for family members and caregivers is immea- absent. The major secondary consideration in this headache type is surable. AD can manifest as early as the third decade of life, but it is the poorly controlled hypertension; 24-h blood pressure monitoring is most common neuropathology contributing to dementia in the elderly. recommended to detect this treatable condition. Patients most often present with an insidious loss of episodic memory followed by a slowly progressive dementia. In typical amnestic AD, TREATMENT brain atrophy begins in the medial temporal lobes before spreading to inferior temporal, lateral and medial parietal, and dorsolateral frontal Hypnic Headache cortices. Microscopically, there are widespread neuritic plaques con- taining amyloid beta (Aβ), neurofibrillary tangles (NFTs) composed Patients with hypnic headache generally respond to a bedtime dose of hyperphosphorylated tau filaments, and Aβ accumulation in blood of lithium carbonate (200–600 mg). One to two cups of coffee, or vessel walls in cortex and leptomeninges (see “Pathology,” below). The caffeine 60 mg orally, at bedtime may be effective in approximately identification of causative mutations and susceptibility genes for AD one-third of patients. Reports suggest that verapamil, 160 mg; flu- has provided a foundation for rapid progress in understanding the narizine, 5 mg nightly; or indomethacin, 25–75 mg nightly, can be biological basis of the disorder. The major genetic risk factor for AD is effective. the ε4 allele of the apolipoprotein E (ApoE) gene. Carrying one ε4 allele increases the risk for AD by two- to threefold in women, whereas car- New Daily Persistent Headache Primary new daily persistent rying two alleles increases the risk 10- to 15-fold in both sexes. Rapid headache (NDPH) occurs in both men and women. It can be of the progress in the development of imaging, cerebrospinal fluid (CSF), and migrainous type, with features of migraine, or it can be featureless, plasma biomarkers of Aβ and phosphorylated tau has enabled detec- appearing as new-onset TTH. Those with migrainous features are the tion of AD pathologic hallmarks in living people, opening the door to most common form and include unilateral headache and throbbing early detection and intervention with biologically specific therapies. pain; each feature is present in about one-third of patients. Nausea, photophobia, and/or phonophobia occur in about half of patients. ■ CLINICAL MANIFESTATIONS Some patients have a previous history of migraine. NDPH may be The cognitive changes of AD tend to follow a characteristic pattern, more common in adolescents. Treatment of migrainous-type primary beginning with memory impairment and progressing to deficits in NDPH consists of using the preventive therapies effective in migraine executive, language, and visuospatial functions. Yet, ~20% of patients (see above). Featureless NDPH is one of the primary headache disor- with AD present with nonmemory complaints such as word-finding, ders most refractory to treatment. Standard preventive therapies can be organizational, or navigational difficulty. In other patients, visual offered but are often ineffective. The secondary NDPHs are discussed processing dysfunction (referred to as posterior cortical atrophy syn- elsewhere (Chap. 17). drome) or a progressive “logopenic” aphasia characterized by difficul- ties with naming and repetition is the primary manifestation of AD ■ FURTHER READING for years before progressing to involve memory and other cognitive Buse DC et al: Demographics, headache features, and comorbidity domains. Still other patients may present with an asymmetric akinetic- profiles in relation to headache frequency in people with migraine: rigid-dystonic (“corticobasal”) syndrome or a dysexecutive/behavioral Results of the American Migraine Prevalence and Prevention (i.e., “frontal” variant of AD). Depression, social withdrawal, and anxi- (AMPP) Study. Headache 60:2340, 2020. ety occur in early disease stages and may represent a prodrome before Charles A, Pozo-Rosich P: Targeting calcitonin gene-related pep- cognitive symptoms are apparent. tide: A new era in migraine therapy. Lancet 394:1765, 2019. In early stages of typical amnestic AD, the memory loss may go Cittadini E, Goadsby PJ: Hemicrania continua: A clinical study of 39 unrecognized or be ascribed to benign forgetfulness of aging. The term patients with diagnostic implications. Brain 133:1973, 2010. subjective cognitive decline refers to self-perceived worsening in mem- Cittadini E et al: Paroxysmal hemicrania: A prospective clinical study ory or other cognitive abilities that may not be noticeable to others of thirty-one cases. Brain 131:1142, 2008. or apparent on formal neuropsychological testing. Once the memory de Boer I et al: Advance in genetics of migraine. Curr Opin Neurol loss becomes noticeable to the patient and spouse and is confirmed on 32:413, 2019. standardized memory tests, the term mild cognitive impairment (MCI) Ferrari MD et al: Migraine. Nat Prim 8:2, 2022. is often used. This construct provides useful prognostic information Goadsby PJ et al: Pathophysiology of migraine: A disorder of sensory because ~50% of patients with MCI (roughly 12% per year) will prog- processing. Physiol Rev 97:553, 2017. ress to the dementia stage over 4 years. Increasingly, the MCI construct Schankin CJ et al: “Visual snow”: A disorder distinct from persistent is being replaced by the notion of “early symptomatic AD” to signify migraine aura. Brain 137:1419, 2014. that AD is considered the underlying disease (based on clinical or bio- Wei DY, Goadsby PJ: Cluster headache pathophysiology: Insights marker evidence) in a patient who remains functionally compensated. from current and emerging treatments. Nat Rev Neurol 17:308, 2021. Even earlier in the course, “preclinical AD” refers to a person with bio- Weng H et al: Phenotypic and treatment outcome data on SUNCT and marker evidence of amyloid pathology (with or without tau pathology) SUNA, including a randomised placebo-controlled trial. Cephalalgia in the absence of symptoms. It is estimated that preclinical biomarker 38:1554, 2018. changes may precede clinical symptoms by 20 years or more, creating a window of opportunity for early-stage treatment and prevention
[PAGE 3476] 3476 PART 13 Neurologic Disorders trials. Emerging evidence suggests that partial and sometimes general- discussed later. Resting tremor with stooped posture, bradykinesia, ized seizures herald AD and can occur even
Figures & Illustrations¶
Reproduced from Harrison's 22nd Edition.
Figure 1¶
Caption: FIGURE 442-3 Amyloid precursor protein (APP) is catabolized by α, β, and γ secretases. A key initial step is the digestion by either β secretase (BASE) or α of secretase (ADAM10 or ADAM17 [TACE]), producing smaller nontoxic products. Cleavage of the β secretase product by γ secretase (Step 2) results in either the toxic Aβ or the nontoxic Aβ peptide; cleavage of the α secretase product by γ secreta 4 s 2 e produces the nont 4 o 0 xic P3 peptide. Excess production of Aβ is a 42 key initiator of cellular damage in Alzheimer’s disease (AD). Therapeutics for AD of have focused on attempts to reduce accumulation of Aβ by antagonizing β or γ 42 secretases, promoting α secretase, or clearing Aβ 42 that has already formed by use of specific antibodies. a
Figure 2¶
![Molecular imaging of Alzheimer’s disease pathophysiology in an [11C]PIB reveals...](../images/figure_02.jpg)
Caption: FIGURE 442-1 Molecular imaging of Alzheimer’s disease pathophysiology in an [11C]PIB reveals extensive radiotracer retention in neocortex, consistent with the known predominantly in the left temporal cortex, consistent with intermediate-stage (non-tau-related) tracer retention. C. Fluorodeoxyglucose (FDG)-PET reveals reduced decreased synaptic activity. The pattern of hypometabolism corresponds more closely neurologic orientation. L, left; R, right; SUVR, standardized uptake value ratio, a Braak neuropathologic staging of neurofibrillary tangles, with early of retention in medial temporal regions, followed by spread into tempo- roparietal and cingulate cortices, dorsolateral prefrontal regions, and
Figure 3¶
Caption: FIGURE 442-2 Neuropathology of Alzheimer’s disease. A. Early neurofibrillary the medial temporal lobes, especially the stellate pyramidal neurons that compose the magnification view reveals the fibrillar nature of tangles (arrows) and the complex immunohistochemistry for Aβ). Scale bars are 500 μM in A, 50 μM in B, and 20 μM in B
Figure 4¶
Caption: FIGURE 442-4 Radiographic staging of amyloid-related imaging abnormalities (ARIAs). A. mild ARIA-E in an asymptomatic patient receiving lecanemab treatment. Cortical with <5 cm of involvement. B. Axial susceptibility-weighted imaging (SWI) depicting lobar microhemorrhages) in an asymptomatic patient receiving lecanemab. C–D. Axial radiographically severe ARIA-H, respectively, in a patient presenting with focal FLAIR imaging reveals multiple regions of cortical edema, with adjacent subcortical including in bilateral frontal and posterior regions of concomitant ARIA-E, as well as
Figure 5¶
Caption: FIGURE 442-4 Radiographic staging of amyloid-related imaging abnormalities (ARIAs). A. mild ARIA-E in an asymptomatic patient receiving lecanemab treatment. Cortical with <5 cm of involvement. B. Axial susceptibility-weighted imaging (SWI) depicting lobar microhemorrhages) in an asymptomatic patient receiving lecanemab. C–D. Axial radiographically severe ARIA-H, respectively, in a patient presenting with focal FLAIR imaging reveals multiple regions of cortical edema, with adjacent subcortical including in bilateral frontal and posterior regions of concomitant ARIA-E, as well as
Figure 6¶
Caption: FIGURE 442-4 Radiographic staging of amyloid-related imaging abnormalities (ARIAs). A. mild ARIA-E in an asymptomatic patient receiving lecanemab treatment. Cortical with <5 cm of involvement. B. Axial susceptibility-weighted imaging (SWI) depicting lobar microhemorrhages) in an asymptomatic patient receiving lecanemab. C–D. Axial radiographically severe ARIA-H, respectively, in a patient presenting with focal FLAIR imaging reveals multiple regions of cortical edema, with adjacent subcortical including in bilateral frontal and posterior regions of concomitant ARIA-E, as well as
Figure 7¶
Caption: FIGURE 442-4 Radiographic staging of amyloid-related imaging abnormalities (ARIAs). A. mild ARIA-E in an asymptomatic patient receiving lecanemab treatment. Cortical with <5 cm of involvement. B. Axial susceptibility-weighted imaging (SWI) depicting lobar microhemorrhages) in an asymptomatic patient receiving lecanemab. C–D. Axial radiographically severe ARIA-H, respectively, in a patient presenting with focal FLAIR imaging reveals multiple regions of cortical edema, with adjacent subcortical including in bilateral frontal and posterior regions of concomitant ARIA-E, as well as
Generated from Harrison's Principles of Internal Medicine, 22nd Edition.