There are a number of neurodegenerative diseases that can lead to amyloid deposition in the brain. The most common of these is AD, where both diffuse and neuritic plaques are deposited in the brain parenchyma (Fig. 8.1a–d). The plaques consist of extracellular deposits of Aβ- protein. The latter results from a cleavage product of AβPP, encoded for a gene in chromosome 21, containing 40 or 42 amino acids through the action of β and γ secretases in a pathologic amyloidogenic pathway. In the “amyloid cascade hypothesis” of AD, Aβ-protein deposition plays a central role in AD pathogenesis [1]. In support of this hypothesis, there is an increase in Aβ deposition in individuals that have one or more copies of the APOe4 allele, in Down’s syndrome, and in familial variants of AD leading to early dementia. However, this hypothesis is not uniformly accepted, and some investigators propose that phosphorylated tau accumulation maybe the primary event in AD pathogenesis [2].

The age-related neuritic core amyloid plaque counts found in the brain are an important component for a pathologic diagnosis of AD. The presence of a few neuritic plaques in an individual 80 or 90 years of age, without dementia, may be considered to be an age-related change but, in a 40-year-old individual, they may represent early onset and/or familial AD. In AD, in addition to amyloid plaques in the neuropil, amyloid deposition occurs in small- and medium-sized blood vessels, resulting in cerebral amyloid angiopathy (CAA) [3]. However, CAA may occur in the absence of AD pathology (see section below; [3]). Mutations in the AβPP protein lead to the Swedish familial variants of AD that are associated with a double mutation adjacent to the β-amyloid secretase (BACE) cleavage site in the N terminus of Aβ. Another group of familial variants of AD involves the V717 mutations, adjacent to presenilin (or γ-secretase) sites near the C terminus of the Aβ moiety. Interestingly, in Down’s syndrome individuals, who have an extra copy of the gene encoding AβPP protein secondary to trisomy 21, it was found that the initial Aβ fibril formation begins intracellularly before the formation of extracellular plaques.

In addition to amyloid plaque deposition, several intracellular inclusions in CNS neurodegenerative disorders also possess at least some of the properties of amyloid. Among them, the phosphorylated tau-rich neurofibrillary tangles (NFT) have a fibrillar structure and Congo red affinity with birefringence under polarized light. Lewy bodies, composed of α-synuclein, are also the defining pathology in Lewy body disease, which may coexist with AD. Both of these proteins are considered amyloidogenic proteins. In fact, gelsolin, another CNS amyloidogenic protein, has been found to colocalize with both brainstem and cortical Lewy bodies [4]. More recently, TDP43 inclusions and skeins in frontotemporal lobar degeneration and amyotrophic lateral sclerosis have also been found to have similar properties as amyloid [5, 6].

Postmortem brain sections, taken to make a diagnosis of AD, typically include the following: frontal cortex, temporal cortex, hippocampus, entorhinal cortex, and the midbrain [7, 8]. The latter is necessary to identify additional coexisting or alternative pathologies to AD, particularly Lewy body/Parkinson’s disease and rare tauopathies. The routine stains used are H & E and a silver stain such as the modified Bielschowsky or Hirano. Although Congo red stains of cortical sections can be performed for the assessment of CAA and plaques, immunohistochemistry against Aβ protein is used more frequently and is more sensitive. Other immunostains routinely used in the evaluation of neurodegenerative disorders include α-synuclein (for Lewy bodies), tau paired helical filament (PHF1) staining for NFT and neuritic changes, and more recently TDP43 used in the evaluation of frontotemporal lobar degenerations. Historically, only silver stains were used to determine a semiquantitative age-related plaque score to indicate definite AD, possible AD, probable AD, and/or no AD [7, 8, 9, 10, 11–13]. More recent consensus guidelines from the National Institute on Aging-Alzheimer’s Association incorporate a more systematic (“ABC”) approach that includes evaluation of the geographic extent Aβ-amyloid protein deposits (A), in addition to staging of neurofibrillary tangles (B) and number of neuritic plaques (C) [14]. In this approach, a larger number of anatomic brain regions are examined, and the contribution of non-AD pathology is also taken into consideration.

A variety of inherited disorders may also be associated with neurodegeneration and amyloid deposition. A recently discovered form of CNS amyloidosis, called familial British dementia (FBD) or familial Danish dementia (FDD), is caused by mutations in the BR12 gene located on chromosome 13 [15]. In FBD, the findings are somewhat similar to classic AD, where CAA and neurofibrillary pathology are found, in addition to parenchymal amyloid deposition. This is less so in FDD. An interesting finding is that there may be a role for wild-type BR12 protein in the pathogenesis of AD itself since, in FDD the amyloid deposition is associated with Aβ [15].

In addition to Aβ protein in AD, prion protein (PrP) in prion disease is frequently amyloidogenic in the CNS. Prion disorders include Creutzfeldt–Jakob disease (CJD), of both the sporadic and familial forms, as well as variant CJD, which is related to bovine spongiform encephalopathy. A variety of plaques may be encountered in these disorders [16], specifically in all cases of kuru, Gerstmann–Straussler–Sheinker (GSS) disease, and variant CJD, but only in 10–15% of sporadic CJD. Plaques in these disorders are composed of prion protein (PrP), variably deposited in the form of amyloid. These include unicentric (kuru plaques), multicentric plaques (characteristic of GSS disease), florid plaques (typical of variant CJD) (Fig. 8.1e, f) [17], and diffuse plaques. Autopsy precautions are necessary in the examination of these specimens [18], and cases in the USA should be reported and sent to the National Prion Disease Surveillance Center at Case Western Reserve University (Sponsored by the American Association of Neuropathologists, AANP).

The most common form of CAA is found in conjunction with AD [3, 19, 20, 21]. Although most cases of AD have CAA, it is usually focal (in the temporal and occipital lobes) and mild. CAA in AD, or aging, is predominantly caused by deposition of the Aβ40 isoform in the vessels (Fig. 8.2). Therefore, the ratio of Aβ40 to Aβ42 levels is a major determinant of the extent and severity of CAA [3]. The V717I β-APP and presenilin mutations, which primarily produce more Aβ42 isoforms, lead to less severe CAA. There are, however, specific mutations in the Aβ protein that can cause CAA almost exclusively and lead to minimal parenchymal Aβ deposition [3]. These include the Dutch-type mutation of the Aβ sequence (E22Q Aβ; HCHWA-D) and the Arctic mutation in the APP sequence (E693G; APP) [3]. Although there may be little parenchymal deposition of amyloid, these individuals can still present with dementia and other cognitive deficits, secondary to vascular and neurofibrillary pathology. CAA of various types demonstrate similar pathology, with thickening of basal lamina by amyloid and smooth muscle cell loss leading to vessel rupture [22].

A particularly severe form of CAA results from cystatin C (Icelandic) mutations [23], as well as mutations that give rise to the FBD and familial Danish dementia (FDD) [15]. Mutations in the gelsolin protein gene can also lead to a severe CNS CAA (Finnish hereditary amyloidosis) [3, 24]. Numerous mutations in the TTR protein (which usually causes a systemic amyloidosis including involvement of peripheral nerves and heart) can also lead to CNS CAA [25, 26]. The primary vessels involved are usually the superficial leptomeningeal (please see also Fig. 5.​2). In addition to the leptomeninges, the eye can also have pathological deposition of mutated TTR protein, where the amyloid leads to vitreous opacity, keratoconjunctivitis, and/or glaucoma (see Fig. 5.​1). Patients with amyloidosis derived from gelsolin (AGel) can develop lattice corneal dystrophy, with amyloid deposits within the stroma of the cornea (see Fig. 5.​13 and Chaps. 5 and 7).

Clinical attention to CAA is more often in the form of intracerebral lobar hemorrhage, frequently multiple. However, in some instances CAA presents with infarcts or diffuse edema mimicking neoplasms. Therefore, brain specimens obtained during clot removal or brain biopsies that appear normal at first glance should be evaluated for the presence of CAA. Histologic clues include thickening of small to medium sized vessels in leptomeninges and superficial brain parenchyma (Fig. 8.2a–d). Veins and/or capillaries may also be rarely involved. “Double barreling” and an “onion-skin” appearance may be present. Perivascular hemosiderin-laden macrophages may be a subtle clue. Immunohistochemistry for Aβ protein is confirmatory in virtually all cases and used more commonly than Congo red special stains (Fig. 8.2e).

A perivascular inflammatory response with increased microglia and complement activation may be a feature of any CAA subtype [3]. In recent years, a form of CNS vasculitis associated with CAA has been increasingly recognized under the term Aβ-related angitis, in which amyloid angiopathy is identified in association with overt granulomatous inflammation [27] (Fig. 8.2f–g). Angiodestruction and leptomeningeal chronic inflammation may be present. Compared to conventional CAA, patients with Aβ-related angitis are younger, have fewer hemorrhages, and a better outcome [28].

Although prions can cause significant parenchymal amyloid deposition, CAA is less likely to occur in most sporadic or familial prion diseases, except for the subtypes that have mutations leading to stop codons in the prion protein gene [29].

Tumefactive amyloid deposits in the CNS (amyloidomas) are composed of light chain amyloid (AL) and typically form in the absence of systemic plasma cell dyscrasia [30–32] (Fig. 8.3). These aggregates of AL amyloid are predominantly lambda light chain derived, which may be tested in formalin-fixed tissues by immunohistochemistry and more accurately by mass spectrometry-based proteomics [33]. The deposits may be extra-axial or intraparenchymal and usually exhibit an indolent clinical course. On imaging studies, the deposits take the form of contrast enhancing masses, single or multiple, involving the white matter, periventricular regions, and/or choroid plexus [31]. A subset of cases affect the trigeminal ganglion (Fig. 8.3a, b). Large, amorphous parenchymal aggregates and variable mural vessel involvement are typical (Fig. 8.3c). An associated hypocellular infiltrate of monotypic plasma cells may be identified. Dural-based or orbital marginal zone lymphomas, plasma-cell rich low grade neoplasms that may mimic meningiomas at the clinical level, are also associated with intracranial kappa or lambda light chain amyloid deposition (Fig. 8.3a, d, e) [34]. The differential diagnosis of tumefactive amyloid deposits in the brain mainly involves immunoglobulin deposition, particularly light chain deposition disease (LCDD), which in contrast to amyloidoma, is Congo red negative, PAS positive, and often associated with a lymphoid neoplasm [33, 35] (Fig. 8.4a–d). Extracerebral deposits in LCDD disease usually contain kappa light chains. Although pathologic light chain deposits in brain may also be composed of kappa light chain [33, 36], several instances of lambda-containing light chain disease have been described in the brain [37–40]. Regardless of the specific aggregate subtype, the identification of light-chain derived deposits in the CNS on biopsy material should trigger a thorough, systematic clinical evaluation for lymphoid neoplasia and plasma cell dyscrasias.