Continuum: Lifelong Learning in Neurology—Neurology of Dementia, Volume 28, Issue 3, June 2022

Abstract

Purpose of Review:

This chapter provides an overview on the neuropathology of common age-related dementing disorders, focusing on the pathologies that underlie Alzheimer’s disease (AD) and related dementias (ADRD), including Lewy Body, Frontotemporal (FTD), Vascular, Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), and Mixed Etiology Dementias. Neurodegenerative diseases have underlying proteinopathies, eg. amyloid-beta, PHF-tau, alpha-synuclein, and TDP-43 pathology. Vascular pathologies include tissue injury (eg. infarcts, hemorrhages) with or without vessel disease.

Recent Findings:

New criteria for AD pathologic diagnosis highlight amyloid-beta as the sine qua non of AD, requires molecular markers of amyloid, and minimum threshold of Braak stage 3. Pathologic diagnosis is separated from clinical disease, ie. pathology diagnosis no longer requires dementia. TDP-43 pathology, a major pathology in a FTD subtype was found as a central pathology in LATE, a newly named amnestic disorder. Multiple pathologies (often co-occurring with AD) contribute to dementia and add complexity to the clinical picture. Conversely, Lewy body, LATE, and vascular dementias often,have accompanying AD pathology. Pathology and biomarker studies highlight subclinical pathologiesin older persons without cognitive impairment. This resilience to brain pathology is common and also known as cognitive reserve.

Summary:

The pathologies of dementia in aging are complex, often mixed, and frequently subclinical..

LEARNING OBJECTIVE

Recognize the common brain pathologies in Alzheimer’s and related dementias, and the importance of mixed pathologies and resilience.

INTRODUCTION

The most common neurodegenerative pathologies underlying common dementias in aging include amyloid beta and paired helical filament (PHF)-tau tangles in Alzheimer’s disease (AD), Lewy bodies in Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), and TDP-43 in Limbic-related Age-Associated TDP-43 Encephalopathy neuropathologic changes (LATE). Frontotemporal dementia (FTD) is less common and has a complex array of pathologies, most commonly FTLD-tau or FTLD-TDP, that may underlie the syndrome. Vascular Cognitive Impairment and Vascular dementia (VCI/VaD) most commonly are caused by ischemic tissue injury in the form of brain infarcts, andmay include other forms of hypoxia and hemorrhage. The location of the tissue injury (brain atrophy or damage) from these pathologic changes underlies the presentation and clinical phenotype of the dementia, including atypical presentations; heterogeneity within the disease process (eg. posterior cortical atrophy with Alzheimer’s disease (AD) pathology) may be related to atypical presentations. Behavioral and language phenotypes (semantic and primary progressive aphasia) of FTD often has underlying lobar atrophy called Frontotemporal lobar Degeneration (most commonly FTLD-tau or FTLD-TDP), but AD pathology has also been implicated, especially in primary progressive aphasia. Another common cause for atypical presentations in age-related dementias is the presence of mixed pathologies in aging. The most common mixed pathologies include Alzheimer’s disease pathology and vascular pathologies, but AD with TDP and AD with Lewy bodies also are common. All of these pathologies may be present in persons who are not cognitively impaired. This subclinical pathology may be present decades prior to the onset of cognitive impairment. There is evidence that cognitive resilience for accumulating brain pathologies in aging is related to a myriad of pathologic, genetic, and environmental factors.

ALZHEIMER’S DISEASE

Alzheimer’s Disease Neuropathologic Changes (ADNC) are defined by the accumulation of two key abnormal proteins, amyloid-beta in the form of extracellular plaques and abnormally phosphorylated microtubule-associated protein tau in the form of neuronal neurofibrillary tangles. [KP 1] Plaques and tangles were first described by Alois Alzheimer in 1906 in a middle age woman with memory loss and behavioral changes who died after 8 years of progressive illness. Her brain at autopsy showed atrophy with microscopic neuronal loss and gliosis. Using special stains and microscopic analysis, Dr. Alzheimer found extracellular plaques and intraneuronal neurofibrillary tangles in multiple cortical brain regions. He used special stains, called “silver stains”, which are still used today in the pathologic diagnosis of AD, especially to distinguish the more toxic “neuritic” plaque from the more benign “diffuse” plaques. The primary component of plaques is the amyloid-beta protein. [KP 2] This abnormal protein is cleaved from a much larger 695 amino-acid amyloid precursor protein, which is the predominant isoform expressed in neurons. The amyloid precursor protein is a transmembrane protein, which can be processed via two pathways, amyloidogenic and non-amyloidogenic. The non-amyloidogenic pathway begins with alpha secretase enzyme, which releases soluble APP alpha (sAPPα) into the extracellular space (ref ¹). The remaining intramembrane fragment is cleaved by gamma secretase releasing a small nonamyloidogenic fragment. Alternatively, APP is cleaved by beta secretase resulting in release of soluble APPβ into the extracellular space. Cleavage of the remaining fragment embedded in the plasma membrane by gamma secretase results in the production of the highly amyloidogenic beta fragment, the amyloid-beta protein, which accumulates and deposits in the brains of persons with AD. There are two major subtypes of the amyloid beta protein that differ in C-terminal length, Abeta40 and Abeta42. Abeta 42 is more amyloidogenic than Abeta40 whereas Abeta 40 accumulates more often in neuritic plaques and exclusively comprises the amyloid within the blood vessels in cerebral amyloid angiopathy.

It is well-recognized adults with trisomy 21, or Down syndrome, commonly have brain accumulation of AD pathology beginning in the 5^th decade in life, or earlier(ref²). [KP 3] Although the extra copy of the APP gene encoded on chromosome 21 plays a central role for the increase in amyloid-β levels, triplication of other genes on chromosome 21 may also play a role in promoting aggregation and deposition of amyloid-β (ref ³). Autosomal dominant forms of AD explain about 5–10% of early onset cases (and less than 1% of all AD cases) that most commonly are caused by highly penetrant mutations in Presenilin 1 (PSEN1), but also in APP and Presenilin2 (PSEN2). The pathogenic mutations result in either overproduction of the amyloid-beta protein or cause a greater ratio of Aβ42 compared to Aβ40 (ref⁴). Interestingly, both PSEN1 and PSEN2 are proteins of the gamma secretase complex (ref⁴).

By contrast, amyloid deposition associated with sporadic forms may be more varied and heterogeneous, possibly because of a combination of upstream or downstream factors. The most common genetic polymorphisms increasing risk of AD in the community occurs in the apolipoprotein gene, a cholesterol transport protein secreted primarily from astrocytes and affecting neurons mostly through low-density lipoprotein (LDL) family of receptors (ref⁵). Human apoE has three main variants, e2, e3, and e4. Most persons have two copies of the e3 variant but about 25% of population harbor at least one copy of the e4 variant which increases risk of AD. Pathologically, those persons with the e4 variant have a greater accumulation of brain amyloid, whereas persons with the less common e2 variant have lesser amyloid beta compared to e3 variant. [KP 4] There are multiple less common genetic polymorphisms in the population that increase risk of AD. Many of these polymorphisms involve complex cellular functions such as immune system, synaptic functioning,and lipid metabolism. Axonal transport, cytoskeletal function, regulation of gene expression, apoptosis and autophagy have also been implicated (ref⁴).

Most, but not all, experts believe that the cerebral deposition of amyloid is the earliest stage in AD pathogenesis. Amyloid accumulation begins in the neocortex and over time progresses to the hippocampus, basal ganglia, midbrain and cerebellum. Amyloid deposition is required for there to be any level of AD pathologic changes (ref ⁶). Multiple pathologic studies have suggested that amyloid accumulates presymptomatically in those without cognitive impairment (ref ⁷) and this has been confirmed using in-vivo PET imaging using amyloid ligands shows that the accumulation of amyloid begins many years to decades prior to the onset of symptoms (ref⁸)). In hemispheric cortical regions there are 2 types of plaques depending on the presence or absence of abnormally distended neurites, thickened processes that disrupt the brain neuropil, best seen on by silver stains, called neuritic plaques. [KP 5] Plaques without these thickened neuritic plaques are referred to as diffuse plaques, and while common along with neuritic plaques in the cerebral cortex, they are typically the exclusive plaque type in subcortical and brainstem regions. Neuritic plaques specifically are associated with a pathologic diagnosis of AD and dementia (ref ⁶) Indeed, earlier pathologic criteria to confirm a clinical diagnosis of AD, Consortium to Establish a Registry for Alzheimer’s disease (CERAD) criteria(ref ⁹), used the density of neocortical neuritic plaques to determine the likelihood that the clinical diagnosis of dementia was due to Alzheimer’s disease. In addition to density of neuritic plaques, these earlier criteria for a pathologic diagnosis of AD also use age and clinical diagnosis to determine whether the pathology confirmed a final diagnosis of AD (ref ⁹).

Neurofibrillary tangles are the other essential pathologic feature of AD. [KP 6] Like amyloid plaques, they accumulate during the course of Alzheimer’s disease but the progression and pattern differs from that of amyloid plaques. Where amyloid is extracellular in location, neurofibrillary tangles are intracellular residing in the neuronal cytoplasm. Neurofibrillary tangles are comprised of abnormally phosphorylated tau protein in the form of paired helical filament neuronal tangles. [KP 7] Normal tau is a protein coded by the microtubule associated protein tau (MAPT) gene on chromosome 17q21 (ref ¹⁰). Tau is essential for microtubule structure and function, especially axonal transport. In aging and disease,the phosphorylation of tau and the formation of NFT results in the loss of the ability to perform these and other pivotal cellular functions. NFT are not specific to AD but also occur in aging and over 30 different diseases. (ref ¹¹). In the context of dementia, tauopathy in other major neurodegenerative diseases include subtypes of Frontotemporal Lobar Degeneration such as Progressive Supranuclear Palsy, Corticobasal Degeneration, Pick’s disease, and FTD with parkinsonism due to MAPT mutations. Although most tauopathies have the accumulation of abnormally phosphorylated tau in neurons, there is also an accumulation of tau in glial cells in aging and disease (ref¹²).

In aging and AD, neurofibrillary tangles typically begin to accumulate in the mesial temporal lobe, specifically the entorhinal and hippocampal cortices. Neurofibrillary tangle accumulation in aging and AD has been described by Braak in 6 stages (ref ¹³). In AD, neuronal neurofibrillary tangles progressively accumulate in the mesial temporal lobe structures followed by accumulation in the neocortical association regions. Three patterns of neurofibrillary tangles in AD have been described in AD (ref ¹⁴). In typical AD, neuronal NFTs are found in both limbic and neocortical regions; in limbic-predominant AD, the tangles are most prominent in the mesial temporal cortex with little involvement of neocortex. By contrast, in some cases, the neurofibrillary tangles predominate in the neocortex, so called limbic-sparing AD. Those with the latter subtype tend to be younger and more often male (ref ¹⁴).

Neocortical neurofibrillary tangles tend to involve association cortices while sparing primary cortical regions (eg. visual, motor, auditory cortices) until late in the course of the pathologic progression of AD (Braak stage 6). NFT deposition is more closely aligned than amyloid with progression of regional atrophy and clinical symptomatology. Paired helical filament tau, the primary component of NFTs, also accumulate in the some, but not all, of the distended neurites of neuritic plaques, the other characteristic feature of AD, i.e. CERAD neuritic plaque score (ref ⁹).

Criteria for the pathologic diagnosis of AD have evolved over the past few decades. Although older criteria incorporated age and clinical diagnosis for the likelihood that a dementia was caused by AD pathology (ref ^{6, 15}), current criteria is agnostic to age and clinical diagnosis (ref⁵). Current AD pathologic diagnosis also newly incorporates molecular pathology into traditional neuritic plaque and/or NFT classifications. Specifically, the new NIA-AA criteria for pathologic diagnosis of AD requires Thal amyloid stage (A) in addition to Braak tangle stage (B), and CERAD neuritic plaque stage (C). (Ref ⁵, Table 9-1). [KP 8] Also new to this pathologic framework is the criterion that the presence of amyloid is required even to diagnose low levels of AD pathology. By contrast, NFT in the absence of amyloid is not consistent with AD pathology, but rather indicative of primary age related tauopathy (PART) or another tauopathy (11). AD neuropathologic changes or ADNC are described by an ABC score (Table 9-2) and further categorized as none, low, intermediate or high level of AD neuropathologic changes. Intermediate and high ADNC are consistent with a pathologic diagnosis of AD. It is important to note that in these new criteria, a clinical diagnosis of dementia is not required for a pathologic diagnosis of AD. As previously noted, it is now well -recognized that AD pathology may be subclinical.

Table 9–1:

AD Neuropathologic Change

CLASSIFICATION

AD neuropathologic change should be ranked along three parameters (Amyloid, Braak, CERAD) to obtain an “ABC score”:

A. Aβ plaque score (modified from Thal, et al. 34]):

A0 no Aβ or amyloid plaques

A1 Thal phases 1 or 2

A2 Thal phase 3

A3 Thal phases 4 or 5

B. NFT stage (modified from Braak for silver-based histochemistry [21] or phosphor-tau immunohistochemistry [89])

B0 no NFTs

B1 Braak stage I or II

B2 Braak stage III or IV

B3 Braak stage V or VI

C. Neuritic plaque score (modified from CERAD [31])

C0 no neuritic plaques

C1 CERAD score sparse

C2 CERAD score moderate

C3 CERAD score frequent

Reprinted from: Raman S, Brookhouser N, Brafman DA. Using human induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which Apolipoprotein E (APOE) contributes to Alzheimer’s disease (AD) risk. Neurobiol Dis. 2020 May;138:104788. doi: 10.1016/j.nbd.2020.104788. Epub 2020 Feb 5. PMID: 32032733; PMCID: PMC7098264.

Table 9–2. Level of AD Neuropathologic Change.

AD neuropathologic change is evaluated using an “ABC” score that drives from three separate four-point scales: Aβ/amyloid plaques (A) by the method of Thal phases, NFT stage by the method of Braak (B), and neuritic plaque score by the method of CERAD (C). The combination of A, B, and C scores receive a descriptor of “Not”, “Low”, “Intermediate”, or “High” AD neuropathologic change. “Intermediate” or “High” AD neuropathologic change is considered sufficient explanation for dementia.

		B: nft SCORE (Braak stage)1
A: Aβ/ amyloid plaques score (Thal phases)2	C: Neuritic plaque score (CERAD)3	B0 or B1 (None or I/II)	B2 (III/IV)	B3 (V/VI)
A0 (0)	C0 (none)	Not4	Not4	Not4
A1 (1/2)	C0 or C1 (none to sparse)	Low	Low	Low5
	C2 or C3 (mod. To freq.)7	Low	Intermediate	Intermediate5
A2 (3)	Any C	Low6	Intermediate	Intermediate5
A3 (4/5)	C0 or C1 (none to sparse)	Low6	Intermediate	Intermediate5
	C2 or C3 (mod. To freq.)	Low6	Intermediate	High

Abbreviations: Consortium to Establish a Registry for Alzheimer’s disease (CERAD), Neurofibrillary tangle (NFT), Moderate (mod.), frequent (freq.)

¹NFT stage should be determind by the method of Braak [21,89]

²Aβ/ amyloid plaques score should be determind by the method of Thal, et al. [34].

³Neuritic plaque score should be determind by the method of CERAD [31].

Reprinted from: Raman S, Brookhouser N, Brafman DA. Using human induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which Apolipoprotein E (APOE) contributes to Alzheimer’s disease (AD) risk. Neurobiol Dis. 2020 May;138:104788. doi: 10.1016/j.nbd.2020.104788. Epub 2020 Feb 5. PMID: 32032733; PMCID: PMC7098264.

LEWY BODY PATHOLOGY (DEMENTIA WITH LEWY BODIES AND PARKINSON’S DISEASE DEMENTIA)

Lewy bodies are intracytoplasmic neuronal inclusions and are commonly found in the aging brain. The presence of these inclusions in the presence of significant substantia nigra neuronal loss are the defining feature for a pathologic diagnosis of idiopathic Parkinson’s disease. It is now well-recognized that Lewy bodies may also localize in cortical neurons where they are strongly related to cognitive impairment and dementia. Lewy bodies in both cortical and subcortical neurons are intraneuronal cytoplasmic inclusions that are eosinophilic, round, and when subcortical often have a clear halo on Hematoxylin and Eosin stains.. The defining protein of Lewy bodies is the phosphorylated alpha-synuclein protein. The two dementia syndromes characteristic of Lewy body pathology are Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB). [KP 9] Other syncleinopathies include multisystem atrophy (MSA) and Hallevorden-Spatz disease (ref¹⁶). The pathologic diagnoses of PDD and DLB are determined by validated consensus criteria (ref¹⁷). In addition, many older persons have cortical Lewy bodies contributing to their dementia when mixed with other pathologies, especially AD (ref ¹⁸). The degree of concomitant AD or other pathologies alters the clinical presentation in persons with both cortical Lewy bodies and AD pathology (ref ¹⁷). With little AD pathology, it is likely that the cortical Lewy bodies will be associated with a specific DLB syndrome which features hallucinations, cognitive fluctuations, and parkinsonism. With increasing AD pathology, however, this clinical syndrome may be obscured, such that the prevalence of Lewy bodies as a contributing feature to an AD dementia may be under-recognized (17). The pathologic progression of Lewy body may take a two or three different pathways, but most commonly the pathologyascends in the brainstem pigmented nuclei (eg. dorsomedial nucleus of the vagus, locus ceruleus, substantia nigra), followed by involvement of the limbic area (entorhinal cortex and anterior cingulate) and finally the neocortex (ref¹⁹). Over the years, pathologic criteria for confirming the diagnosis of DLB have remained relatively stable and classified as nigral type disease, limbic predominant, and neocortical based on presence and/or severity of Lewy bodies in each of these regions. [KP 10] Additional pathologic features of DLB pathology are spongiform change, especially in the entorhinal cortex and other temporal cortical regions, and alpha-synuclein neurites especially in regions that Lewy bodies are observed, as well as in neurites in CA2 sector of the hippocampus. Brains with Lewy bodies disease often have some level of AD pathology and conversely it is common for those with AD pathology to have coexisting Lewy bodies. The distinction between PDD and DLB is based on clinical information, with DLB showing cognitive changes prior to the motor symptoms and PDD starting with motor findings and later onset cognitive impairment.

LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE)

TDP-43 proteinopathy was first described in FTLD/ALS, but it was quickly revealed that TDP-43 pathology was also a prominent pathology in aging, often but not always accompanied by AD pathology. [KP 11] In aging and AD, the predominance of the TDP pathology is in the limbic regions, and there is no associated lobar atrophy or layer 2 spongiform change. Unlike FTLD, TDP in aging is associated with an amnestic disorder that can be mistaken as AD. The acronym LATE was introduced in 2017 to highlight and increase recognition of the role of TDP-43 in amnestic disorders of aging (ref ²⁰). A clinical diagnosis of LATE is currently uncommon except in tertiary and specialty care centers because of the lack of a clear LATE-specific biomarker and because concomitant AD is common. As AD biomarkers gain traction, however, the absence of amyloid and tau biomarkers in the presence of an amnestic syndrome and hippocampal atrophy most likely signals a diagnosis of LATE (ref ²¹). Isolated LATE-associated cognitive decline progresses more slowly than in AD. When TDP and AD are concomitant, there is accelerated cognitive decline (ref ²²). The pathologic progression of LATE is divided into 3 stages. [KP 12] In the first stage, TDP-43 pathology is in the amygdala. Currently there is no evidence that there are associated cognitive deficits in this early stage. Over time, TDP-43 progresses to involve the entorhinal, hippocampus, and dentate cortex, stage 2. The final LATE stage 3 is neocortical. Both LATE stage 2 and LATE stage 3 are associated with cognitive impairment with a predominant amnestic changes but other domains of cognitive function are also involved, especially language. Many persons with LATE also have brain atrophy, especially significant and accelerated atrophy of the hippocampus. Indeed, over 90% of cases of hippocampal sclerosis of aging is associated with LATE (ref ²³). [KP 13]

HIPPOCAMPAL SCLEROSIS

Hippocampal sclerosis (HS) is a nonspecific pathologic term for severe neuronal loss and gliosis in the hippocampus. Hippocampal sclerosis is not specific for one disease but may be the associated with one of several different pathologic processes including temporal lobe epilepsy, hypoxic/ischemic brain injury, and neurodegenerative diseases of aging. [KP 14] In hypoxic/ischemic disease and neurodegenerative disease, HS commonly involves severe neuronal loss and gliosis in CA1 sector of hippocampus and the adjacent subiculum. In aging and neurodegeneration, HS is mostly commonly associated with TDP-43 pathology (LATE neuropathologic changes) with or without concomitant AD or Lewy body disease pathology. [KP 15] HS also is observed in some cases of FTLD. Finally, HS characterizes some cases of temporal lobe epilepsy and in much of the imaging literature is referred to as mesial temporal sclerosis. The HS of temporal lobe epilepsy has unique histopathologic features, including significant involvement of CA4/3 sectors of the hippocampus, granule cell dispersion, the presence of extensive mossy fiber sprouting, and no association with TDP-43 (ref²⁴). Both HS and LATE neuropathologic changes are strongly related to old age and unlike AD pathologic changes does not plateau in the 9^th decade of life (ref²⁵).

VASCULAR PATHOLOGIES

The nomenclature used to refer to dementia related to vascular disease is heterogeneous. Currently, most experts refer to the dementia related to ischemic or hemorrhagic tissue injury as vascular dementia or vascular cognitive impairment. Other terms include multi-infarct dementia, strategic-infarct dementia, and Binswanger’s disease. There are currently no specific criteria for a pathologic diagnosis of vascular dementia. The pathologic substrates include gross (lacunar or cystic) or microscopic infarcts and /or hemorrhages (lobar, deep, and microbleeds). [KP 16] Other vascular pathologies include enlarged perivascular spaces and white matter lesions and are best visualized on MRI. The likelihood of dementia from ischemic or hemorrhagic tissue injury is dependent on multiple factors including the size, location, and number of vascular lesions. The tissue changes are often but not always accompanied by small vessel (arteriolosclerosis, cerebral amyloid angiopathy ), intracranial large vessel (atherosclerosis), or extracranial vessel diseases. Most older persons have some combination of vessel pathologies and tissue injury in their brain (ref ²⁶). Other vessel pathologies such as ruptured aneurysms and vascular malformations are less common substrates. Cardiac and non-cardiac systemic causes of brain ischemia or hemorrhage, such as embolic infarcts and global hypoxic/ischemic injury are also well known causes of vascular dementia.

Small Vessel Disease (SVD)

Small Vessel Disease is a term that often refers to some combination of arteriolosclerosis or cerebral amyloid angiopathy, often with associated white matter changes and small or microinfarcts. Interestingly while the small and microscopic infarcts are related to arteriolosclerosis; intracranial atherosclerosis (large vessel disease) is also independently associated with microinfarcts and therefore contributes to what is considered SVD (ref ²⁷). Indeed, SVD is the most common underlying pathologic substrate for vascular cognitive impairment and dementia in aging. [KP 17] Age, diabetes and hypertension are strong risk factors for arteriolosclerosis and associated infarcts and white matter damage. Aalthough midlife elevations in blood pressure are a strong risk factor, high blood pressures in later life also related to more severe SVD (ref ²⁸). SVD pathology including arteriolosclerosis and microinfarcts is also common in the watershed regions of the brain suggesting low flow states may also be important in the pathogenesis of tissue injury in aging (ref ²⁹). Additional factors involved in vascular cognitive impairment in aging and AD include disruption of the Blood Brain Barrier (BBB), neurovascular unit, and impaired clearance mechanisms.

Arteriolosclerosis

Arteriolosclerosis refers to the concentric hyalinized thickening of small arterioles. Changes are prominent in the deep gray (basal ganglia and thalamus) and white matter of the brain. Arteriolosclerosis is also common in the basis pontis and cerebellar white matter. Typically, arteriolosclerosis is accompanied by loss of smooth muscle actin in the vascular wall and there is concomitant luminal constriction. These vessel wall changes are common in aging, diabetes, and hypertension and are related to white matter hyperintensities and microbleeds on MRI. Arteriolosclerosis has also been implicated in brain atrophy. Clinically, arteriosclerosis is related to vascular, Alzheimer’s, and mixed dementias and also plays a role in age-related parkinsonism.

Cerebral amyloid Angiopathy (CAA)

Unlike most age-related vascular diseases that are associated with vascular risk factors such as hypertension and diabetes, Cerebral Amyloid Angiopathy (CAA) is associated with risk factors for AD including the accumulation of the amyloid beta protein. While, Aβ-CAA is related to Alzheimer’s disease pathology in aging, not all persons with AD pathology have CAA and conversely severe CAA with hemorrhage is rarely associated with clinical AD. Similar to AD, apolipoprotein E4 is a risk factors for the CAA but unlike AD, apoE 2 allele also confers risk of CAA. Hereditary forms of CAA with the accumulation of Aβ are well known with the APP Dutch variant mutation being the best characterized. Interestingly, familial forms of Aβ–CAA are caused by missense mutations within the part of the APP gene that codes for Aβ, whereas APP mutations outside of the Aβ coding region are characteristic of C21 dominantly inherited AD (ref ³⁰). Small and medium sized vessels of the cortical parenchyma and overlying meninges are predominantly involved in CAA and there is an occipital predilection for more severe accumulation. CAA is associated with hemorrhages, infarcts, and cognitive impairment. The hemorrhages may be large and lobar (especially occipital) but are more commonly incidental microbleeds, seen on imaging as small cortical hemorrhages. Superficial siderosis is also a common imaging finding in CAA. Cognitive impairment may manifest as an AD dementia with our without transient neurologic symptoms. Rarely, CAA may be associated with pathologic inflammation and edema and cause a potentially reversible encephalopathy (ref ³¹).

MIXED PATHOLOGIES

AD is often considered the most common underlying pathology of dementia in aging; however, in the vast majority of older persons with dementia, the etiology of the underlying dementia is related to the accumulation of multiple pathologies including neurodegenerative (amyloid, PHF-tau neurofibrillary tangles, cortical Lewy bodies, and TDP-43 inclusions) and vascular pathologies. [KP 18] Mixed dementia is often used to refer to the combination of AD and vascular pathologies, however in reality all of the aforementioned pathologies commonly co-occur (ref³²). Indeed, much of what clinicians call “Alzheimer’s Disease” is an amnestic clinical syndrome related to the accumulation of multiple neurodegenerative and vascular pathologies (Case 9–1). Each of the pathologies, when in sufficient severity contribute to cognitive impairment and dementia. Because there are often multiple pathologies in the aging brain contributing to the cognitive impairment, most neuropathologists will report on all of the pathologies that potentially can be contributing to dementia. [KP 19] Separating the terminology of AD pathology (amyloid and tangles) from AD dementia (a multi-domain amnestic dementia), as recommended the AD proposed Research Framework (ref ³³), provides a mechanism to improve on the clarity of dementia nomenclature.

CASE 9–1

An 80 year old woman with a history of hypertension presents with memory loss. History is obtained from her daughter. She reports her mother began having gradually progressive difficulties after the death about 4 years ago, but in this past year her memory has suddenly declined more rapidly. She notes that her mother has been having trouble remembering their telephone conversations and has been missing appointments and other events. She thinks she may be “depressed” as she has been very quiet during family gatherings. There is have been no fluctuations, behavior issues, or history of stroke. She does have some difficulties remembering names. She has a past medical history of hypertension, stage 1 breast cancer s/p lumpectomy and radiation, and hypothyroidism. She is on amlodipine and synthroid. There is no family history of AD or dementia. She lives by herself. There are no other neurologic symptoms. On examination, BP was 140/90. The patient acknowledged she may be having some problems with her memory but “nothing too bad”, “all of her friends have the same problems”. General physical examination was unremarkable. Neurologic examination was remarkable for a left pronator drift and left Babinski sign. Sensory exam showed loss of vibration at the toes. Coordination was normal. On cognitive examination, MMSE was 16. There was moderate loss of episodic memory and some mild language difficulties. MRI and laboratory tests were unremarkable. The patient was diagnosed with Alzheimer’s disease and started treatment. She progressed over the next few years and died at the age of 83. At autopsy, the brain showed diffuse atrophy especially in the hippocampus and temporal lobes. Histopathologic examination showed an intermediate level of AD pathology, A2B2C2 (Thal amyloid stage of 3 (A2), moderate neocortical neuritic plaques (C2), and Braak score of 4 (B2). In addition there was TDP-43 pathology in the amygdala and hippocampus consistent with Limbic-predominant Age-related TDP-43 Encephalopathy Neuropathologic Changes (ADNC) stage 2, and a lacunar infarct in the right posterior thalamus with moderate arteriolosclerosis (SVD). Final pathologic diagnoses were AD, LATE, and infarct pathologies consistent with a mixed etiology dementia including both neurodegenerative and vascular pathologies.

FRONTOTEMPORAL LOBAR DEGENERATION

Frontotemporal Lobar Degeneration (FTLD) is a distinct pathologic entity that is typically linked to a clinical diagnosis of frontotemporal dementia (FTD). [KP 20] FTD is an uncommon clinical syndrome with early behavioral and/or language impairment. The distribution of the pathology, as the name implies, is frontal and temporal and often spares the hippocampus early in the disease, consistent with the lack of early memory impairment. [KP 21] Persons with FTLD often have stark focal severe atrophy of the frontal and temporal lobes, which is sometimes referred to as “knife-edge atrophy”. Underlying this atrophy is severe cortical degeneration with neuronal loss and gliosis. The neocortex also shows superficial vacuolization, called “layer 2 spongy change”. The two main pathologic types of FTLD are FTLD-TDP and FTLD-tau. [KP 22] As the names imply, the proteinopathies are associated with distinct forms of FTLD called TDP-43 and abnormally phosphorylated tau protein, respectively. The TDP-43 protein was recently found to be major component of FTLD and ALS with “ubiquitin-positive inclusions”, nonspecific inclusion types. A hexanucleotide repeat expansion in C9orf72 is the most common cause of FTD and amyotrophic lateral sclerosis (c9FTD/ALS). This repeat induces the formation of aberrant stress granules and pTDP-43 inclusions (ref ³⁴). A neuropathological hallmark is the intracellular accumulation of RNA foci. Mutations in the progranulin gene (GRN), is associated with FTLD-TDP. Genetic polymorphisms in TMEM106 is a risk factor for both familial and sporadic FTLD-TDP. Another familial form of FTLD is “FTD with parkinsonism linked to chromosome 17”, which maps to the MAPT locus and has tau pathology. Probably the best known of pathology of FTLD is that of Pick’s disease. Pick bodies are composed of abnormally phosphorylated tau protein but unlike that of AD are straight rather than paired helical filaments. They form circular basophilic round intracytoplasmic inclusions in the frontal and temporal cortical neurons. In addition to Pick bodies, cortical regions also contain distended neurons called Pick cells (ballooned neurons). In older literature, the name “Pick’s disease” was often the nomenclature for all types of FTLD.

SUBCLINICAL PATHOLOGIES AND COGNITIVE RESILIENCE

Most dementia related pathologies, whether they be neurodegenerative or vascular, accumulate over time. Epidemiologic studies have been pivotal to our understanding of aging, neuropathology, and dementia. Depending on age and other cohort characteristics, about 1/3 of older persons have a pathologic diagnosis of intermediate or high ADNC in their 7^th decade of life in spite of having normal cognition proximate to death. [KP 23] These research findings have been confirmed with molecular PET studies that can image amyloid pathology in-vivo. Thus, the brain is able to tolerate some level of pathology before clinical symptoms ensue. This cognitive resilience varies across individuals and may be related to genetics, pathology, or environment. [KP 24] Probably one of the biggest tipping points for the resilient brain is the accumulation of additional pathologies. This is best recognized in persons with subclinical AD pathology who have a clinical stroke, but also can occur as other subclinical neurodegenerative and/or vascular pathologies accumulate with age. Many other person-specific factors are important in cognitive resilience and include but not limited to years of education, physical activity, cognitive activity, social activity, diet and mood or anxiety disorders, etc. Genetic factors including polymorphisms related to immune function, cellular stress, and lipid metabolism are also likely to play an important role in cognitive resilience. [KP 25]

NEURONAL NEUROFIBRILLARY TANGLES IN OTHER DISORDERSAND AGING

Neuronal neurofibrillary tangle pathology is not unique to AD and FTLD. They have also been described commonly in aging, are the central proteinopathy in chronic traumatic encephalopathy (see below), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). [KP 26] PSP and CBD are sometimes categorized with the FTLD-tau diseases. Other brain disease with neuronal neurofibrillary tangles include post-encephalitic Parkinson’s disease, Pellagra, and Niemann-Pick type C (ref ³⁵).

PRIMARY AGE-RELATED TAUOPATHY

Neuronal neurofibrillary tangles are nearly ubiquitous in the aging brain, specifically in the entorhinal and hippocampal cortices. The presence of tangles in the mesial temporal lobe in aging is referred to as Primary Age-Related Tauopathy (PART).(ref ³⁶) [KP 27] The tangles in PART are morphologically indistinguishable from the tangles observed in AD, containing both 3R and 4R, and accumulating in the mesial temporal lobe, a location affected early in AD. However, much evidence suggests that PART and AD are separate processes, including differing genetic risk factors for PART and AD, and the lack of elevated soluble amyloid in PART. PART may be related to mild memory changes in aging but is only rarely related to dementia.

TRAUMATIC BRAIN INJURY AND CHRONIC TRAUMATIC ENCEPHALOPATHY

Traumatic Brain Injury (TBI) is a risk factor for Alzheimer’s and other neurodegenerative diseases dementia; however, the data is conflicting and the pathologic mechanism (s) is not always clear especially when the trauma is mild. In a recent community based study, persons with a history of mild TBI with loss of consciousness had an increased risk of Parkinsonism and Lewy bodies (ref ³⁷). Other studies have shown an association with other neurodegenerative pathologies including AD, but this research is still on-going.

Chronic traumatic encephalopathy describes the specific pathology of the brain condition associated with multiple repetitive concussive and/or subconcussive hits to the head. [KP 28] AD like changes to the brain were initially described in professional boxer’s and the syndrome was called “punch drunk syndrome”. Recently the literature has focused on professional sports of American football, hockey, and soccer. The neuronal neurofibrillary tangles in CTE show a specific perivascular pattern, especially in the depths of the cortical sulci of the frontal cortex. [KP 29] In addition to an accumulation of perivascular neuronal neurofibrillary tangles, CTE also show a progressive accumulation of tangles more diffusely throughout the brain including the hippocampus and brainstem. Supportive pathologic features for CTE also includes perivascular glial tau, subpial tau in the depths of the sulci, patchy distribution of pathology. Many persons with CTE pathology also have “mixed pathologies” especially AD, Lewy body and TDP-43 pathology, and vascular disease, specifically arteriolosclerosis. Years of play is related to the tangles and other proteinopathies whereas the vascular pathology appeared to have a different risk factor (ref ³⁸). All of the pathologies contribute to the cognitive impairment in these former athletes with cognitive impairment. Aging, AD, and CTE all have neuronal neurofibrillary tangles composed of 3R and 4R; yet, the microstructure of the tangles in CTE appears to be distinct from those in aging (PART) and AD.

PROGRESSIVE SUPRANUCLEAR PALSY (PSP) AND CORTICOBASAL DEGENERATION (CBD)

Neuronal neurofibrillary tangles are a central pathology to both PSP and CBD, both atypical parkinsonian disorders. [KP 30] In both diseases, cognitive impairment may be the presenting or predominant feature. The neuronal neurofibrillary tangles are prominent in the substantia nigra in both PSP and CBD. In PSP, other subcortical regions such as globus pallidus, subthalamic nucleus, and basis pontis are heavily involved. In CBD there is neuronal loss and degeneration involving the perirolandic cortex (especially postcentral gyrus) and characteristic achromatic or ballooned neurons are seen. This pathology results in the characteristic cortical sensory loss. Unlike AD and PART, only 4R tau comprises the tangles of these diseases. While typically considered atypical parkinsonian disorders, cognitive impairment is common in these disorders and may occur early in these disease or even be a presenting feature.

ARTAG

It has been long recognized that tangles can accumulate not only in neurons but also within glia cells in persons with tauopathies. While the astrocytic plaques of corticobasal degeneration and the tufted astrocytes of Progressive Supranuclear Palsy are well described, recent in depth pathologic studies show that astrocytic tangles are especially prominent in aging and AD. This is astroglial pathology also known aging-related tau astrogliopathy (ARTAG) is also a common astrocytic pathology in the elderly and in those with AD (ref ³⁹). [KP 31] ARTAG has two tangle types called thorn-shaped astrocytes and granular fuzzy astrocytes; and may be located in gray matter and/or white matter in multiple locations. The glia tau has a propensity also for subpial and perivascular regions of the cortex. ARTAG in the gray matter may be related to cognitive impairment in aging and AD (Robinson et al) but the clinical significance of the pathology continues to be investigated.

OTHER LESS COMMON DEMENTIA RELATED PATHOLOGIES

There are numerous other less common dementia related pathologies across different age groups and under differing neurologic disease subtypes. Several examples are described below. Creutzfeld Jakob Disease though rare is unique in that it may be infectious, hereditary, or sporadic. Hungtington’s disease, historically a pathologically diagnosed entity, now can be detected using genetic testing. Finally, Wernicke-Korsakoff is important and is probably under recognized syndrome with a unique pathologic footprint.

Creutzfeldt Jakob Disease (CJD)

CJD is a very rare rapidly progressive dementia caused by prion proteins. CJD is unique disease, being both infectious, genetic, and sporadic. [KP 32] The infectious agent responsible for CJD and other spongiform encephalopathies is the Prion protein and these infections have no viral particles. Prion proteins are able to self-propagate from neuron to neuron, and some cases are transmitted via iatrogenic means, such as dural or corneal transplants. CJD causes transmural spongiform change with severe neuronal loss and gliosis throughout the cortex. Ingestion of infected cow meat from the spongiform encephalopathy, “mad cow disease” causes an atypical form of CJD or variant CJD. There are also genetic forms of spongiform encephalopathy including fatal familial insomnia and familial CJD.

Huntington’s Disease

Huntington’s Disease is a rare dominantly inherited neurodegenerative disease caused by mutations, specifically CAG (polyglutamine) expansion repeats, within the Huntington gene (huntingtin) on Chromosome 4. [KP 33] The size of the expansion is associated with the severity of the disease and accelerated age of onset. The brain shows prominent atrophy of the caudate and putamen with lesser atrophy of the cerebral cortex. Striatal pathology can be graded on a scale from 0 to 4 (ref ⁴⁰) and is related to loss of medium spiny neurons and gliosis. Cortical neuronal loss is most prominent in the frontal cortex. Similar to other neurodegenerative diseases, HD is characterized by inclusion bodies formed from Huntingtin protein misfolding (aggregated mHTT) and aggregation of the abnormal protein. In HD, the inclusions are intranuclear and formed by the mutant huntingtin protein.

Wernicke-Korsakoff

Wernicke encephalopathy and Korsakoff syndrome (WKS) are diseases related to thiamine deficiency. Often described in association with alcoholism, WKS is also observed in other forms of malnutrition and in liver disease. [KP 34] In the acute phase, Wernicke’s encephalopathy is marked by mental status changes, ophthalmoplegia, and ataxia, whereas the chronic phase of Korsakoff’s syndrome results in a dementia including memory loss and confabulations. The most prominent acute pathology of Wernicke-Korsakoff involves bilateral mammillary body destruction, with destruction of neuropil, hemorrhagic lesions, and preservation of neurons. In chronic disease, particularly Korsakoff syndrome, there is involvement of bilateral medial thalamic nuclei and diencephalic periventricular damage is prominent (ref ⁴¹).

CONCLUSION

Alzheimer’s disease, Lewy body disease, LATE, and vascular pathologies are the most common underlying pathologies in common age-related dementias. [KP 35] AD is composed of amyloidβ plaques and pHF-tau neuronal neurofibrillary tangles. Alpha-synuclein comprises the main component of Lewy bodies and is the sine-qua-non of both Dementia with Lewy bodies and Parkinson’s Dementia Dementia. LATE describes a late onset amnestic dementia which is typified by limbic predominant TDP-43 inclusions. Vascular pathologies in aging are common and include both vessel pathology and tissue injury, both of which contribute to cognitive impairment. Most clinical diagnoses of AD dementia have mixed pathologies especially AD with LBD, TDP-43, or vascular pathologies. There has been increased recognition of other common age-related pathologies including PART and ARTAG. Their role in dementia, however, is not clear. Many older persons have significant AD and other pathologies in spite of intact cognition; this is consistent with cognitive or neural reserve. Frontotemporal dementias are less common causes of dementia, and the main FTD pathologies include FTLD-tau and FTLD-TDP. Also described are several less common neuropathologic causes of dementia including CTE, PSP, CBD, CJD, and Wernicke-Korsakoff syndrome.

KEY POINTS.

Alzheimer’s Disease Neuropathologic Changes (ADNC) are defined by the accumulation of two key abnormal proteins, amyloid-beta in the form of extracellular plaques and abnormally phosphorylated microtubule-associated protein tau in the form of neuronal neurofibrillary tangles.

The primary component of plaques is the amyloid-beta protein.

It is well-recognized adults with trisomy 21, or Down syndrome, commonly have brain accumulation of AD pathology beginning in the 5^th decade in life, or earlier(ref²).

Pathologically, those persons with the e4 variant have a greater accumulation of brain amyloid, whereas persons with the less common e2 variant have lesser amyloid beta compared to e3 variant.

In hemispheric cortical regions there are 2 types of plaques depending on the presence or absence of abnormally distended neurites, thickened processes that disrupt the brain neuropil, best seen on by silver stains, called neuritic plaques.

Neurofibrillary tangles are the other essential pathologic feature of AD.

Neurofibrillary tangles are comprised of abnormally phosphorylated tau protein in the form of paired helical filament neuronal tangles.

Current AD pathologic diagnosis also newly incorporates molecular pathology into traditional neuritic plaque and/or NFT classifications. Specifically, the new NIA-AA criteria for pathologic diagnosis of AD requires Thal amyloid stage (A) in addition to Braak tangle stage (B), and CERAD neuritic plaque stage (C). (Ref ⁵, Table 9-1).

Two dementia syndromes characteristic of Lewy body pathology are Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB).

Over the years, pathologic criteria for confirming the diagnosis of DLB have remained relatively stable and classified as nigral type disease, limbic predominant, and neocortical based on presence and/or severity of Lewy bodies in each of these regions.

TDP-43 proteinopathy was first described in FTLD/ALS, but it was quickly revealed that TDP-43 pathology was also a prominent pathology in aging, often but not always accompanied by AD pathology.

The pathologic progression of LATE is divided into 3 stages.

Indeed, over 90% of cases of hippocampal sclerosis of aging is associated with LATE.

Hippocampal sclerosis is not specific for one disease but may be the associated with one of several different pathologic processes including temporal lobe epilepsy, hypoxic/ischemic brain injury, and neurodegenerative diseases of aging.

In aging and neurodegeneration, HS is mostly commonly associated with TDP-43 pathology (LATE neuropathologic changes) with or without concomitant AD or Lewy body disease pathology.

The pathologic substrates include gross (lacunar or cystic) or microscopic infarcts and /or hemorrhages (lobar, deep, and microbleeds).

SVD is the most common underlying pathologic substrate for vascular cognitive impairment and dementia in aging.

AD is often considered the most common underlying pathology of dementia in aging; however, in the vast majority of older persons with dementia, the etiology of the underlying dementia is related to the accumulation of multiple pathologies including neurodegenerative (amyloid, PHF-tau neurofibrillary tangles, cortical Lewy bodies, and TDP-43 inclusions) and vascular pathologies.

Because there are often multiple pathologies in the aging brain contributing to the cognitive impairment, most neuropathologists will report on all of the pathologies that potentially can be contributing to dementia.

Frontotemporal Lobar Degeneration (FTLD) is a distinct pathologic entity that is typically linked to a clinical diagnosis of frontotemporal dementia (FTD).

The distribution of the pathology, as the name implies, is frontal and temporal and often spares the hippocampus early in the disease, consistent with the lack of early memory impairment.

The two main pathologic types of FTLD are FTLD-TDP and FTLD-tau.

Depending on age and other cohort characteristics, about 1/3 of older persons have a pathologic diagnosis of intermediate or high ADNC in their 7^th decade of life in spite of having normal cognition proximate to death.

This cognitive resilience varies across individuals and may be related to genetics, pathology, or environment.

Many other person-specific factors are important in cognitive resilience and include but not limited to years of education, physical activity, cognitive activity, social activity, diet and mood or anxiety disorders, etc. Genetic factors including polymorphisms related to immune function, cellular stress, and lipid metabolism are also likely to play an important role in cognitive resilience.

Neuronal neurofibrillary tangle pathology is not unique to AD and FTLD. They have also been described commonly in aging, are the central proteinopathy in chronic traumatic encephalopathy (see below), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).

Neuronal neurofibrillary tangles are nearly ubiquitous in the aging brain, specifically in the entorhinal and hippocampal cortices. The presence of tangles in the mesial temporal lobe in aging is referred to as Primary Age-Related Tauopathy (PART).

Chronic traumatic encephalopathy describes the specific pathology of the brain condition associated with multiple repetitive concussive and/or subconcussive hits to the head.

The neuronal neurofibrillary tangles in CTE show a specific perivascular pattern, especially in the depths of the cortical sulci of the frontal cortex.

Neuronal neurofibrillary tangles are a central pathology to both PSP and CBD, both atypical parkinsonian disorders.

This is astroglial pathology also known aging-related tau astrogliopathy (ARTAG) is also a common astrocytic pathology in the elderly and in those with AD (ref ³⁹).

CJD is a very rare rapidly progressive dementia caused by prion proteins. CJD is unique disease, being both infectious, genetic, and sporadic.

Huntington’s Disease is a rare dominantly inherited neurodegenerative disease caused by mutations, specifically CAG (polyglutamine) expansion repeats, within the Huntington gene (huntingtin) on Chromosome 4.

Wernicke encephalopathy and Korsakoff syndrome (WKS) are diseases related to thiamine deficiency. Often described in association with alcoholism, WKS is also observed in other forms of malnutrition and in liver disease.

Alzheimer’s disease, Lewy body disease, LATE, and vascular pathologies are the most common underlying pathologies in common age-related dementias.