Dementia Pathology

Multiple neuropathologic processes may underlie dementia, including both neurodegenerative diseases and vascular disease. ^[1] Under the current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), dementia is considered a major neurocognitive disorder, in which a deficit in cognitive functioning is acquired rather than developmental. ^[2]  All dementia share common molecular mechanisms responsible for disease etiology and progression, such as hypoxia and oxidative stress, neuroinflammation, mitochondrial bioenergetics, neurodegeneration, and blood–brain barrier permeability. ^[1]

Dementia is most common in elderly individuals, with advancing age being the strongest risk factor. Furthermore, comorbidity is the rule rather than the exception for dementia in elderly persons. ^{[3, 4, 5, 6, 7]}  About 47 million people live with dementia globally; by 2050, there will be an almost three-fold increase to an estimated 131 million people afflicted with dementia. ^[7]

The following conditions will be discussed:

• Alzheimer’s disease
• Vascular dementia
• Dementia with Lewy bodies (Lewy body disease)
• Less common neurodegenerative dementing diseases

Alzheimer disease (AD) is the most common neurodegenerative disease responsible for dementia. About half of dementia cases result from AD ^{[3, 4]} ; however, a variable but measurable amount of AD pathologic changes exist in most cognitively intact elderly individuals who undergo autopsy, indicating that AD is a chronic disease with latent and prodromal stages and suggesting that individuals may have varying abilities to compensate, either biologically or functionally, for the presence of AD. ^[8]

As with many neurodegenerative diseases, both rare autosomal-dominant forms of AD and more common sporadic forms with genetic risk factors without causative mutations exist. Abnormalities in three genes are known to cause AD with high penetrance: APP, PSEN1, and PSEN2. Autosomal-dominant forms of AD tend to be more severe and occur at a younger age than sporadic AD, but these are relatively rare. Sporadic AD accounts for the vast majority of AD cases. The neuropathologic changes of autosomal-dominant and sporadic AD are largely the same.

AD is characterized grossly by progressive atrophy and gliosis, first of the hippocampus and medial temporal lobe, followed by other association cortices (frontal and parietal lobes), and finally by primary motor or sensory cortex (occipital lobe). ^[9]

AD is characterized diagnostically by two histologic findings: (1) extracellular amorphus eosinophilic deposits of amyloid consisting of Aβ peptides (a cleavage product of amyloid precursor protein [APP]), which are referred to as amyloid plaques, and (2) intraneuronal aggregates of abnormally modified microtubule-associated protein tau (neurofibrillary tangles) (see the image below). ^[9]

Dementia pathology. Bielschowsky silver staining of the cortex at 400× magnification demonstrates a neurofibrillary tangle (black arrow) and a neuritic plaque (white arrow).

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Both amyloid plaques and neurofibrillary tangles are readily identified using silver staining techniques such as Bielschowsky or Gallyas. Amyloid plaques are sometimes referred to as “senile plaques” in older literature because of their long association with dementia. Amyloid plaques with evidence of damaged neuronal processes are called neuritic plaques. ^[10]

Accumulating evidence suggests that Aβ is involved in the etiology of AD, although the mechanism has not been fully elucidated. Amyloid angiopathy is another pathologic finding in the AD spectrum, in which Aβ accumulates in the media of small arteries. Amyloid angiopathy can be identified using stains for amyloidal protein (Congo red, thioflavin-S), or immunohistochemical staining against Aβ (see the image below). Although amyloid angiopathy has been associated with lobar hemorrhages, it is not a strong predictor of cognitive status.

Dementia pathology. Congo red staining of a small cortical artery at 400× magnification demonstrates salmon-colored amyloid deposition in the media of the vessel.

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Pathologic criteria for the diagnosis of AD require the presence of neuritic plaques ^[10] ; however, neuritic plaque burden does not correlate well with cognitive status during life. Instead, neurofibrillary tangle distribution is more strongly associated with cognitive status.

The staging criteria for neurofibrillary tangle distribution has six levels (I-VI) referred to as the Braak stage, with each successive stage demonstrating tangles in additional brain regions. ^[11] Neurofibrillary tangles are present in transentorhinal cortex in stage I, in the CA1 sector of the hippocampus in stage II, in the subiculum in stage III, in other areas of the hippocampus and the entorhinal cortex in stage IV, in the association cortex in stage V, and in the primary motor or sensory cortex or the granule neurons of dentate fascia in stage VI. ^{[11, 12, 13]}

Vascular brain injury (VBI) is widely recognized as a common cause of cognitive impairment (vascular cognitive impairment) culminating in vascular dementia. ^[14] Most vascular dementia cases are sporadic and share risk factors with peripheral vascular disease.

A widely used method for the clinical diagnosis of vascular dementia in life is the Hachinski Ischemic Score, which is assessed by determining whether the individual has experienced an abrupt onset or stepwise progressive course of specific signs and symptoms and the presence of vascular risk factors. ^[15] Pathologic assessment of VBI has been hindered by the lack of a clear, standardized, and widely accepted rubric for diagnosis and staging. Gross ischemic infarcts, lacunar infarcts, arteriolosclerosis, and microscopically identified infarcts (cortical, subcortical) (see image below) have all been independently associated with vascular dementia. ^[14]  "The best predictors of vascular cognitive impairment "appear to be "small or lacunar infarcts, microinfarcts, perivascular space dilatation, myelin loss, arteriolosclerosis, and leptomeningeal cerebral amyloid angiopathy." ^[14]

Dementia pathology. A: Hematoxylin-eosin-Luxol fast blue staining of the basal ganglia at 100× magnification demonstrates a cavitary infarct. Calcific medial sclerosis of small arteries is also present. B: At 400× magnification, numerous foamy macrophages are present within the center of the infarcted tissue.

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With the widespread adoption of magnetic resonance imaging (MRI) (beyond its ability to enhance the diagnosis of ischemic infarcts), more subtle ischemic injury can appreciably be visualized as T2 signal hyperintensities in white matter in living individuals. Although these changes are often classified under the rubric of "small-vessel disease," their precise pathologic correlates are not well understood but may include ischemia-induced demyelination and/or axonal loss, arteriolosclerosis, microscopic infarcts, breakdown of the blood brain barrier, and/or breakdown of the blood-cerebrospinal fluid barrier. ^[14]  

In a literature review of studies that utilized samples from the Medical Research Council Cognitive Function and Ageing Study neuropathology cohort to identify cerebral white matter lesions, Wharton et al indicated that expression of hypoxia-related molecules and other injury and protective cellular pathways reported in immunohistochemical and gene expression microarray studies suggest that hypoxia and ischemia play a role in the pathology of white matter lesions. ^[16] Other pathogenic factors included immune activation, blood-brain barrier dysfunction, altered cell metabolic pathways, and glial cell injury. The investigators reported that these abnormalities were not confined to white matter lesions but were also found in apparently normal white matter in brains with lesions, suggesting a field effect of white matter abnormality within which lesions arise. They concluded that white matter lesions have a complex pathogenesis that may offer a number of primary and secondary intervention targets. ^[16]

Two criteria that have been suggested for the pathologic diagnosis of vascular dementia include (1) multiple large and/or strategic infarcts in cerebrum ^[17] or (2) a threshold of three or more microscopic infarcts identified in a systematic screening of cerebral cortex and deep cerebral structures. ^{[3, 4, 18]} VBI is commonly comorbid with AD in elderly patients with dementia, especially in a community setting.

A rare autosomal-dominant disease that causes multiple small strokes and may culminate in vascular dementia is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). ^[9] CADASIL is caused by mutations in NOTCH3. ^[9]

Lewy body dementia (LBD) refers to pathologic changes that underlie several closely related syndromes. Most manifest with a movement disorder component, and the clinical diagnosis received in life often depends on the interval between the diagnosis of dementia and the onset of movement disorder symptoms. If a clinical diagnosis of Parkinson disease is followed by dementia a minimum of 1 year later, then a diagnosis of Parkinson disease dementia is assigned. ^[19] If the onset of dementia precedes or is roughly concurrent with the onset of Parkinson disease, then the clinical diagnosis of dementia with Lewy bodies (not to be confused with LBD) is used.

By the time the postmortem diagnosis of LBD can be confirmed, years would have passed since the initial clinical diagnosis, making Parkinson disease dementia and LBD difficult to distinguish. Most LBDs are sporadic and are frequently associated with increased age and the male sex. Organophosphate pesticide exposure is a known risk factor. Of interest, several lines of evidence suggest that a history of cigarette smoking may protect from the processes that lead to LBD.

LBD and Parkinson disease dementia share characteristic neuropathologic changes, such as "deposition of alpha-synuclein in Lewy bodies and neurites, and loss of tegmental dopamine cell populations and basal forebrain cholinergic populations." ^[19]

Lewy bodies are spherical eosinophilic intraneuronal inclusion bodies surrounded by a clear halo (see image "A" below). Lewy body distribution and number are the diagnostic findings of LBD. In pigmented neurons, LBs are easy to identify with standard hematoxylin and eosin–stained sections.

Lewy bodies comprise a number of different aggregated proteins, the most diagnostically useful of which is alpha-synuclein. ^[20]  Loss of pigment-bearing neurons is seen in the pigmented nuclei of the brainstem accompanied by the presence of neuromelanin in scavenger macrophages (pigment "incontinence"). Pigment loss in Parkinson disease is most severe in the ventrolateral tier of the substantia nigra, which contrasts with normal aging, in which some pigment loss is seen in the dorsal tier. Immunohistochemical staining against alpha-synuclein aids in detection of Lewy bodies in nonpigmented neurons such as in cortex (see image "B" below).

Dementia pathology. A: Hematoxylin and eosin staining of the substantia nigra at 400× magnification demonstrates multiple Lewy bodies within a pigmented neuron. The Lewy bodies are round with a densely eosinophilic core surrounded by a clear halo. B: Immunohistochemical staining (brown) against alpha-synuclein at 400× magnification reveals a round Lewy body within the soma of a neuron.

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Distribution of Lewy bodies in the central nervous system progresses in a rostral manner. Incidental Lewy bodies present only in the medulla are usually clinically silent or may be associated with premortem symptoms of autonomic dysfunction. A brain stem–predominant distribution of LB in the medulla and substantia nigra may be clinically silent or associated with a premortem clinical diagnosis of Parkinson disease. Limbic distribution involves brainstem structures, as well as the amygdala, entorhinal cortex, and cingulate gyrus. The clinical correlate for this stage is unclear but may include cognitive impairment.

Diffuse distribution involves all of the brainstem and limbic structures, as well as the isocortex. In diffuse LBD, the cortex is variably atrophic, and, in more severe cases, vacuolization of the superficial cortical layers often exists. Most cases of LBD can be classified using hematoxylin and eosin sections of substantia nigra and immunohistochemical staining against alpha-synuclein in sections of medulla, amygdala, cingulate gyrus, and frontal cortex. ^{[21, 22]} Pathologic changes of LBD and AD may also coexist in patients with dementia.

Alzheimer disease (AD), vascular brain injury (VBI), and Lewy body disease (LBD) are all highly prevalent disease processes and often occur simultaneously. ^{[3, 4, 5, 6]} Furthermore, clinically silent pathology is very common in the aging population. Over 50% of all individuals who undergo autopsy and 40% of individuals without dementia have intermediate or high AD pathology. Approximately 60% of these individuals have chronic VBI.

In the elderly population, comorbidity is the rule rather than the exception (see the image below). The likelihood that an individual had clinical dementia preceding death increases with the number of comorbid pathologies.

Dementia pathology. Comorbid brain pathologies are common in the elderly population. This Venn diagram demonstrates the co-occurrence of brain pathologies as evident from population-based autopsy studies of brain aging.

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Frontotemporal dementia

Frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that are characterized clinically by early onset (usually sixth and seventh decade of life), loss of executive function, disrupted language and motor function, and relative sparing of memory and visuospatial functions. ^[9] Pathologically, they have variable atrophy of the frontal and temporal lobes that is often asymmetric. FTDs are heterogenous with multiple etiologies, and many have characteristic histopathologic changes. ^[23]

Pick disease is probably the most well-known of the FTDs and is characterized by widespread presence of spherical intraneuronal Pick bodies that are positive for microtubule-associated protein tau (MAPT), as well as other proteins (see the image below). Pick bodies may also be identified using silver staining techniques such as Bielschowsky or Gallyas.

Dementia pathology. A: Hematoxylin and eosin staining at 400× magnification of the dentate fascia of the hippocampus reveals round eosinophilic Pick bodies (arrows) in the soma of granular neurons. B: Immunohistochemical staining (brown) against tau at 400× magnification reveals round intraneuronal Pick bodies in cortical neurons.

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One FTD characterized by the presence of ubiquitin-positive inclusions (FTD-U) occurs as part of a disease spectrum with motor neuron disease. A familial form of FTD, FTD with parkinsonism linked to chromosome 17, was later found to map to the MAPT locus and has characteristic tau pathology. Multiple other FTDs exist; some have characteristic neuronal inclusions (eg, neurofilament, TAR DNA binding protein-43), whereas others lack distinctive histopathologic changes. Single gene defects have been identified for many FTDs, including PGRN, FUS, CHMP2B, and VCP. The prevalence of FTD is low, and the population prevalence of sporadic and genetic disease is not known.

Prion diseases

Prion diseases, also known as transmissible spongiform encephalopathies, are a family of rapidly progressive neurodegenerative diseases. ^[9] These diseases are unique in two ways. First, they are transmissible but not infectious. Second, the transmitting agent is a misfolded protein called the prion protein, capable of causing native, normally folded protein to adopt this disease-associated conformation when introduced into an organism. ^[9] Spontaneous misfolding of the prion protein is the most common cause.

The transmissibility of prion diseases was first described in studying an endemic prion disease called kuru among the Fore tribe of Papua New Guinea. ^[9] Kuru is characterized by rapid loss of motor and intellectual function, body tremors, and pathologic laughter. Further study revealed that Fore funeral practice included cannibalism. Ever since this practice was outlawed among the Fore, the disease has disappeared.

Creutzfeldt-Jakob disease (CJD) is the most common form of prion disease and occurs at a rate of approximately one case per one million population per year. Both sporadic and autosomal-dominant genetic forms of CJD exist. ^[9] Pathologically, prion diseases are characterized by spongiform encephalopathy and deposition of highly protease-resistant prion protein aggregates (see the image below). Spongiform encephalopathy—the appearance of coalescent vacuoles within the grey matter neuropil—is accompanied by neuron loss and gliosis. The vacuoles are dilated neuronal processes. Diagnosis of prion diseases requires biochemical analyses of the glycosylated forms of the abnormal prion protein.

If a prion disease is suspected by a physician, contacting the National Prion Disease Pathology Surveillance Center is imperative.

Dementia pathology. A: Hematoxylin and eosin staining at 400× magnification of the cerebral cortex reveals the coalescent clear vesicles characteristic of spongiform encephalopathy. B: Immunohistochemical staining (brown) against protease-resistant prion protein reveals the granular immunoreactivity seen in Creutzfeldt-Jakob disease.

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Huntington disease

Huntington disease (HD) is unique among the dementing illnesses in that it is always caused by a defect in a single gene, HTT. It is almost always autosomal dominant and, essentially, no sporadic form exists, although rare de novo mutations exist. HD is caused by a trinucleotide (CAG) repeat expansion in HTT that causes an elongated polyglutamine repeat in the Huntington protein. ^[24] Clinically, HD is primarily characterized by its characteristic choreiform movement disorder, but it also includes psychiatric disturbances and, ultimately, dementia. ^[25] No cure exists.

Pathologically, HD is characterized primarily by neuronal loss, atrophy, and gliosis of the caudate and putamen beginning in the anterior medial caudate. As the disease progresses, this neuronal loss, atrophy, and gliosis may involve multiple brain regions. Immunohistochemical staining against polyglutamine reveals intraneuronal inclusions, although this finding is usually not necessary for the diagnosis. Pathologic staging is performed by assessing the amount of atrophy, neuronal loss, and gliosis in the caudate and putamen. ^[26]

Tauopathies

Tauopathies are a heterogenous group of neurodegenerative disorders that may culminate in dementia and are characterized by abnormal accumulations of tau protein, often both in neurons and glia (see the image below). ^{[27, 28]}  Other pathologic hallmarks of brain regions affected by tau pathology are activated microglia, astrocytes, and elevated levels of proinflammatory molecules. ^[28]

This group of neurogenerative disorders includes corticobasal ganglionic degeneration, the Parkinson-dementia complex of Guam (also called Bodig-Lytigo), and argyrophilic grain disease. Several lines of evidence suggest that AD is also a tauopathy. ^{[28, 29]} The clinical presentation of these diseases varies and includes both cognitive impairment and movement disorders. ^{[29, 30]}

Dementia pathology. Immunohistochemical staining (brown) against tau at 400× magnification reveals glial immunoreactivity that is characteristic of this case of cortico-basal ganglionic degeneration.

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A novel aspect of tauopathies is the potential for cell-to-cell propagation. ^[30]