In advanced cases, gross examination of the brain shows striking atrophy, with brain weights of 1, 000 g or less, prominent atrophy of the cerebral cortex and hippocampus, and marked hydrocephalus ex vacuo. In subjects in the early stages of dementia, the brain weight can be in the normal range and the cortical atrophy mild, but hippocampal atrophy tends to be easily detectable at this time (Fig. 20.1). Microscopic changes are characterized by the deposition of cerebral amyloid or β-amyloid (Aβ) in the parenchyma (Fig. 20.2) and blood vessels of the cerebral cortex (Fig. 20.3) and the development of senile plaques (Fig. 20.2) and neurofibrillary tangles (NFTs) (Fig. 20.4). Senile plaques can be divided into diffuse (Fig. 20.5) and neuritic (Fig. 20.6) plaques. The latter are used for establishing the neuropathologic diagnosis of AD according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD).¹⁰ Microscopic lesions of AD are traditionally examined by staining the histologic sections with silver by the Bielschowsky method or one of its many modifications.⁹ With this method, it is possible to distinguish NFTs and various types of senile plaques: diffuse, cored, and neuritic (Fig. 20.6). The neuritic plaques contain dystrophic neurites filled with paired helical filaments, cytoskeletal proteins, multiple vesicular organelles, lysosomes, and amyloid precursor protein.¹¹, ¹², ¹³ Staining with thioflavin S also allows for the detection of neuritic senile plaques and NFTs.

The histopathologic changes of AD may also be examined by immunocytochemistry for the various protein abnormalities present in this disease. Aβ antibodies identify diffuse amyloid deposits, senile plaques (Figs. 20.5 and 20.7), and vascular amyloid (Fig. 20.3). Antibodies for phosphorylated tau identify the paired helical filaments present in NFTs (Fig. 20.8), tau or neuropil threads (Fig. 20.9), and the neuritic components of the plaques (Fig. 20.10). It is also recommended to immunostain for a-synuclein to detect Lewy bodies. The advantage of using immunocytochemistry is that it is less expensive to use than silver stains; the background of the stain is cleaner, allowing a faster and unequivocal identification of lesions; and it is easier to identify alternative or coexisting
pathologies, such as tauopathy¹⁴, ¹⁵, ¹⁶ and a-synucleopathy.¹⁷, ¹⁸ The disadvantage is that current criteria for pathologic diagnosis of AD are based on silver stains and not on immunostains.

Because the neuropathologic lesions of AD may also be present in the brains of cognitively normal subjects, it has been necessary to develop pathologic diagnostic criteria based on the semiquantitative assessment of neuritic plaques and NFTs. The CERAD criteria rate the density of neocortical senile plaques in a scale from none to frequent (Fig. 20.11).

The Braak classification applies to the distribution of NFTs throughout the brain, from 0 to VI.¹⁹ These pathologic descriptors, in combination with clinical information, are the bases for clinicopathologic algorithms to determine whether AD is possible, probable, or definite (CERAD), or whether the probability that the dementia can be attributed to AD is low, intermediate, or high (NIA-Reagan Institute).²⁰

The clinical features of PD include resting tremor, akinesia, rigidity, cog-wheeling, loss of postural reflexes, poor stance and gait stability, and frequent falls. The early motor abnormalities are often unilateral. The motor abnormalities in PD are the result of the progressive degeneration of dopaminergic neurons in the pars compacta of the substantia nigra and their projection to the striatum. The disease is not limited to the striatonigral system; however, as the disease progresses, other brain regions become involved, and the majority of patients with PD develop some degree of cognitive impairment or dementia. More than 70% of patients with PD may suffer from cognitive deficits 8 years after diagnosis.²¹ Although for many years PD was considered predominantly a sporadic disorder, more recently, a growing number of affected kindreds have been described and causative mutations identified, such as a-synuclein, parkin, DJ-1, and LRRK2.²² As happens with other neurodegenerative disorders, familial cases of PD tend to have earlier onset than do sporadic cases. The motor manifestations of PD, tremor in particular, respond to therapy with levodopa or dopamine agonists, but these therapies do not arrest the relentless progression of the disease.

The diagnosis of MSA is based on the presence of parkinsonism, cerebellar ataxia, autonomic failure, urinary dysfunction, and corticospinal dysfunction.²⁸ The terms MSA-P or MSA-C are applied
to patients who have predominantly parkinsonian or cerebellar involvement, respectively.

Grossly there is no generalized atrophy, but localized atrophy is common. In MSA-P, the putamen may be atrophic and have gray discoloration, and the substantia nigra and locus coeruleus appear pale. In MSA-C, cerebellar and brainstem atrophy is common. Microscopically, there is variable neuronal loss in several regions, including putamen, globus pallidum, and substantia nigra. In the cerebellum, the Purkinje cells are more vulnerable than other neurons and their loss is most severe in the vermis. The histologic hallmark of MSA, however, is the glial cytoplasmic inclusion. This inclusion in the cytoplasm of oligodendrocytes was first described with the Gallyas silver staining method, ²⁹ but it is more easily detected with ubiquitin or α-synuclein immunostains (Fig. 20.19). In addition to oligodendroglial inclusions, brains in MSA may also show perikaryal, neuritic, and nuclear α-synuclein inclusions in neurons.