o is depleted of neurons, becomes spongy, and displays a dense astrofibrosis. The white matter is variably devoid of myelin, which is replaced by astrogliosis. Astrocytes in the cerebral cortex and oligodendrocytes in the white matter may display argyrophilic and tau-immunoreactive cytoplasmic inclusions.

Dementia with Parkinsonism Linked to Chromosome 17

Clinical features. This is a familial dementia inherited in an autosomal dominant pattern: The interest of the disease lies in its association with mutations in the Tau gene on chromosome 17. The disease begins between the ages of 30 and 50 years and manifests with behavioral changes, features of Kluver-Bucy syndrome, cognitive decline, frontal lobe dementia, and akinetic rigidity that is unresponsive to dopamine therapy.

Pathology. Frontotemporal atrophy and discoloration of the substantia nigra and locus ceruleus are distinct gross findings. Major histologic changes are neuronal losses and the presence of argyrophilic tauimmunopositive cytoplasmic inclusions in the neurons, astrocytes, and oligodendrocytes. Common sites of neuronal losses and replacement gliosis are the frontal and limbic cortex, substantia nigra, basal ganglia, and amygdala. The neuronal inclusions are round, oval, or ring-shaped, and are found in the cerebral cortex and affected subcortical gray structures. Astrocytes with tau deposits appear as tufted astrocytes and astrocytic plaques. Oli-godendrocytes in the cerebral, cerebellar, and brainstem white matter display coil-shaped inclusions.

Dementia with Corticobasal Degeneration Clinical features. Corticobasal degeneration (CBD) is a slowly progressive neurodegenerative disease of mid to late life. It occurs sporadically; few familial cases have been recorded. Prominent clinical features include combinations of:

• Limb dystonia and apraxia, often unilateral or asymmetrical

• Akinetic-rigidity

• Postural instability

• Postural and action tremor and

• Cortical sensory impairment

• Eye-movement abnormalities

• Focal myoclonus

• Alien limb phenomenon (the extremity feels foreign)

• Frontal lobe behavioral changes

• Cognitive decline

Pathology. Grossly, the atrophy is confined to the superior frontoparietal convolutions, including the pre- and postcentral convolutions; to the basal ganglia; and to the midbrain tegmentum. The substantia nigra is depig-mented, and the globus pallidus may have a rustye color. The temporal lobe is usually spared, except in cases presenting with aphasia and severe dementia. The histology is characterized by (a) the presence of achromatic neurons, (b) tau-immunoreactive neuronal inclusions, (c) glial inclusions, (d) neuropil threads, and (e) neuronal losses and gliosis.

The achromatic or ballooned neurons are devoid of Nissl substance, stain faintly with eosin, are weakly argyrophilic, and immunoreact for phosphorylated neurofilaments, a-B-crystalline, and tau protein. They are found chiefly in the affected frontal cortex, limbic areas, and amygdala (Fig. 5.15).

The tau-positive, argyrophilic neuronal inclusions, called corticobasal bodies, are widely distributed in the cortex, subcortical gray structures, and brainstem.

The glial inclusions are argyrophilic, tau-positive astrocytic plaques, thorn-shaped and tufted astrocytes in the cerebral cortex; and oligodendrocytic coiled bodies in the white matter. The tau-positive neuropil threads of glial and neuronal origin are abundant in the gray and white matter. Neuronal losses and astrogliosis, usually moderate, occur in the cerebral cortex, substan-tia nigra, striatum, thalamus, midbrain, medullary olives, and cerebellar dentate nuclei.

FTLDs with Ubiquitin-Only Pathology

Dementia with Motor Neuron Disease

In this rare condition, the patient presents with behavioral changes, frontal lobe dementia, and an amyotrophic picture showing weakness, muscle wasting, fasciculation and, ultimately, dysarthria and dysphagia.

Grossly, the frontotemporal lobes are atrophic, and the substantia nigra is discolored. Histologically, the spinal cord and brainstem show degeneration of the motor neurons. Neuronal losses are present in the atro-phic cortex, striatum, thalamus, and substantia nigra. Ubiquitinated neuronal cytoplasmic inclusions are characteristic, and occur in the granule cells of the dentate fascia of the hippocampus, frontal and temporal cortex, brainstem, and spinal motor neurons.

Dementia with Ubiquitin-Only-Positive Neuronal Inclusions

Clinically, this group of dementias is often referred to as dementias with motor neuron disease-inclusions, although features of amyotrophic lateral sclerosis (ALS) are not present. Grossly, the brain shows a circumscribed atrophy of the frontal and/or temporal lobes (Fig. 5.18). The histology is distinguished by the presence of ubiquitin-only immunoreactive neuronal inclusions. They are neither argyrophilic nor eosinophilic, and they do not immunoreact for tau protein. The inclusions are commonly found in the granule cells of the dentate fascia of the hippocampus. Ubiquitin-positive neurites and occasional neuronal inclusions occur in the superficial cortical layers (Fig. 5.19). The limbic and neocortical areas show neuronal losses and microvacu-olation, chiefly in the external layers. Astrogliosis is moderate to severe in the affected areas.

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