Frontotemporal Dementias

These are a group of disorders that were first gathered under a single broad term because they shared clinical features (progressive deterioration of language and changes in personality)

that corresponded to degeneration and atrophy of temporal and frontal lobes. These entities have recently been better understood through a combination of immunohistochemical and

biochemical studies as well as genetic insights.[158] [159]

Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 (FTD(P)-17)

As the name implies, this is a genetically determined disorder in which the clinical syndrome of a frontotemporal dementia is often accompanied by parkinsonian symptoms. In these

families, the disease has been mapped to chromosome 17; in particular, it has been linked to a variety of mutations

in the tau gene. Tau is a microtubule binding protein that has numerous sites of potential phosphorylation and exists in six splice forms as the result of alternative splicing of exons 2, 3

and 10.[160] The protein contains either three or four copies of the microtubule binding domain depending on whether exon 10 is included (4 repeat tau) or not (3 repeat tau).

Morphology.

There is evidence of atrophy of frontal and temporal lobes in various combinations and to various degrees. The pattern of atrophy can often be predicted in part by the clinical

symptomatology. The atrophic regions of cortex are marked by neuronal loss and gliosis as well as the presence of taucontaining neurofibrillary tangles. These tangles may contain either

4 repeat tau or a mixture of 3 and 4 repeat tau, depending on the underlying genetic basis for the disease. Nigral degeneration may also occur. Inclusions can also be found in glial cells

in some forms of the disease.

Pathogenesis and Molecular Genetics.

The study of families with frontotemporal dementia led to the recognition that in some, but not all, pedigrees, there is linkage to mutations in the tau gene. The mutations fall into several

broad categories: coding region mutations and intronic mutations that affect the splicing of exon 10.[161] The intronic mutations result in increased production of 4 repeat forms of tau.

Coding region mutations appear to have several different consequences, including alterations in the interaction of tau with microtubules (mutations in exon 10 will change this

interaction only for 4 repeat tau) and altering the intrinsic tendency to aggregate.

Pick Disease

Pick disease (lobar atrophy) is a rare, distinct, progressive dementia characterized clinically by early onset of behavioral changes together with alterations in personality (frontal lobe

signs) and language disturbances (temporal lobe signs).[162] While most cases of Pick disease are sporadic, there have been some familial forms identified and linked to mutations in tau.

Morphology.

The brain invariably shows a pronounced, frequently asymmetric, atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior two thirds of the superior temporal

gyrus and only rare involvement of either the parietal or occipital lobe. The atrophy can be severe, reducing the gyri to a thin wafer ("knife-edge" appearance). This pattern of lobar

atrophyis often prominent enough to distinguish Pick disease from Alzheimer disease on macroscopic examination. In addition to the localized cortical atrophy, there may also be

bilateral atrophy of the caudate nucleus and putamen.

On microscopic examination, neuronal loss is most severe in the outer three layers of the cortex. Some of the surviving neurons show a characteristic swelling (Pick cells) or contain

Pick bodies,which are cytoplasmic, round to oval, filamentous inclusions that are only weakly basophilic but stain strongly with silver methods. Ultrastructurally, these are composed of

straight filaments, vesiculated endoplasmic reticulum, and paired helical filaments that are immunocytochemically similar to those found in Alzheimer disease and contain 3 repeat tau.

Unlike the neurofibrillary tangles of Alzheimer disease, Pick bodies do not survive the death of their host neuron and do not remain as markers of the disease.

Progressive Supranuclear Palsy (PSP)

This is an illness characterized clinically by truncal rigidity with dysequilibrium and nuchal dystonia; pseudobulbar palsy and abnormal speech; ocular disturbances, including vertical

gaze palsy progressing to difficulty with all eye movements; and mild progressive dementia in most patients. The onset of the disease is usually between the fifth and seventh decades,

and males are affected approximately twice as frequently as are females. The disease is often fatal within 5 to 7 years of onset.

Morphology.

There is widespread neuronal loss in the globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter, and dentate nucleus of the cerebellum. Globose

neurofibrillary tangles are found in these affected regions, in neurons as well as in glia. Ultrastructural analysis reveals 15-nm straight filaments that are composed of 4 repeat tau.

Mutations in tau have not been found in PSP. Analysis of the tau gene has shown that there is an extended haplotype (a series of polymorphic markers spread out along the gene that are

in complete linkage disequilibrium; that is, recombination events do not appear to occur between the sites). Of the two haplotypes, one of them is strongly overrepresented in PSP

patients.[163] How this haplotype influences the risk of PSP is unknown.

Corticobasal Degeneration (CBD)

This is a disease of the elderly, with considerable clinical and neuropathologic heterogeneity. The extrapyramidal signs and symptoms result in this disorder's also being grouped with

syndromes of basal ganglia dysfunction.

Morphology.

On macroscopic examination, there is cortical atrophy, mainly of the motor, premotor, and anterior parietal lobes. The regions of cortex show severe loss of neurons, gliosis, and

"ballooned" neurons (neuronal achromasia) that can be highlighted with immunocytochemical methods for phosphorylated neurofilaments. Tau immunoreactivity has been found in

astrocytes ("tufted astrocytes"), oligodendrocytes ("coiled bodies"), basal ganglionic neurons, and, variably, cortical neurons.[164] [165] Clusters of tau-positive processes around an

astrocyte ("astrocytic plaques") and the presence of tau-positive threads in gray and white matter may be the most specific pathologic findings of CBD.[166] The substantia nigra and

locus ceruleus show loss of pigmented neurons, neuronal achromasia, and tangles. Similar to

PSP, the tau deposits in CBD contain predominantly 4 repeat tau. Recently proposed consensus diagnostic criteria for CBD focus on the presence of tau-positive inclusions in neurons

and glia of the cortex and striatum, including astrocytic plaques, associated with neuronal loss from substantia nigra and cortex.[167]

Clinical Features.

The disease is characterized by extrapyramidal rigidity, asymmetric motor disturbances (jerking movements of limbs: "alien hand"), and sensory cortical dysfunction (apraxias, disorders

of language); cognitive decline occurs, and may be prominent in some cases.[168] [169] The same extended tau haplotype is linked to CBD as to PSP.[170] Although tau deposits are a

hallmark of CBD, it is rare to find CBD pathology in individuals with mutations in the tau gene.[171]

Date: 2016-04-22; view: 670