Frontotemporal lobar degeneration (FTLD) encompasses several disorders that preferentially affect the frontal and/ or temporal lobes. As a result, these disorders have certain shared clinical features, such as progressive deterioration of language and changes in personality. The term degeneration is applied to describe the neuropathologic changes; clinically, these syndromes commonly are referred to as frontotemporal dementias. Depending on the disease distribution (frontal or temporal), behavioral changes or language problems may dominate. In general, behavioral and language problems precede memory disturbances, a distinction that assists in the clinical discrimination between FTLD and AD. The onset of symptoms occurs at younger ages for FTLD than for AD.
In addition to the clinical classification, two pathologic subgroups exist that are distinguished based on the composition of characteristic neuronal inclusions, which may contain tau or TDP43. One well-recognized subtype of FTLD-tau is Pick disease, which is associated with smooth, round inclusions known as Pick bodies. How tau aggregation may lead to neurodegeneration was discussed earlier, in the context of Alzheimer disease. The other major form of FTLD is characterized by aggregates containing the DNA/RNA-binding protein TDP43 (FTLD-TDP43). It is uncertain how this leads to neurodegeneration; both loss of TDP43 activity and a toxic gain-of-function related to the protein aggregates remain possibilities. TDP43 neuronal inclusions also are found in a large proportion of cases of amyotrophic lateral sclerosis (ALS). This overlap is manifest clinically, as many individuals with ALS also show evidence of FTLD.
MORPHOLOGYThegrossappearanceisindependentofthetypeofinclusions,withatrophyoffrontalandtemporallobesofvariableextentandseverity,accompaniedbyneuronallossandgliosis(
Fig.
23.26A–B ).InFTLD-tau,thecharacteristicadditionallesionisthepresenceoftau-containingneurofibrillarytangles,similartothetanglesfoundinAD(see
Fig.23.26C ).InFTLD-TDP,thereislossofnuclearstainingforTDP43associatedwiththeappearanceofTDP43-positiveinclusions(see
Fig.23.26D
Parkinson disease (PD) is a neurodegenerative disease marked by a hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra. Parkinsonism is a clinical syndrome characterized by tremor, rigidity, bradykinesia, and instability. These types of motor disturbances may be seen in a range of diseases that damage dopaminergic neurons, which project from the substantia nigra to the striatum and are involved in control of motor activity. Parkinson-ism can be induced by drugs such as dopamine antagonists or toxins that selectively injure dopaminergic neurons. Among the neurodegenerative diseases, most cases of parkinsonism are caused by PD, which is associated with characteristic neuronal inclusions containing α-synuclein.