CHAPTER NINE
DEGENERATIVE DISEASES

FRONTOTEMPORAL LOBAR DEGENERATIONS

Frontotemporal dementia (FTD) is a clinical term that refers to a group of progressive neurodegenerative disorders that affect the frontal and temporal lobes causing personality change (apathy, disinhibition, loss of insight and emotional control), loss of the ability to recognize the meaning of words and objects, language dysfunction, and global cognitive decline. Three clinical FTD syndromes are recognized: behavioral variant of FTD, semantic aphasia, and progressive nonfluent aphasia. Because behavior and personality change may be a presenting symptom, FTLDs are often initially diagnosed as psychiatric disorders. FTDs have an earlier onset than AD and, at an early stage, do not cause the memory loss and visuo-spatial disorientation that are so characteristic of AD. There is an overlap between FTDs, extrapyramidal syndromes, and motor neuron diseases. There are several clinicopathological entities in the FTLD group, which together account for 10 to 20 percent of dementia.

The term Frontotemporal Lobar Degeneration (FTLD) refers to the neuropathology of the FTDs. Pathologically, the FTLDs are characterized by atrophy of the frontal and temporal lobes (lobar atrophy) which contrasts the diffuse atrophy of AD, and by some or all of the following microscopic findings: neuronal loss and gliosis, vacuolization of the superficial cortex (spongiosis), and ballooned neurons. All FTLDs show also abnormal protein inclusions in neurons and glial cells. Based on the chemical nature of these inclusions, two groups of FTLDs are recognized: FLDTs with tau-positive inclusions (tauopathies); and FTLDs with tau-negative, alpha-synuclein-negative inclusions which contain the protein TDP-43 conjugated with ubiquitin (TDP-43 proteinopathies).  Though degeneration in FTLDs is primarily cortical, there are pathological changes in the substantia nigra and other subcortical structures.

Our concept of FTDs and FTLDs is still evolving but significant progress has been made recently in sorting out these entities and other non AD dementias and getting insights into their pathogenesis and genetics.

TAUOPATHIES
Tau (the Greek letter) is a microtubule associated protein, encoded by the gene MAPT gene on 17q21. Normally, tau is phosphorylated and is present mainly in axons where it binds and stabilizes microtubules. Tauopathies are characterized by abnormal deposits of hyperphosphorylated tau in the form of paired helical or straight filaments. The tauopathies include:

Pick's Disease Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 (FTDP-17) Corticobasal Degeneration Progressive supranuclear palsy

AD is also in part a tauopathy. In AD, the tau deposits (NFTs and neuropil threads) are present in the neuronal body and dendrites. In other tauopathies, both, neurons and glial cells are affected.

PICK’S DISEASE

Pick's disease: Left:lobar atrophy. Right:Pick inclusion bodies.	Pick cell

Described almost 2 decades before AD, Pick's disease has long been the prototype of FTLDs and tauopathies. It presents between 45-65 years with confusion and FTLD symptoms and has a progressive course lasting 2-5 years, sometimes more. In advanced stages it cannot be distinguished clinically from AD. The brain shows atrophy of frontal and temporal lobes, Pick bodies (tau-positive spherical cytoplasmic neuronal inclusions, composed of straight filaments), and Pick cells (ballooned neurons with dissolution of chromatin). Older patients may also have AD pathology.

TDP-43 PROTEINOPATHIES
TDP-43, encoded by the TARDBP gene on chromosome 1, is a highly conserved nuclear protein, which is expressed in many tissues. Its functions have not been completely defined. In the TDP-43 proteinopathies, abnormally folded, hyperphosphorylated TDP-43, conjugated with ubiquitin, is deposited in neurons and glial cells in the form of intranuclear, cytoplasmic, and neuritic inclusions. The core clinical and pathological phenotype of the TDP-43 proteinopathies is similar to that of other FTLDs. In addition, there is an overlap between TDP-43 proteinopathies and motor neuron diseases. Clinically, a significant proportion of ALS patients present with FTLD symptoms or develop cognitive impairment later. Pathologically, TDP-43 inclusions are present in degenerating motor neurons in ALS and are also seen in the cortex and other locations. TDP-43 deposits are also seen in some cases of Alzheimer's disease, Pick's disease, Parkinson's disease, and diffuse Lewy body disease.

Most clinicopathological entities included in the FTLDs have sporadic and familial, usually autosomal dominant variants. The best known familial FTLD is Frontotemporal Dementia with Parkinsonism, Linked to Chromosome 17 (FTDP-1), caused by a mutation of MAPT.

Further reading:
Kwong LK, Uryu K, Trojanowski JQ, Lee VM-Y. TDR-43 Proteinopathies: Neurodegenerative Protein Misfolding Diseases without Amyloidosis. Neurosignals 2008:16;41-51. PubMed

Josephs KA. Frontotemporal Dementia and Related Disorders: Deciphering the Enigma. Ann Neurol 2008;64:4-14. PubMed

Updated: November, 2008