Frontotemporal Lobar Degeneration Syndromes
FTLD is the term used to capture a neuropathologically linked group of non-AD dementing conditions associated with frontotemporal and basal ganglia pathology. FTD subsumes three clinical syndromes, bvFTD, semantic variant primary progressive aphasia (svPPA), and nonfluent variant primary progressive aphasia (nfvPPA). Recent evidence indicates that FTLD is closely related to several other neurodegenerative disorders: CBD, PSP, and motor neuron disease (Figure 68-2).
Frontotemporal lobar degeneration (FTLD) and potential associations to other neurodegenerative syndromes.
The core anatomic feature of FTLD is the focal, often asymmetric cortical degeneration of frontal and anterior temporal regions with general sparing of posterior cortical structures. The resultant brain atrophy can be severe, sometimes described as “knife-edge,” and the brain can weigh as little as 750 g (Figure 68-3). Patients present with a primary behavioral or language deficit that typically corresponds to the region of greatest brain atrophy and dysfunction. Patients presenting with primary behavioral deficits are classified as suffering with bvFTD. bvFTD overlaps considerably with the two syndromes that present with predominant language deficits, svPPA and nfvPPA. In most centers bvFTD accounts for more than 50% of all cases with the others divided between svPPA and nfvPPA. The neuropathologic basis for nearly one-half of these diseases is the abnormal accumulation of tau protein with a similar percentage associated with abnormal aggregates of TDP-43. Less than 10% show aggregates of the FUS protein. Many FTD patients are misdiagnosed as having AD during life. In addition to changes in personality and behavior, features that should alert physicians to the possibility of FTD include early abnormalities in social conduct, loss of sympathy and empathy for others, repetitive motor behaviors, or hyperorality. When cognitive testing is completed, suspicion should be raised when abnormalities in executive functioning occur in the absence of prominent amnestic complaints or cognitive features localizing to posterior structures, such as problems with calculations and visuospatial tasks.
T2-weighted axial (right) and T1-weighted coronal (left) brain magnetic resonance imaging (MRI) in a 59-year-old woman with pathology-confirmed Pick disease.
Patients who present with isolated language symptoms that exist for at least 2 years in the initial stages of cognitive decline are termed to have primary progressive aphasia (PPA). As a group, patients with PPA have greater atrophy on the left than the right of the perisylvian region, the anterior temporal lobes, and the basal ganglia. Inferior parietal lobule atrophy has also been described in PPA and is associated with predominantly word-finding deficits. Called logopenic aphasia by Gorno-Tempini and colleagues, this form of PPA is usually due to underlying AD pathology. As the syndrome progresses, patients presenting with nfvPPA go on to develop features of PSP or CBD or even amyotrophic lateral sclerosis (ALS). Thus, careful attention to the development of motor symptoms is necessary to help with the prediction of the underlying pathology. The emergence of artistic behavior has been described in some patients with primary language difficulty.
Efforts to distinguish the various PPA syndromes from each other may have clinical ramifications. Based on apolipoprotein epsilon 4 expression in clinical studies, it appears likely that the logopenic variety of PPA is a language presentation of AD; although pathologic confirmation of this correlation is lacking. As the term implies, these patients have decreased speech output. They typically have slow speech with impaired syntactic comprehension and naming. The logopenic variety is associated with short-term phonologic memory deficits. These patients exhibit profound echoic memory deficits manifested as forgetting portions of longer phrases during repetition tasks. As pathologic studies become available, if confirmed to be AD in etiology, these patients may be amenable to treatment with cholinesterase inhibitors or emerging amyloid-directed treatment strategies.
Nonfluent Variant Primary Progressive Aphasia
Patients with nfvPPA typically have apraxic, labored speech with errors in grammar, and difficulty with more complex syntax. Speech apraxia is the inability to produce speech caused by difficulty in programming the sensorimotor commands for the positioning and movement of muscles used to produce speech. This leads to difficulty with initiation of speech, sound substitutions, omissions, transpositions of syllables, and a slower rate of expressing sentences punctuated with inappropriate starts and stops. The errors produced in apraxic speech are typically inconsistent. Patients may display difficulty with articulating multisyllabic words. Speech apraxia is localized to the left opercular and anterior insular region.
Anomia is variably present and phonemic paraphasias are frequently observed. Speech output is decreased and dropped words, often articles such as “the” occur. In patients with nfvPPA, sentences tend to have more nouns than verbs. In contrast to patients with svPPA, these patients maintain single word comprehension and semantic knowledge. Thus, nfvPPA is not likely in a patient who has preserved articulation, preserved grammar, and deficits in semantic knowledge. Insight into the condition can be exquisitely preserved with nfvPPA, and patients often develop depression. Behavioral problems are uncommon in early stages of disease.
The evaluation of brain MRIs in 11 patients with nfvPPA using voxel-based morphometry (VBM) identified regions of atrophy that are typically asymmetrically left-dominant with preferential involvement of the inferior frontal lobe, the insular region, and the caudate. Hypometabolism of the left frontal region can be observed on FDG positron emission tomography (PET). The majority of patients show tau pathology at autopsy with CBD followed by PSP and Pick changes. Approximately 20% show TDP pathology, usually TDP-43 type A.
Semantic Variant Primary Progressive Aphasia
In contrast to patients with nfvPPA, patients with svPPA have fluent speech that is grammatically accurate, but they exhibit the hallmark loss of semantic knowledge. Semantic memory is the encyclopedic knowledge of people, objects, facts, and words. Unlike episodic memories, individuals are not aware of where or when they learned these facts. Eventually individuals lose all knowledge about the fact or word and exhibit features of a multimodality agnosia. Therefore, even when they are provided with the name of the object, the object is not recognized. Early in the disease, patients are often aware of word-finding difficulties but are unaware of comprehension difficulties. Semantic paraphasias are frequent, with supraordinate substitutions of words and common use of nonspecific grouping words such as “stuff” and “things.” Repetition and prosody are preserved as is syntax and verb recognition.
Patients with svPPA display surface dyslexia manifest by difficulty pronouncing irregularly spelled words, such as “gnat,” “heir,” or “pint,” when pronunciation does not follow standard phonologic rules. On neuropsychological testing, patients with svPPA have difficulty with category fluency and confrontational naming, particularly with low-frequency words. Often, svPPA patients have difficulty naming famous people. In contrast to AD, many svPPA patients have greater deficits for remote compared to recent memory, when memory deficits become involved.
Of all the PPA syndromes, svPPA has the greatest propensity to include behavioral problems, which are included as supportive evidence in diagnostic criteria. As with FTD, the behavioral issues seen with svPPA often involve hyperorality, disinhibition, and aberrant motor behavior. Diagnostic criteria include behaviors such as loss of sympathy and empathy, narrowed preoccupations, and parsimony (excessive frugality, stinginess). Rigidity in thinking can be striking. svPPA patients can develop compulsions and have been described to have visual hypervigilance, such as recognizing that a hair is subtly out of place on an examiner or quickly seeing a coin on the street. They may exhibit difficulty in the interpretation of emotions, particularly negative emotions such as sadness, anger, and fear. Emergence of behavioral symptoms correlates with duration of illness but can also be an early finding. The presence of early behavioral issues in a patient with a PPA syndrome should alert to the possibility of svPPA.
Anatomic studies may explain why svPPA patients often exhibit behavioral abnormalities. The disorder begins in the amygdala and anterior temporal lobes. When it starts on the left side, language deficits predominate, while right-sided presentations are characterized by loss of empathy for others or deficits in the recognition of familiar people. These patients sometimes meet research criteria for bvFTD while others are more typical of svPPA. While svPPA begins in the anterior left temporal lobe, it typically spreads anteriorly to involve the frontal regions. Eventually it spreads to the right medial frontal lobe, the right orbitofrontal lobes, and the right insular region, areas associated with behaviors such as disinhibition and apathy. The absence of behavioral problems in the logopenic variety of PPA and in nfvPPA may be due to the general sparing of these same structures in those diseases.
Patients with svPPA often have TDP-43 type C–positive, tau-negative inclusions at autopsy. The etiology for svPPA and for TDP type C aggregates is unknown. Rarely are these cases familial. Recent work suggests that a significant subset of these patients have a history of autoimmunity and increased levels of tumor necrosis factor (TNF) in the serum.
Behavioral Variant Frontotemporal Dementia
bvFTD presents with the insidious onset of change in personality and inappropriate behaviors. The mean age of onset is in the mid-fifties. Most commonly, symptoms include disinhibition, poor impulse control, loss of sympathy or empathy for others, overeating, compulsive behaviors, and deficits in executive controls or multitasking (Table 68-4). Patients can develop stereotyped behaviors, defined as repetitive, invariant behaviors that lack purpose. Examples include counting, pacing, organizing, or the repetitive use of catch phrases. Socially inappropriate activities can include shoplifting and other criminal behavior, public urination, offensive speech, and public masturbation. Perseveration is common. Cravings for sweets are often observed. When associated with the decreased sense of satiety that can occur, large, unhealthy weight gain results. Hyperorality and oral exploratory behavior can occur.
TABLE 68-4BEHAVIOR SYMPTOMS SEEN IN FRONTAL VARIANT FTD |Favorite Table|Download (.pdf) TABLE 68-4 BEHAVIOR SYMPTOMS SEEN IN FRONTAL VARIANT FTD
Change in beliefs (hyperreligiosity, change in attitude)
Cravings (sweets, weight gain)
Criminal behavior (theft, assault, public urination)
Euphoria (inappropriate jocularity)
Hyperorality (oral exploratory behavior in late disease)
Hypersexuality (offensive statements, masturbation)
Impotence and decreased sexual drive
Loss of empathy (coldness, self-centered)
Stereotyped behavior (counting, pacing, repetitive use of catch phrases)
Patients with bvFTD are often misdiagnosed as having psychiatric illness. In other instances, any patient with an atypical dementia syndrome is considered to have bvFTD. Delusions can occur, often with bizarre or grandiose overtones. Patients exhibit lack of empathy and can have a cold, blunted effect. When the anterior cingulate and medial frontal lobes are involved, apathy can be particularly prominent. Some patients undergo large changes in their beliefs and attitudes, including religious sentiments. In contrast to AD, depression is uncommon in bvFTD.
Neuropsychological testing demonstrates abnormalities in executive functioning, working memory, and social cognition with general sparing of visuospatial skills and verbal memory. Consequently, the MMSE score can be quite high even among patients with marked functional disability. bvFTD patients also display problems with set-shifting, concept formation, and abstract reasoning. They may demonstrate disinhibition, impulsivity, and poor judgment during testing. These behaviors can falsely lower verbal memory scores. When closely scrutinized, poor scores on such tests are accompanied by frequent intrusions of novel words and endorsement words that were not part of the original list learned (false positives on recognition testing).
Behavioral symptoms are a common late finding in most dementia syndromes. Thus the emergence of behavior and personality symptoms in a patient with well-established dementia should be looked upon with caution when considering a change in diagnosis to bvFTD. The importance of the first symptom (often the presenting symptom) in the evaluation of patients with neurodegenerative disorders cannot be overstated.
Patients with bvFTD will typically have profound, usually bilateral, frontal, anterior insular, and anterior temporal lobe atrophy. Patients with greater atrophy on the right frontal lobe than left have more severe behavioral symptoms. Stages of atrophy have been described with the earliest stage involving only mild atrophy of the orbital and superior medial frontal lobes and hippocampus. As the disease progresses, the anterior frontal and temporal cortices and basal ganglia are increasingly involved. The severity of atrophy increases as disease advances. William Seeley has demonstrated that in many instances, the first neurons afflicted in bvFTD are von Economo neurons that sit in the anterior insular and cingulate cortex. SPECT and FDG-PET techniques have been used to differentiate FTD from AD with PET receiving Food and Drug Administration (FDA) approval for this indication. Both SPECT and FDG-PET demonstrate bilateral frontal hypometabolism/perfusion in patients with FTD. Amyloid imaging is extremely valuable in separating AD from bvFTD, particularly in patients under the age of 70 in whom the presence amyloid is not highly prevalent.
Pick disease is a pathologic diagnosis and occurs in approximately 20% of clinical cases presenting with signs and symptoms of bvFTD. Less commonly it presents as nfvPPA. First described in 1892 by a German neurologist, Arnold Pick, the pathologic hallmark of Pick disease are argyrophilic cellular inclusions known as Pick bodies and swollen achromatic tau-positive neurons termed Pick cells. This is invariably associated with loss of large pyramidal neurons, resulting in a spongiform histologic appearance with selective atrophy of the frontal and anterior temporal lobes. Pick bodies are localized to the limbic cortex, paralimbic cortex, and predominantly the ventral aspect of the temporal lobe. The pre- and postcentral gyri are notably spared. The largest concentration of Pick bodies is found in the hippocampus and amygdala. Pick bodies are composed of randomly arranged tau filaments. In AD, tau pathology (neurofibrillary tangles) can spare the dentate gyrus; however, in Pick disease, this region is heavily involved.
Other FTLD Neuropathologies
FTLD is associated with tau pathology in about half of cases. The tau gene product has six isoforms, half of which result in three microtubule-binding repeats (3Rtau) and the other half result in four microtubule repeats (4Rtau). Pick disease is usually associated with 3Rtau. PSP and CBD, in contrast, are associated with 4Rtau. The clinical features and neuropathology of PSP and CBD are described later in this chapter.
Among FTLD cases that do not stain for tau protein, the histopathology will typically indicate a variable pattern of neuronal loss and gliosis without characteristic features such as neurofibrillary tangles or Pick bodies. Historically, the term “dementia lacking distinctive histology” (DLDH) was employed; however, new discoveries led to the reclassification of many such cases to FTLD-U (ubiquitin), and because DLDH is extremely rare, the term is disappearing. FTLD-TDP account for around 50% of all non-tau FTLD cases. In these cases, neuronal inclusion bodies with prominent ubiquitin staining are seen. These inclusion bodies stain negative for tau and are localized throughout the neocortex and within anterior horn cells. This pathology has been identified in patients with and without concurrent motor neuron disease.
More recently, TDP-43 neuropathology has been subdivided into four types, TDP-A to TDP-D, depending on the pattern of the TDP inclusions within the nucleus and cytoplasm. TDP type A is often associated with mutations in the progranulin gene, although sporadic cases have been seen. Type B is often associated with motor neuron disease, and the most common genetic mutation associated with familial FTD-ALS, C9orf72, often shows type B changes. TDP-C is the pattern associated with svPPA, while type D is seen with the rare FTD-causing mutation in valosin.
Our understanding of the genetics of FTLD is evolving. In 1998 it was discovered that a mutation in the microtubule-associated protein tau (MAPT) was responsible for a familial form of FTD associated with Parkinson disease (FTDP-17). This mutation appears to be more common in Southern Europe and France than in Northern Europe, and a few mutations have been reported in China and Japan. The disease onset with mutations is variable with several variants presenting in the third of fourth decade. Mean disease onset is approximately 52 years. The mechanism for disease pathogenesis with tau mutations appears to be variable. In some cases, a mutation in an intron adjacent to exon 10 leads to an excess of the 4R form of tau with abnormal aggregation of tau. In other mutations, abnormal microtubule-binding or excessive formation of oligomers appears to be the mechanism for neurodegeneration.
A mutation in the progranulin (GRN) gene (only 1.7 Mb away from the tau gene) was identified in 2006. This mutation appears to account for up to 11% of sporadic and 25% of familial FTD cases. Disease onset tends to be later than with tau, and approximately 10% of gene carriers remain asymptomatic after age 70. There are genes that modify progranulin expression that may be partially responsible for this clinical variability. The onset of disease can range from 35 to 80 years. The phenotype is more variable than with MAPT, and syndromes vary from bvFTD, nfvPPA, CBD, and Parkinson disease to AD. Asymmetry is common with one hemisphere massively atrophic and the other relatively normal. The pathomechanisms associated with GRN mutations are also debated: loss of neuronal growth attributed to low levels of the progranulin protein versus excessive inflammation associated with low progranulin levels or a relative increase in the granulins proteins cleaved from progranulin. All of the hypothesized mechanisms probably contribute to illness. Autoimmunity is seen in more than 10% of gene carriers and can precede neurologic disease.
In 2011 a mutation in the C9orf72 gene was discovered as the major cause for familial forms of FTD, ALS, and FTD-ALS. A huge expansion of a hexanucleotide repeat in the intron of C9 leads to massive overproduction of RNA and the production of dipeptides generated from the RNA in a non-ATG manner. The clinical onset is typically in the sixth decade but patients in the fourth and eighth decades have been described. The illness often begins as a psychiatric illness with highly variable symptoms ranging from borderline personality disorder, bipolar illness, depression, and conversion disorder to drug addiction. Similarly, whether a gene carrier is diagnosed with bvFTD or ALS is also variable, and in some instances, both syndromes emerge together. The mechanism for disease seems to reflect RNA-mediated neurodegeneration caused by large nuclear RNA aggregates that interfere with nuclear functions, the toxic effects of dipeptides, and possibly gene haploinsufficiency.
Other isolated cases of FTLD-related mutations have been described, including valosin-containing protein gene (VCP) and charged multivesicular body protein 2B (CHMP 2B). Patients with the VCP mutation develop a rare disease with inclusion body myopathy, early Paget disease of bone, and FTD (IBM-PDB-FTD). Additionally, predominantly ALS but sometimes bvFTD phenotypes can occur with mutations in the TDP-43 and FUS proteins.
Treatment approaches for FTD and related disorders are generally aimed at symptom management, as there are no known disease-modifying therapies. Selective serotonin reuptake inhibitor (SSRI) medications may be beneficial for behavioral symptoms, including carbohydrate craving and compulsions. If delusions are problematic, atypical neuroleptics can be considered. There is no theoretical basis for the use of cholinesterase inhibitors, which can aggravate agitation. Attention to caregiver issues is important as the stressors often differ from those seen in typical AD and can be particularly burdensome. The different social and behavioral issues presented to FTLD compared to AD caregivers and the younger age of both patients and caregivers in FTLD can result in a feeling of isolation in typical AD support groups.
Disease-modifying approaches are being led by Adam Boxer at UCSF. Tau-lowering strategies are emerging for tau forms of FTD including tau mutations, Pick disease, PSP, and CBD. Monoclonal antibodies that target tau appear to show efficacy in animal models and have potential to diminish the brain’s tau burden. With progranulin mutations, histone deacetylase (HDAC) inhibitors appear to double the progranulin production by the healthy gene. Clinical trials are beginning in symptomatic gene carriers with the hope that normalization of progranulin levels will slow progression or possibly provide symptomatic relief. While no trials are yet underway for C9orf72 gene carriers, recent laboratory efforts have focused around developing small molecules that can turn off gene expression.