Frontotemporal lobar degeneration

Frontotemporal lobar degeneration
A human brain showing frontotemporal lobar degeneration causing frontotemporal dementia.
OMIM	600274
DiseasesDB	10034
MeSH	D003704

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qasim Khurshid, M.B.B.S [1]. Kiran Singh, M.D. [2]

Synonyms and keywords:

Frontotemporal lobar degeneration, FTD, FTLD, Frontotemporal dementia, Pick’s disease

Overview

Frontotemporal lobar degeneration (FTLD) is an umbrella term that refers to a group of progressive brain diseases, which are heterogeneous concerning neuropathology and etiology but share atrophy of the frontal and/or temporal cortex as a morphological feature. The clinical manifestations of the disorder depend on the primary site of atrophy and dominated by behavior alterations and language impairment. The mean survival after diagnosis is from 3 to 10 years.

Historical Perspective

Historically, patients having symptoms of frontotemporal lobe degeneration were diagnosed as Pick disease after Arnold Pick described a 71-year-old man with dementia with behavioral symptoms and sensory aphasia for the first time in 1892. This patient demonstrated severe atrophy of frontotemporal lobes on autopsy.Histopathologic examination of tissue samples showed “ballooned” achromatic neurons, which was referred to as Pick cells and argyrophilic inclusions within frontal neurons that were referred to as Pick bodies( composed of insoluble filaments of the microtubule-associated protein tau). Later on, autosomal dominant forms of Pick disease were reported, and the mutations in the gene encoding the microtubule-associated protein tau (MAPT) located at 17q21 were identified. At present, 42 mutations in MAPT have been described in 119 families with FTLD or related disorders. However, in an estimated 60% to 70% of all patients with FTLD undergoing autopsy, no tau pathologic characteristics can be demonstrated. This autopy finding suggets that insoluble tau is not necessary for the clinical phenotype to develop..

Classification

Frontotemporal lobe degeneration patients can be classified into three different clinical syndromes depending on the early and predominant symptoms. The overlap between these clinical syndromes can occur as the disease progresses to involve both temporal and frontal lobes more diffusely.

1. Behavioural-Variant Frontotemporal Dementia (bvFTD)

1. Semantic Dementia (SD)
2. Progressive Nonfluent Aphasia (PNFA)

Behavioural-Variant Frontotemporal Dementia (bvFTD)

Behavioral variant frontotemporal dementia is characterized by a progressive decline in executive and interpersonal skills, with altered emotions and the emergence of a variety of abnormal behaviors including disinhibition, obsessions, apathy, and stereotypes. The bvFTD can develop indolently, and early detection may depend on small changes of social circumstances, reduced libido, idiosyncratic lapses of taste or social awareness, and altered dietary or musical preferences.

Semantic Dementia (SD)

Semantic dementia is also known as semantic variant primary progressive aphasia (svPPA) is a highly characteristic syndrome led by the progressive breakdown of semantic memory—a type of long term memory system that stores knowledge about concepts and objects based on the individual’s accumulated experience of the world. Typically, semantic dementia initially presents with progressive loss of semantic knowledge about words, concepts and objects.

Progressive Nonfluent Aphasia (PNFA)

Progressive Nonfluent Aphasia (PNFA) is characterized by a progressive breakdown in language output with slow, impaired production, effortful speech, and comprehension of grammar, and motor speech deficits. Apraxia of speech is highly characteristic of PNFA, and dysarthria is more variably present. Some patients have expressive agrammatism with terse telegraphic phrases as the dominant feature of the disease, whereas, in others, the syndrome is dominated by speech sound (phonemic) or articulatory (phonetic, speech apraxic) errors.

Frontotemporal Lobar Degeneration (FTLD) Overlap Syndromes

The frontotemporal degeneration spectrum overlaps with the syndromes of corticobasal degeneration(CBD), progressive supranuclear palsy(PSP), and FTD with motor neuron disease. CBD patients present with dystonia, limb apraxia, postural instability, Axial, and limb rigidity, myoclonus, supranuclear gaze palsies, the ‘alien limb phenomenon,’ and cortical sensory loss. The progressive supranuclear palsy syndrome(PSP) is characterized by impairment of vertical gaze, frontal behavioral changes with marked cognitive slowing, and early postural instability with falls.

Pathophysiology

FTLD is strongly familial, with up to 40% of patients having a history of a similar disorder within their family, indicating that genetic factors play a significant role in its etiology. An autosomal dominant pattern of inheritance is documented in about 10%. Three significant causal genes have been identified. Mutations in MAPT on chromosome 17 (71,160), not unexpectedly, drive FTLD-tau pathology. FTLD-TDP pathology, by contrast, is not, or perhaps only rarely, associated with mutations in the TDP-43 gene, TARDBP. Instead, it is represented by mutations in the progranulin gene (GRN) on chromosome 17 (9,34) or expansions in C9orf72 on chromosome 9 (40,134). Mutations in other genes have also, less commonly, been associated with FTLD. Of these, most notable are CHMP2B mutations on chromosome 3 (20,56,148) occurring almost exclusively within a single pedigree within the Jutland region of Denmark (20,56,74). NCI is present in such cases, and although these are ubiquitinated, the target protein remains to be identified. The classification, FTLD-UPS, has been applied in recognition of the involvement of the ubiquitin-proteasome system in the disease. The vast majority of cases with FTLD-FUS pathology appear to be sporadic. Other rare genetic forms of FTLD involve mutations in valosin containing protein (VCP) (174), SQSTMI (also known as p62), optineurin (OPTN) (104), ubiquitin 2 (UBQLN2) and TANK binding-kinase 1 (TBK1. Although collectively, such cases are numerically few, they do provide essential clues to pathogenesis since all involve TDP-43 proteinopathy, and all have functioned within the cell’s protein degradation systems.

Causes

FTD patients have an abnormal buildup of altered brain proteins in the frontal and temporal lobes of the brain, the tau protein, and the transactive response DNA binding protein-43 (TDP-43) are commonly involved. The specific functions of these proteins are not entirely known, but these proteins are critical for the proper function of neurons. In patients with FTD, these proteins are misfolded, clumped, or aggregate together, leading to atrophy of frontal and temporal lobes.

• Almost 60% of patients have sporadic or non familial form of disease
• Almost 40% of patients have family history of neurodegenerative disorder
• Almost 10-25% of patients following major gene mutations have been identified.
  • MAPT
  • GRN
  • C9ORF72
• Following gene mutations are rare causes of FTD.
  • VCP
  • TARDBP,
  • FUS
  • CHMP2B
  • TBK1

Differential Diagnosis

• Other neurocognitive disorders

• Alzheimer's disease
• Lewy bodies
• Parkinson's disease

• Other neurological conditions

• Corticobasal degeneration
• Motor neuron disease
• Progressive supranuclear palsy

• Other mental disorders and medical conditions

• Bipolar disorders
• Major depression
• Schizophrenia

• The following table outlines the main findings of the diseases which must be differentiated from dementia with frontotemporal lobar degeneration as they may share common characteristics of cognitive impairment:

Cause of dementia	Clinical features											Associated features	Nature of progression	Histopathological findings
	Cognitive impairment
	Recall	Recollection	Cue requirement for recall	Infirngement of thoughts	Semantic memory	Procedural memory	Working memory	Awareness	Attention	Executive functioning issues	Visuo-spatial skills
Alzheimer's disease	+++ (Slow cognitive and functional decline with early loss of awareness)	+++	Not helpful	+++	++	-	++	+++	++	++	++	Focal neurological signs absent during early stage (may develop later) Mild extrapyramidal signs	Has the following clinical stages: Pre-clinical Mild cognitive impairment Advanced dementia (full blown dementia)	Neurofibrillary tangles Senile (neuritic) plaques
Lewy body dementia	++	-	Helpful	+++	+	+	+++	+	+++	+++	+++	Focal neurological signs present in majority Strongly associated with extrapyramidal signs Autonomic changes	Early visual hallucinations Muscle rigidity Sleep disturbance	α-synuclein deposits present in neurons
Frontotemporal lobar degeneration	+/-	-	Helpful	+++	+	-	+++	+++	++	+++	-	Focal neurological signs present (motor neuron disease) Extrapyramidal signs present (familial frontotemporal lobar degeneration) Onset in young age Strong familial association Focal atrophy of frontal and temporal lobes Knife-edge atrophy noted on MRI Personality and behavioral changes Language impairment	Two major variants: Progressive nonfluent aphasia Semantic variant Progressive supranuclear palsy	Pick bodies Corticobasal degeneration Ubiquitinated inclusions
Vascular dementia	+ (Dysexecutive syndrome)	-	Helpful	+	+	+	++	-	++	+++	+	Focal neurological signs present typically Mild extrapyramidal signs Depression Mild motor signs in subcortical vascular dementia Slowed processing speed Presentation might be similar to Alzheimer's disease	Stepwise progression and focal neurologic signs (also known as multi-infarct dementia or poststroke dementia)	Multifocal and/or diffuse lesions (lacunes and microinfarcts) The following brain areas may be involved: Subcortical area Thalamus Frontobasallimbic system White matter lesions Hippocampal sclerosis Diffuse post-ischemic lesions

Epidemiology and Demographics

The prevalence of FTD in population-based studies varied from 2.7/100,00 to 9.4 /100,000 in the 60-69-year-old group in the Zuid-Holland district, Netherlands. Two studies reported a similar incidence of FLD in adults with early-onset dementia in Cambridge, UK( 3.5/100,000 person-years in 45-64 years old group), and Rochester, USA( 3.3/100,000 person-years in 50-59 age group).

The majority of the patients manifest the disease in the sixth decade of life, but the age of onset can vary widely from the third to the ninth decade. Although FTLD is generally considered presenile dementia, individuals over the age of 65 years account for almost 20–25% of all cases.

Risk Factors

• Genetic predisposition
• There are no other risk factors.

Screening

There is insufficient evidence to recommend routine screening for FTLD.

Natural History, Complications, and Prognosis

The clinical course of FTLD syndromes is steadily progressive, with declining function in everyday life, and patients are dependent for activities of daily living. With time they have cognitive, social, and neurological disabilities leading to complete dependency requiring institutional care. Based on a meta-analysis, the survival duration is highly variable among the FTD syndromes. The FTD associated with motor neuron disease is most aggressive and leads to death within three to five years of symptoms onset. However, patients with semantic dementia can survive for over a decade. There tends to be a convergence of syndromes with time, and the precise clinical trajectory is difficult to predict in individual cases. Wandering and intrusive behaviors, incontinence, apathy dysphagia, and mutism are common issues toward the end of life, and important sources of caregiver distress. Compared with other neurodegenerative diseases, caregivers of patients with FTD suffer from more burden.

Diagnosis

Diagnostic Study of Choice

There is no single gold standard test to diagnose frontotemporal degeneration. The diagnosis of this disorder generally involves the following.

• Medical history and detailed neurological examination
• Neuropsychological examination to assess language, memory,behavior, visual-spatial, and executive functions.
• Neuroimaging to determine brain atrophy.
• Lumbar puncture and blood tests to rule out other diseases that can mimic FTLD

History and Symptoms

Behavioral variant FTD is the most common clinical subtype and comprise approximately half of all cases of FTD. The main clinical feature of bvFTD is a progressive change in personality and behavior. The following are the first behavioral changes in bvFTD.

• Disinhibition – Examples of disinhibition or socially inappropriate behavior include public urination without concern, and touching or kissing strangers.
• Hyperorality – Hyperorality manifest as altered food preferences. For example, carbohydrate cravings, particularly for sweet foods, and binge eating.
• Apathy – Apathy manifests as losing interest in activities and social relationships. Patients may participate less in conversations and grow passive.
• Compulsive behaviors – Stereotyped, perseverative, or compulsive ritualistic behaviors include stereotyped speech and complex ritualistic behaviors such as cleaning, hoarding, or checking.
• Agitation
• Frequent mood changes

Most patients of FTLD lack insight into their behavioral changes and the distress experienced by family members.

Physical Examination

• Patients with initial stages of disease generally lack cranial nerve, cerebellar, sensory, pyramidal, and extrapyramidal motor findings.
• Front release signs may be seen, but these findings are not specific to this disease.
• Parkinsonism may also emerge in advanced stages of the disease. and patients may have following physical findings.
  • Rigidity
  • Bradykinesia
  • Resting tremor
  • Mask like face
  • Magnetic gate
• Almost 10-15 % of patients with bvFTD may develop concomitant motor neuron disease.

Laboratory Findings

Following tests may be done to exclude other causes that can mimic the FTD.

• Thyroid function tests
• Vitamin B12
• HIV
• Syphilis
• CSF analysis

Electrocardiogram

There are no ECG findings associated with FTLD.

X-ray

There are no X ray findings associated with FTD.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with FTLD.

Neuroimaging with CT and MRI

Routine brain imaging with MRI or computed tomography (CT) is used to rule out other diseases mimicking FTD and usually remarkable only for cerebral atrophy. Some patients may show variable regional atrophy depending on the genetic and clinical phenotype.

In the majority of the patients, the following dominant patterns of regional loss are demonstrated.

• bv FTD: bilateral frontal atrophy, especially the medial frontal cortex and sometimes with anterior temporal lobe atrophy.
• sv PPA: left temporal lobe
• non-fluent variant of PPA: left insula and frontal operculum
• FTLD-FUS: bilateral caudate nuclei
• FTLD-TDP : right frontal, lateral temporal and parietal lobes
• FTLD-TDP due to C9orf72 mutation: bilateral hemispheres
• FTLD-tau: due to MAPT mutation: bilateral temporal lobes
• PNFA: mostly have perisylvian, left hemisphere atrophy, involving the frontal lobe and insula, extending into the temporal lobe

Other Imaging Findings

A fluorodeoxyglucose positron emission tomography (FDG-PET) scan or SPECT (single photon emission CT) can help to differentiate between FTD and Alzheimer's disease. FDG-PET scans show functional changes in glucose metabolism of the brain and are often positive earlier than MRI. SPECT reflects blood flow more than metabolic change; therefore, it is less sensitive to diagnose FTD. The FDA has approved three different versions of a PET tracer for amyloid – currently valuable to FTD diagnosis as a negative scan ruling out Alzheimer’s disease.

Other Diagnostic Studies

Electrophysiologic testing is sometimes used to rule out nonspecific seizures in patients with FTD.

Diagnostic criteria for bvFTD

The International Behavioral Variant FTD Criteria Consortium (FTDC) published new criteria for bvFTD in 2011. The FTDC criteria synthesize clinical features, neuroimaging, neuropathology, and genetic testing . The FTDC criteria are structured as a diagnostic hierarchy. A diagnosis of possible bvFTD is based solely on the clinical syndrome and aims to identify patients at the mildest stages of the disease.

Possible bvFTD requires a combination of three of six clinical features:

●Disinhibition

●Apathy/inertia

●Loss of sympathy/empathy

●Perseverative/compulsive behaviors

●Hyperorality

●Dysexecutive neuropsychologic profile

Probable FTD requires the same clinical criteria, plus demonstrable functional decline and imaging findings that reflect the principal anatomic location of neurodegeneration in bvFTD (i.e., frontal and/or temporal lobe atrophy, hypometabolism, or hypoperfusion).

Treatment

Medical Therapy

Non Pharmacological Intervention

First-line therapy for behavioral disturbances in FTLD should be nonpharmacological. The current drug therapies are modestly effective and have serious adverse effects. A management plan that does not include a nonpharmacological intervention will not be successful. The main goals of nonpharmacological treatment include family and caregiver education, behavioral, and physical interventions to minimize the occurrence and consequences of undesired behaviors. Additional helpful interventions include physical and speech therapy, home safety evaluations, and the implementation of augmentative communication devices. A frank discussion about end-of-life decisions and goals of care is imperative.

Behavioural and Cognitive Symptoms

There is no cure for FTLD, and current pharmacotherapy focuses primarily on symptomatic, neurotransmitter base treatments. There is no drug developed for these patients, and the rationale for the use of medications is their efficacy in treating similar neurodegenerative disorders. Most of the FLTD treatments reported in the literature are based on single case reports or small series.

Drugs affecting the serotonin level have the most robust rationale since there is strong evidence of serotonin deficiency in these patients. Patients with FTD have alterations of serotonin metabolites in CSF and significant neural loss in the serotonergic dorsal raphe nuclei. Many behavioral symptoms of FTLD, such as depression, disinhibition, compulsions, stereotypical movements, repetitive behaviors, and dysregulated eating, respond to selective serotonin reuptake inhibitors (SSRIs).

FLD patients with severe behavioral disturbances (agitation, psychosis) should be treated with atypical antipsychotic medications. This class of medications should be used with great caution, mainly due to two reasons. First, antipsychotic medications are associated with increased mortality in elderly patients with dementia, and secondly, these patients are susceptible to extrapyramidal side effects. Increased mortality appears to be related to infections and an increase in cardiovascular events. Furthermore, these medications may also reflect a nonspecific effect of sedation in this vulnerable population. Often, atypical antipsychotics are necessary only as a temporizing measure and can be tapered as patients become more apathetic as the disease progresses.

Patients with parkinsonism should be treated with a trail of levodopa/carbidopa. However the response to these medications is inadequate in CBD and PSP. Patients not responding to levodopa should receive dopamine agonists such as pramipexole or ropinirole.

Urinary incontinence is common in FLD patients and may occur due to multiple mechanisms. For optimal treatment of bladder dysfunction, these patients should be referred for urodynamic studies to determine the underlying cause. Upper motor neuron dysfunction can be treated with anticholinergic drugs. However, anticholinergic drugs should be used with caution as they can exacerbate the cognitive and neuropsychiatric deficits. When necessary, trospium chloride or darifenacin are preferred medications due to lower CNS penetration. Intermittent catheterization should be considered for patients with lower motor neuron dysfunction. Constipation is common in these patients and responds in most cases to a daily bowel regimen.

Surgery

Surgery is not recommended for FLD patinets.

Primary prevention

There are no established measures for the primary prevention of FTLD.

Secondary Prevention

There are no established measures for the secondary prevention of FTLD.

See also

• Corticobasal degeneration

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