Pick Disease

Etiology

Although the majority of frontotemporal dementia presentations are sporadic, the disease is highly heritable, and a family history of dementia has been reported in up to forty percent of cases.[2][3] Ten to twenty percent of patients feature genetic mutations with an autosomal dominant pattern of inheritance.[2][4] Three primary genes have been documented as agents of disease etiology, microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72 with a number of other genes implicated with less frequency.[5][6] 

Few studies have evaluated modifiable risk factors for frontotemporal dementia; however, research has identified diabetes mellitus, history of head injury, and autoimmune disorders as potentially contributing to the development of frontotemporal dementia.[7] Hypertension, smoking, obesity, and a history of cerebrovascular accidents have also been analyzed.[7] More investigation is required to confirm these associations and formally recommend lifestyle modification to mitigate the risk of frontotemporal dementia.[7]

Epidemiology

Frontotemporal dementia is the second most common etiology of early-onset dementia in patients under 65 years of age constituting ten percent of pathologically confirmed cases. Three percent of dementias in patients of any age are attributable to frontotemporal disease.[5] While the condition manifests most often in the fifth and sixth decades of life, onset has been recorded in patients as young as their thirties and over seventy.[1][8]

The behavioral variant of frontotemporal dementia comprises sixty percent of cases with the primary progressive aphasia subtypes occurring less frequently. Estimates for prevalence and incidence are 15 to 22 per 100,000 and 2.7 to 4.1 per 100,000, respectively, with those statistics likely under-representing actual figures due to the diagnostic difficulties of frontotemporal dementia.[1][9] The United States and national numbers are similar; however, developing countries are poorly represented in most epidemiologic studies, and data on non-white populations is also lacking.[9] Studies have not revealed any differences in gender distribution.[9]

Pathophysiology

While the pathophysiology of Alzheimer's dementia is well-established and consistent among cases, the mechanism behind frontotemporal dementia is heterogeneous and complex, requiring continued investigation amongst researchers.[10] Atrophy of the frontal and anterior temporal lobes secondary to intraneuronal deposition of abnormal protein inclusion bodies is the primary pathological focus. Tau, transactive response DNA binding protein 43 (TDP-43), and RNA-binding protein fused in sarcoma (FUS) have been identified as the principal proteins responsible for frontotemporal dementia.[11] They have been attributed to individual genetic mutations and are associated with the varying phenotypic expressions of the different frontotemporal dementia subsets.[11]

History and Physical

Initial presentations of frontotemporal dementia are individualized based on the disease variant being expressed; however, in later progression, there is a significant overlap between behavioral and language subsets. Being a mostly clinical diagnosis, a thorough history must be obtained from patients and families to confirm the disorder and delineate which variant is present. 

Symptoms of behavioral variant frontotemporal dementia (bvFTD) can be organized into six categories of behavioral or cognitive decline. Behavioral disinhibition featuring socially inappropriate behavior, loss of social decorum, or impulsive, careless actions are often observed. Apathy is common and is frequently misdiagnosed as depression. Loss of empathy or sympathy is characterized by a lack of interest or disregard for other's feelings. Perseverative, stereotyped, or compulsive behaviors manifest as repetitive movements, compulsive and ritualistic routines, and stereotyped speech. Hyperorality and dietary changes can include binge eating, change in preference for sweets and alcohol, and pica with oral exploration. Executive dysfunction can occur, sparing loss of episodic memory and visuospatial skills characteristic of Alzheimer's dementia. Deficits in three of these six diagnostic criteria are required for a definitive diagnosis of behavioral variant frontotemporal dementia (bvFTD).[1] 

The language variant of frontotemporal dementia known as primary progressive aphasia (PPA) is divided into three clinical syndromes, nonfluent/agrammatic primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA), and logopenic aphasia. Clinical criteria for nfvPPA include effortful speech, speech apraxia, and agrammatism. Object knowledge and single-word comprehension are unaffected; however, complex sentence understanding may be impaired. Semantic dementia features anomia and impaired single-word comprehension. Along with these classic findings, three of the following four phenomena must be present: impaired object knowledge, surface dyslexia, and dysgraphia, spared repetition, and no disruption of speech production. Patients with logopenic variant PPA exhibit word-finding difficulty and repetition of sentences and phrases. Phonological speech errors are displayed, while single-word comprehension, object knowledge, motor speech, and simple grammar are unaffected. As with all frontotemporal dementia presentations, language variants are heterogeneous, and later stages feature overlapping symptoms as neurodegenerative pathologies spread to varied cerebral structures.[1] 

Further overlap can be seen in frontotemporal dementia-related syndromes such as motor neuron disease, corticobasal degeneration, and progressive supranuclear palsy. The ALS-parkinsonism-dementia complex has been described and demonstrates the coexistence of these motor neuron pathologies with frontotemporal dementia. Corticobasal degeneration presents with asymmetric movement impairment, and progressive supranuclear palsy features supranuclear gaze palsy with postural instability and falls. These conditions can coincide with behavioral and language deficits found in frontotemporal dementia.[1]

Evaluation

Imaging and fluid biomarkers are the primary focus in current and future evaluations of frontotemporal dementia. Standard, structural magnetic resonance imaging (MRI), and computed tomography (CT) modalities can demonstrate characteristic atrophy of frontal and temporal lobe grey matter.[2] At the vanguard of frontotemporal dementia imaging applications are diffuse tensor imaging for evaluating white matter integrity loss, fluorodeoxyglucose positron emission tomography (FDG-PET) to monitor localized brain metabolism, amyloid and tau PET traces which detect cerebral protein deposition, arterial spin labeling (ASL) measuring regional perfusion, and resting-state functional MRI (RS-fMRI) analyzing functional connectivity between brain structures.[2][6] 

Further studies are necessary to implement these techniques in diagnosing frontotemporal dementia, isolating which disease subset is present, differentiating between other dementia syndromes such as Alzheimer's, and longitudinal monitoring of disease progression. 

Cerebrospinal fluid and serum protein biomarkers are presently utilized to exclude Alzheimer's disease in the assessment of frontotemporal dementia and are under appraisal for prospective diagnostic indications and monitoring pathologic progression and response to potential therapies. Elevated CSF tau proteins and decreased beta-amyloid 42 protein concentrations can accurately confirm Alzheimer's dementia and are validated for eliminating frontotemporal dementia from the differential.[6]

Neurofilament light chain (NFL) proteins are increased in serum and CSF samples of patients with frontotemporal dementia and other neurodegenerative disorders and have promising applications in future frontotemporal dementia assays.[6] Gene-specific biomarkers such as progranulin and poly (GP) have the potential for investigating the expression of GRN and C9orf72 frontotemporal dementia mutations, respectively.[6] As with potential imaging techniques, more data is needed to implement fluid biomarkers into a comprehensive frontotemporal dementia evaluation strategy.

Treatment / Management

No current disease-modifying, curative therapies exist for frontotemporal dementia. Treatment must center upon symptom management with particular consideration for supportive measures for patients, families, and caregivers. There is a consensus that selective serotonin reuptake inhibitors (SSRIs) are beneficial in the management of behavioral symptoms.[1][12] Low-dose atypical antipsychotics may be implemented for aggressive or disruptive behaviors; however, caution must be advised due to black-box warning for cardiac events in the elderly.[3] Therapeutics for Alzheimer's dementia, such as cholinesterase inhibitors, are ineffective and may precipitate behavioral abnormalities in frontotemporal dementia.[3] 

Non-pharmacologic interventions have a prominent role in addressing symptoms and delaying disease progression. Physical therapy and exercise can slow cognitive decline while speech therapy may mitigate language deficits in patients with the primary progressive aphasia variants.[1] With the functional decline, patients will require assistance with activities of daily living, and a safe home environment must be secured. Formulating non-pharmacologic behavioral management strategies and implementing them consistently may assuage the physical, mental, and social burden of patient misconduct.[12]

Patient and caregiver education is paramount and can ameliorate the guilt and stigma associated with the neuropsychiatric features of the disease. Support groups and community resources must be made available to caregivers, and their psychological health should be featured in family discussions.[13] A conservatorship can be established to address financial and legal distress associated with the condition.[12]

Differential Diagnosis

There are abundant symptom overlaps between frontotemporal dementia and other neuropsychological disorders. Psychiatric conditions such as depression, bipolar disorder, and, most significantly, schizophrenia can mimic behavioral variant frontotemporal dementia and are often misdiagnosed during early presentations of frontotemporal disease.[5] Onset and progression patterns can assist in differentiating schizophrenia from frontotemporal dementia. While frontotemporal dementia generally occurs in patients over forty-five years of age, initial presentations of schizophrenia are observed in younger age groups.[5] A consistently advancing disease course characterizes frontotemporal dementia, while schizophrenia progression is variable and can plateau.[5] 

Distinguishing other dementia syndromes from frontotemporal dementia can also be challenging. A predominance of memory and visuospatial deficits suggests the more prevalent Alzheimer's dementia variant. Lewy body dementia should be considered in the setting of visual hallucinations and parkinsonism.[8] 

Several miscellaneous conditions can present with neuropsychiatric and behavioral symptoms similar to frontotemporal dementia including, infections, toxins, neoplasms, trauma, paraneoplastic disease, autoimmune disorders, thyroid syndromes, hepatic encephalopathy, and various genetic pathologies.[8]

Prognosis

The heterogeneous nature of frontotemporal dementia, as well as its relatively low prevalence compared to Alzheimer's disease, has led to difficulty defining accurate prognosis and life-expectancy figures. Survival rates feature a wide distribution depending on the subset of phenotypes being evaluated. Patients with the motor neuron disease variant have the shortest disease course at two to three years from diagnosis to death.[9] The median life expectancy for behavioral variant frontotemporal dementia is nine years, while patients with semantic dementia have survival rates of twelve years, comparable to the generally slower progression of Alzheimer's dementia.[3][9]

Complications

The functional and cognitive decline associated with frontotemporal dementia spawn predictable somatic, psychological, and social complications for patients and their caregivers. Dysphagia is likely responsible for the increased incidence of pneumonia and respiratory failure, a significant cause of mortality in frontotemporal dementia.[13] Sequelae of swallowing difficulties include weight loss, protein-calorie malnutrition, and subsequent failure to thrive.[13][14] 

Cardiac disease, attributed to patient's sedentary and bedridden immobility status, is implicated in the most significant number of frontotemporal dementia deaths.[13][14] Gait disturbances precipitate an increased risk of falls and traumatic injury.[13]