Dementia associated with degenerative atrophy of frontal and temporal lobes includes a heterogeneous group of sporadic and familial diseases that result in personality and behavioral changes, with variable degrees of language and cognitive impairment. Historically, it has been a significant clinical challenge to separate frontotemporal dementia from Alzheimer’s disease and primary psychiatric disorders.
Frontotemporal dementia, also known as frontotemporal degeneration, is a recent term that encompasses several variant forms of dementia that include Pick’s disease, primary progressive aphasia, semantic dementia, and corticobasal degeneration.
The term was derived from the observation that the behavioral and personality changes associated with frontotemporal atrophy, as described by Arnold Pick, actually occur in a broader spectrum of patients without the classic lobar atrophy or histopathological finding of Pick bodies. Pick’s disease used to be an overreaching term that referred to dementia associated with behavioral symptoms, aphasia, and frontotemporal atrophy on gross postmortem examination. With the advent of the term frontotemporal dementia, however, Pick’s disease defines only the pathologic variant with cytoplasmic neuronal inclusions called Pick bodies, now recognized to be found in only a minority of cases of dementia associated with frontotemporal degeneration.
The DSM-IV-TR lists dementia due to Pick’s disease within the category of dementia due to other general medical conditions, and there are no separate diagnostic criteria for Pick’s disease or other frontotemporal dementias. In 1994, the Lund and Manchester Groups wrote a consensus statement proposing clinical and neuropathological criteria for frontotemporal dementia. They described it as a behavioral disorder arising from frontal and temporal cerebral atrophy, and identified three patterns of histological changes: frontal lobe degeneration type, Pick-type, and motor neuron disease type. Pick-type was distinguished from frontal lobe degeneration type by the presence of classic Pick bodies, and more “intense and circumscribed.” atrophy and gliosis. The motor neuron disease type was considered to have the same gross histological changes as frontal lobe degeneration type, but was less severe in nature.
In 1998, an international workshop that included members from the Lund and Manchester groups refined their previous consensus and developed clinical diagnostic criteria for frontotemporal lobar degeneration, now called frontotemporal dementia. The consensus specified features of three syndromes included within the category of frontotemporal lobar degeneration, called frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia.
Later in 2000, another international conference, the Work Group on Frontotemporal Dementia and Pick’s Disease, reassessed the clinical and neuropathologic criteria. It was the recommendation of this group to use the term frontotemporal dementia to categorize the many variants of clinical and pathological presentations that include Pick’s disease, primary progressive aphasia (formerly progressive nonfluent aphasia), and semantic dementia. In another conceptual change, frontotemporal lobar degeneration came to represent a diagnosis of exclusion, used only after immunohistochemical methods fail to identify other distinctive pathological conditions. Frontotemporal lobar degeneration is now also known as dementia lacking distinct histopathological features .
The Work Group on Frontotemporal Dementia and Pick’s Disease proposed clinical criteria for frontotemporal dementia that require the presence of either personality changes that result in behavioral disturbance or cognitive deficits manifested by language dysfunction. In addition, the criteria require a gradual onset of symptoms with progressive functional decline. Similar to the DSM-IV-TR dementia, these criteria also specify that deficits must cause significant impairment in social and occupational functioning, must not be due to other conditions, and must not occur solely in the context of delirium (see Table 11). The Work Group also proposed neuropathological criteria to delineate five categories using t-positive inclusion bodies, the number of microtubule-binding repeats in the insoluble t, or the presence of ubiquitin-positive inclusion bodies as distinguishing characteristics. .
Frontotemporal dementias have been estimated to account for between 5% and 20% of degenerative dementias. Clearly accepted prevalence rates are not available, but recent epidemiological studies have reported estimated rates to range between 10 and 80 per 100,000, depending on the study and the age of the sample. In younger populations (<65), for example, frontotemporal dementia probably accounts for a larger percentage of total dementia cases, but overall prevalence rates remain relatively low. In older populations Alzheimer’s and vascular dementia are responsible for the vast majority of cases. It is well recognized that frontotemporal dementia is more likely to affect younger populations and the age of onset ranges between 35 and 75 years old. Several recent studies have found the mean age of onset to be in the 6th decade. Men and women are probably equally affected, and studies have documented that between 20% and 40% of patients have a family history of frontotemporal dementia.
The etiology remains unclear, but in some cases genetic linkage to chromosome 17 has been found, in addition to various t protein mutations. On pathological examination, there may be evidence of gliosis, neuronal loss, and atrophy of the frontal and temporal cortices.
The Work Group on Frontotemporal Dementia and Pick’s disease identified two core clinical patterns of dementia: 1) gradual changes in personality and behavior, and 2) progressive language dysfunction. The hallmark of the behavioral presentation is typically a combination of disinhibition, apathy, and limited insight. Patients may be irritable, inappropriate, impulsive, and potentially aggressive. They may exhibit perseveration of words or actions, with stereotyped behavior, mental rigidity and inflexibility. Other disinhibition phenomena are sometimes categorized as the Kluver-Bucy syndrome of hypersexuality, hyperorality, and the need to touch and examine all objects within reach (utilization behavior).
The other presentation of frontotemporal dementia is characterized by gradual and progressive changes in language function. Depending on the nature of the dysfunction, the terms primary progressive aphasia and semantic dementia have been used to describe these patients. Patients have expressive deficits, with difficulty in word finding and naming. Early in the course of the disease speech may be impoverished or lack spontaneity, but there may be relative preservation of other cognitive functions, such as memory. As concentration and attention worsen, memory problems become increasingly evident. Eventually, impairments in word meaning, reading, and writing develop. With disease progression, speech may become perseverative and echolalic with eventual mutism. Behavioral changes may also develop.
Because the initial presentation of frontotemporal dementia may be behavioral, it is easily confused with other primary psychiatric disorders. Apathy and social withdrawal may be mistakenly treated as depression. Alternatively, disinhibition, inappropriate, bizarre, or aggressive behavior can appear manic or psychotic, or even mimic substance intoxicaton. In addition, frontotemporal dementia can only be considered after ruling out other potential medical causes of dementia (see table 3 and section on evaluation of dementia).
Frontotemporal dementia is typically characterized by asymmetric focal atrophy of the frontemporal regions (See image 8 and 9 – Pick’s Gross pathology). There is underlying neuronal loss, gliosis and subsequent spongiform changes in the affected cortices. Pick cells are pathognomonic in Pick’s disease and they appear swollen and stain pink on hematoxylin-eosin staining (see image 10-Pick Bodies). Frontotemporal dementias may also have t-positive inclusion bodies in oligodendroglial cells and astrocytic processes. Ubiquitin-positive inclusion bodies have been described in a variant called frontotemporal dementia with progressive motor neuron disease, and recently a possible genetic marker has linked these cases to chromosome 9. Structural imaging studies with CT or MRI may reveal frontotemporal atrophy. Functional imaging with SPECT and PET has demonstrated decreased perfusion of the frontal and temporal lobes.
Frontotemporal dementia is treated symptomatically and, to date, there is a dearth of randomized placebo controlled trials investigating treatment for either the cognitive or behavioral disturbances of these illnesses. Trazodone, antipsychotics, and anticonvulsants may help agitation and aggressive behavior. Selective serotonin reuptake inhibitors are used for associated symptoms of depression, irritability, and apathy. Although decreased cholinergic activity may contribute to cognitive impairment in frontotemporal dementia, controlled trials with acetylcholinesterase inhibitors are needed to support the use of these medications. Current efforts are focused on improving methods for early and accurate diagnosis.