Frontotemperal dementia G31.0+F02.0*

Arnold Pick was the first to describe frontotemporal dementia (FTD) in 1892 based on a patient with aphasia, lobar atrophy and presence dementia. Alois Alzheimer recognized the characteristic association with Pick's bodies in 1911 and named the clinicopathological entity "Pick's disease" (Bang 2015).

In 1974, Constantinides divided Pick's disease into 3 subtypes, only one of which had Pick's corpuscles (Olney 2017).

In 1982, Mesulam described a linguistic subtype of FTD that was later termed "primary progressive aphasia" (Bang 2015).

In 1994, the consensus conference defined the pathological and clinical criteria for frontotemporal lobar degeneration (FTLD), the so-called Lund- Manchester criteria, which were revised in 1998. The latter are sometimes referred to as the "Neary criteria."(Wallesch 2012).

Progressive supranuclear palsy syndrome (PSP- S) was first described by Steele, Richardson, and Olzewski in 1964 (Olney 2017).

Corticobasal syndrome (CBS) was described by Rebeiz in 1968 (Olney 2017).

Frontotemporal dementia (FTD) is a group of clinical symptoms caused by frontotemporal lobar degeneration (FTLD) (Kasper 2015) and characterized in particular by atrophy of the frontal and / or temporal lobes (Wallesch 2012).

The disease manifests itself in progressive deficits in behavior, language, and executive functions (Bang 2015).

Frontotemporal dementia, along with Alzheimer's disease, Lewy body dementia, Parkinson's disease, Creutzfeldt- Jacob disease or prion disease, and corticobasal degeneration, is one of the primary neurodegenerative dementias (Tumani 2019).

Early-stage FTD (Deuschl 2016) is divided into:

- a. Behavioral variant / behavioral variant (BV- FTD).

This occurs most frequently (Kasper 2015).

- b. Primary progressive aphasia (PPA- FTD) with the triad agrammatism, naming disorders, paraphasias (Herold 2022), in the Anglo-Saxon area also called non-fluent / agrammatic variant primary progressive aphasia (nfvPPA) (Olney 2017).

- c. Semantic dementia with semantic aphasia (SV- PPA) (Herold 2022 / (Bang 2015).

As the disease progresses, these stages may merge (Deuschl 2016).

Related FTD- disorders include:

- Frontotemporal dementia with motor neuron disease (FTD- MND):

FTD may be accompanied by FTD- MND. This most commonly occurs in BV- FDT (Kasper 2015).

FTD- MND occurs in approximately 12.5% of patients and manifests as:

- Hyperreflexia

- spasticity

- muscle weakness

- muscle atrophy

- fasciculations

- dysphagia

- Dysarthria (Bang 2015)

- Progressive supranuclear palsy syndrome (PSP- S):

This typically begins after the age of 40 and can manifest as postural instability with falls, vertical supranuclear gaze paralysis, personality changes, reduced mental speed, etc. Definitive biomarkers are not yet known (Olney 2017).

- Corticobasal syndrome (CBS):

In this, symptoms such as asymmetric appearance, limb rigidity or akinesia, limb dystonia or limb myoclonus, apraxia, and cortical sensory deficit are found (Olney 2017).

FTD occurs primarily in the presenium (Herold 2022). Approximately 10% develop the disease < 45 years of age, 60% between 45 - 64 years of age, and 30% > 64 years of age (Bang 2015).

The disease is the third most common form of dementia in all age groups after Alzheimer's disease and dementia with Lewy bodies, and is one of the leading forms of early-onset dementia. The prevalence ranges from 3%-26% (Bang 2015). According to previous studies, men are more commonly affected, but recent studies have questioned this (Kasper 2015).

A familial cluster is found in about 50 % of those affected (Herold 2022). However, autosomal dominant inheritance is present in only 10-20% of all cases (Kasper 2015).

Neuro- or histopathologically, there are:

- gliosis

- neuronal loss

- microvacular changes in the frontal lobes, insular cortex and anterior cingulate cortex (Bang 2015).

As neuro- or histopathological inclusions may be present:

- Tau proteins

- TAR DNA binding protein 43 kDa-TDP-43

- fused sarcoma- ubiquitinated inclusions (Khouri 2021).

Behavioral variant BV- FTD shows right hemispheric or symmetrical anterior cingulate or medial prefrontal, orbital, and anterior insular degeneration (Kasper 2015).

In primary progressive aphasia, there is left (dominant) degeneration of the frontal operculum and precentral gyrus (Kasper 2015).

Semantic dementia is associated with left anterior temporal atrophy (Kasper 2015).

The clinical picture is very variable.

It is found in the behavioral variant a change in nature with:

- socially inappropriate behavior

- disinhibition

- impulsivity

- personal neglect

- stereotypy

- rituals

- motor and verbal perseverations

- mental rigidity (Herold 2022)

- hallucinations in about 20% (Bang 2015)

- loss of empathy

- Hyperorality (Bang 2015) with:

- Binge- Eating (Kasper 2015).

- also non-edible things are put into the mouth

- alcohol abuse

- aggression (Bang 2015)

- decreased libido

- occurrence of criminal behaviors (Bang 2015)

- Fiscal missteps leading to financial ruin (Bang 2015).

- Primary progressive aphasia manifests with a triad of:

- agrammatism

- naming disorders

- paraphrasias (Herold 2022)

- pronounced motor speech disorders (Kasper 2015).

The speech disorders remain the main symptom in the first 2 years of the disease.

- Hallucinations occur in approximately 6% (Bang 2015).

In semantic dementia, one finds a

- semantic aphasia (Herold 2022), by which patients lose the ability to decode word, person, object, and emotion meanings (Kasper 2015). In addition to anomia, word-finding disorders and impaired word comprehension are found (Bang 2015).

In the early phase of the disorder, fluency and correct grammar are maintained (Bang 2015).

There are certain criteria from Rascovsky et al (2011) that indicate FTD:

l. BV- FTD

- Progressive increase in cognitive deficits (to be ascertained by own observations or external history) and / or behavioral deficits (Deuschl 2016).

ll. Possible BV- FTD

A possible BV- FTD is present if 3 of the symptoms A - F are present, persist or recur:

- A. Early onset behavioral disinhibition [one of the following symptoms (A.1.-A.3.) must be present].

- A. 1. socially inappropriate behavior

- A. 2. loss or decency of manners

- A. 3. impulsive, reckless, or thoughtless actions

- B. Early onset apathy or passivity [one of the following symptoms (B.1.-B.2.) must be present]

- B. 1. apathy

- B. 2. passivity

- C. Early loss of empathy or sympathy [one of the following symptoms (C.1.-C.2.) must be present]

- C. 1. responsiveness to the feelings and needs of others is markedly diminished

- C. 2. decreased interest in relationships, social contacts, and decrease in personal warmth

- D. Early ritualized/compulsive or perseverative stereotypic behavior [one of the following symptoms (D.1.-D.3.) must be present]

- D. 1. simple, repetitive movements

- D. 2. complex ritualized or compulsive behavior

- D. 3. speech stereotypies

- E. Changes in eating habits and hyperorality [one of the following symptoms (E.1.- E.3.) must be present]

- E. 1. change in previous food preferences

- E. 2. binge eating, increase in consumption of alcohol or nicotine

- E. 3. non-edible material is placed in the mouth and consumed

- F. Neuropsychological profile [all of the following symptoms (F.1.-F.3.) must be present]

- F. 1. deficit in tasks with an executive component

- F. 2. episodic memory is relatively preserved

- F. 3. visual-spatial performance is relatively preserved (Deuschl 2016)

lll. Probable BV- FTD:

For this, all of the following symptoms must be present to meet the criteria:

- A. The above criteria for probable BV- FTD are met.

- B. Significant progression of functional deficits (to be assessed by extraneous history or clinical scales (such as the Clinical Dementia Rating Scale or the Functional Activities Questionnaire) is evident.

- C. Imaging findings are consistent with a diagnosis of BV- FTD [one of the following features (C.1.-C.2.) must be present].

C. 1. frontal and / or anterior- temporal atrophy is evident on MRI or CT, respectively

C. 2. frontal and / or anterior- temporal shows hypoperfusion or hypometabolism in SPECT or PET, respectively (Deuschl 2016)

lV. BV- FTD with proven pathological changes of a FTLD.

Criterion A must be present along with criterion B or C:

A. The above criteria for a possible or probable BV- FTD are met.

B. Histopathological evidence of FTLD is found in a biopsy or post-mortem examination.

C. Presence of a known pathogenic mutation (Deuschl 2016).

V. Exclusion criteria for BV- FTD are:

Criteria A and B below may not be met for the diagnosis of BV- FTD. Criterion C may be positive for a possible BV- FTD and must be negative for a probable BV- FTD.

A. The pattern of deficits is better explained by another medical disorder or other nondegenerative nervous system disease.

B. The behavioral deficits are better explained by a psychiatric diagnosis.

C. Biomarkers strongly suggest other neurodegenerative processes or Alzheimer's disease (Deuschl 2016).

If there is uncertainty in the differential diagnosis, FDG- PET (fluorodeoxyglucose PET) or HMPAO- SPECT (brain perfusion scintigraphy) can be used. However, these examinations are not recommended for regular use (Deuschl 2016).

In some patients, normal MRI and PET examination results are found. In this case, the course of the disease is markedly slowed (over decades) with gradual progression of cognitive impairment. This clinical picture is classified as a "phenocopy" of FTD (Bang 2015).

Structural MRI / CT.

Here, atrophy patterns are predominantly seen frontally, temporally, or in the frontoinsular region (Bang 2015).

Functional MRI

There is disproportionate hypoperfusion and hypometabolism frontal, temporal or in the frontoinsular region (Bang 2015).

FDG- PET / HMPAO- SPECT / Single- Photon Emission- CT.

FDG- PET also demonstrates disproportionate hypoperfusion and hypometabolism frontally, temporally, or in the frontoinsular region (Bang 2015).

FDG- PET has a sensitivity of 73% and a specificity of 98% against AD, HMPAO- SPECT 72% and 78%, respectively (Maier 2011).

- Tau- proteins or TDP- 43 are detectable in more than 90% of patients (Kasper 2015)

- Gliosis

- microvacuation

- Neuron loss (Kasper 2015)

Other forms of dementia such as:

- M. Alzheimer:

Here, for example, the beta-amyloid concentration in the cerebrospinal fluid is reduced (Bang 2015) and the cholinergic system is also affected (Kasper 2015). There are pronounced visual-spatial impairments, episodic or visual memory deficits, etc. (Bang 2015).

- Lewy body dementia:

These patients are found to have more pronounced parkinsonism, more frequent cognitive fluctuations, and more visual-spatial deficits (Bang 2015).

- Normal pressure hydrocephalus

- Parkinson's dementia complex

- Vascular dementia (Kelley 2016).

- Various psychiatric disorders such as obsessive-compulsive disorder, depression, bipolar disorder, schizophrenia, etc.

- Toxic disorders

- Inflammatory disorders (both autoimmune and neoplastic)

- Infections with e.g., syphilis, HIV, etc. (Bang 2015)

- Forms of encephalopathy such as metabolic, endocrine, drug induced encephalopathy etc.

- Abuse of drugs such as cocaine, methamphetamine, psychostimulants, etc. (Kelley 2016)

- Parkinsonism:

This is found in about 20% of patients with FTD. It is also most common in BV- FDT and manifests as:

- asymmetric parkinsonism

- sensory-motor cortical dysfunction

- dystonia

- alien limb syndrome

- instability with falls

- erectile dysfunction

- apathy

- impulsivity

- decreased saccade velocity (Bang 2015)

There are currently no causal therapeutic options. Antidepressants, especially SSRIs, or antipsychotics can be used to improve symptoms (Kasper 2015).

However, a treatment recommendation cannot be given for FTD (B llb) (Deuschl 2016).

The drugs approved for Alzheimer's disease do not improve symptoms in FTD. Acetylcholinesterase inhibitors even show a worsening of symptoms in studies by Kimura and Takamatsu (2013).

Survival time after diagnosis is about 6-11 years from onset of symptoms. FTD with motor neuron disease (FTD- MND) has the worst prognosis with 2 years survival, and the semantic variant the most favorable with ≥ 5 years (Bang 2015).

Patients most commonly die from pneumonia or other secondary infections (Bang 2015).

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