How is frontotemporal degeneration diagnosed? Take a look at the latest Chinese expert consensus

Frontotemporal degeneration (FTLD) is the third type of neurodegenerative cognitive impairment disease after Alzheimer's disease (AD) and dementia with Lewy bodies
.
With the increase in life expectancy and the rapid aging of the population, the incidence of these diseases is gradually increasing, bringing heavy social and family burdens
.
Based on the previous expert consensus, Chinese experts combined with new evidence-based evidence, and discussed and formulated this consensus after discussion by experts in the study group to standardize the whole process management of FTLD and promote basic and clinical research
.

Diagnostic process

Figure 1 Simplified diagnostic protocol flow of FTLD

Clinical classification and characteristics

1.
bvFTD

bvFTD is the most common clinical subtype of FTLD, accounting for more than
50% of all patients with FTLD.
In bvFTD, episodic memory impairment is not as typical as AD, and patients mainly present with personality changes and behavioral abnormalities, that is, early manifestations are decompression, apathy, stereotyped behavior, dietary preferences and dietary behavior changes, decreased empathy, and executive dysfunction
.
Some of these early symptoms, such as decreased empathy, help diagnose
bvFTD.
Impaired early episodic memory is still considered a criterion
for exclusion from bvFTD.
The most commonly affected anatomical sites for bvFTD are the prefrontal, orbitofrontal, and pretemporal cortex, which can be
asymmetrical.
The pathological manifestations are very heterogeneous, and the correlation between clinical symptoms and pathological subtypes is not clear, and the diagnostic criteria are shown in Table 1
.

2.
PPA

PPA is a neurodegenerative syndrome
diagnosed in patients with isolated progressive language disorders.
The PPA International Research Group conducted a systematic classification description based on specific types of language or language defects, and developed diagnostic criteria
for 3 variants of PPA: svPPA, nfvPPA and logopenic variant progressive aphasia (lvPPA).
Each subtype has a different pattern
of language defects.

(1) svPPA: PPA syndrome with the most consistent clinical symptoms, neuropathology and genetics, naming disorders and word comprehension defects are its core features, which are necessary conditions
for diagnosis.
Diagnostic criteria are shown in Table 2
.

(2) nfvPPA: also known as grammatical disorder variant PPA, its core characteristics are fluency disorders of spontaneous language and grammatical lack in sentences, which is manifested by the incorrect use or omission
of grammatical words (such as word order, pronouns, prepositions and other small grammar words).
The most obvious anatomical feature of nfvPPA is cortical atrophy in the inferior frontal gyrus and superior temporal gyrus in the "Broca zone", partially involving the temporoparietal junction
.
70% of the pathological subtype of nfvPPA was FTLD-tau, followed by FTLD-TDP, Aβ, or other related pathological changes, and the diagnostic criteria are shown in Table 3
.

(3) lvPPA: Not classified as FTLD because its pathology is more inclined to Alzheimer's disease (AD)-like changes
.
The unique anatomical pattern of lvPPA involvement is located in the posterior lateral fissure and parietal lobe Diagnostic criteria are shown in Table 4
.

Recommendation 1: The clinical diagnosis of FTLD draws on the diagnostic criteria (level I recommendation, level A evidence)
published by EFNS guidelines, the International BvFTD Standards Alliance and the Chinese expert consensus on frontotemporal degeneration.

Recommendation 2: impaired early episodic memory in patients with bvFTD is still considered an exclusion criterion for bvFTD (level II recommendation, level A evidence); Early dietary preferences and dietary behavior changes can be useful clinical features for predicting potential pathological subtypes of bvFTD (level II recommendation, level A evidence); Psychiatric symptoms such as hallucinations and delusions are rare in bvFTD, and the presence of psychiatric symptoms should be alerted to the possibility of other disorders (level II recommendation, level C evidence).

Recommendation 3: Language impairment is the main symptom in patients with PPA in the early stages of the disease, and each subtype has a different pattern of language deficits (level I recommendation, level A evidence).

3.
FTLD-related diseases combined with neurodegenerative dyskinesia:

(1) FTD-MND: Clinical, pathological and genetic evidence confirms that FTLD-MND is a continuous disease process, and FTLD, MND and FTLD-MND are called FTLD-MND disease spectrum
.
At present, there is no unified diagnostic standard for FTLD-MND, and most of the disease diagnosis is based on the respective diagnostic criteria of FTLD and MND
.

(2) CBD: CBD is a heterogeneous syndrome
characterized by changes in behavior, cognition, and movement.

(3) PSP: Patients with PSP can present as frontal lobe dementia (PSP-bvFTD), non-fluent variant primary aphasia (PSP-nfvPPA) or cortical-basal ganglia syndrome (PSP-CBS).

Neuropsychological assessment

Recommendation 4: Clinicians must have access to some common assessment scales for screening for FTLD (see Table 5) (expert consensus).

Recommendation 5: FTLD-CDR scale is recommended for comprehensive impairment assessment of cognitive function, psychobehavioral symptoms, language function, etc.
(level I recommendation, level A evidence).

Recommendation 6: NPI and FBI are recommended for psychobehavioral symptom assessment, and FBI is more sensitive and effective (level II recommendation, level B evidence).

Recommendation 7: It is recommended to evaluate language function in combination with other assessment scales in addition to BNT to improve the sensitivity and specificity of differential diagnosis of different subtypes (level II recommendation, level B evidence).

Recommendation 8: Patients with motor symptoms are recommended to undergo clinical scale assessment of motor symptoms, such as UPDRS and PSPRS (level III recommendation, level B evidence).

Recommendation 9: CBI or APEHQ are recommended for assessment of eating behavior and swallowing function according to the actual situation of the patient (level II recommendation, level B evidence).

Multimodal neuroimaging evaluation

Recommendation 10: MRI is a routine basic examination for FTLD diagnosis and differential diagnosis, and MRI is recommended for disease diagnosis, follow-up and prognosis (level I recommendation, level A evidence).

Recommendation 11: Multimodal brain imaging provides very early objective evidence through comprehensive analysis of cortical atrophy, loss of white matter integrity, brain function and brain metabolism changes, and assists clinical diagnosis and progression prediction of diseases, but is not used as a routine diagnostic examination
for FTLD.
PET is recommended to improve diagnostic accuracy (level II recommendation, level B evidence).

Neurobiomarkers

Recommendation 12: CSF is recommended as a routine test for patients with FTLD (expert consensus).

Recommendation 13: Combined CSF t[1]tau, p-tau181, Aβ42 and NfL are recommended in patients with probable FTLD to improve the sensitivity and specificity of diagnosis (Level II recommendation, level B evidence).

Genetics and neuropathology

Recommendation 14: In view of the genetic characteristics of FTLD, it is recommended that patients with a clear family history of dementia, early-onset sporadic cases, special clinical phenotypes, and superimposed syndromes undergo genetic testing as soon as possible to assist diagnosis and subtype classification, which is conducive to early intervention (level I recommendation, level A evidence).

Recommendation 15: Those with negative candidate genetic tests can undergo whole gene or whole exome sequencing
according to the specific situation.
The C9ORF72 gene should be detected by repeated primer PCR (expert consensus).

Management and treatment

Recommendation 16: As there are currently no approved drugs for the treatment of FTLD, patients or insiders must be fully informed of the benefits of treatment and possible adverse effects (expert consensus).

Recommendation 17: The safety and tolerability of memantine is good, can relieve some psychobehavioral symptoms, and may be effective in improving language dysfunction (level II recommendation, level B evidence).

Recommendation 18: Manlotate sodium supports the treatment of FTLD by inhibiting neuroinflammation and tau protein production, and still needs large clinical trial studies (level II recommendation, level B evidence).

Recommendation 19: Non-pharmacological treatment is recommended first for mild psychobehavioral symptoms, followed by selective serotonin reuptake inhibitors (level II recommendation, level B evidence).

In addition to anti-dementia drug therapy, if non-pharmacologic psychobehavioral symptoms cannot be controlled by medical treatment, short-term low-dose combination of atypical antipsychotic drugs can be used, and the clinical benefit and potential risk of the patient need to be fully considered (level III recommendation, level B evidence).

Fig.
2 Integrated management strategy of frontotemporal degeneration

Medical Pulse Compiled from: Geriatric Neurology Group, Geriatric Branch of Chinese Medical Association, Frontotemporal Degeneration Expert Consensus Writing Group.
Chinese expert consensus on the diagnosis and treatment of frontotemporal degeneration[J].
Chinese Journal of Geriatrics,2022,41(8):893-907.
)