Phenocopy of frontotemporal dementia: An unusual case with 20 years onset and preserving cognitive skills

Abstract

Phenocopy frontotemporal dementia (phFTD) manifests with behavioral symptoms resembling behavioral variant FTD (bvFTD) but without cognitive decline or neuroimaging progression. Differentiating phFTD from bvFTD remains clinically challenging. We reported a 71-year-old man with a 20-year history of behavioral changes, characterized by apathy and reduced spontaneity, with a dysexecutive profile, and frontal atrophy. Despite multiple psychiatric treatments and stable structural imaging findings, the patient has remained functioning independently, with preserved memory, language, and visuospatial skills. PhFTD is a FTD spectrum of symptoms without progressive cognitive or functional decline. This case demonstrates the importance of distinguishing phFTD from bvFTD, late-onset psychiatric disorders.

Resumen

La fenocopia de la demencia frontotemporal (phDFT) tiene síntomas conductuales que se asemejan a la demencia frontotemporal variante conductual (vcDFT) sin deterioro cognitivo ni progresión en la neuroimagen. Diferenciarlas es un desafío clínico. Presentamos el caso de un hombre de 71 años con historia de 20 años de cambios conductuales, apatía y disminución de la espontaneidad, perfil disejecutivo y atrofia frontal. A pesar de múltiples tratamientos psiquiátricos y hallazgos estables en neuroimagen estructural, el paciente es independiente, tiene memoria, lenguaje y habilidades visuoespaciales preservadas. Resaltamos la importancia de distinguir la phDFT de la vcDFT y trastornos psiquiátricos de inicio tardío.

Introduction

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by behavioral and/or language deterioration, associated with marked atrophy of the temporal and frontal lobes [1]. Behavioral variant FTD (bvFTD) manifests with symptoms such as disinhibition, apathy or inertia, loss of empathy or sympathy, perseverative or compulsive behaviors, hyperorality, and executive dysfunction, which are often accompanied by neuroimaging abnormalities and significantly affect patient functioning independently [2]. Some cases have been reported where patients clinically diagnosed with bvFTD present with minimal or normal neuroimaging findings but do not progress to dementia over time. These patients have been referred to as “slow progressors”, “benign variant”, or “phenocopy” FTD (phFTD). Others hypothesize that this condition may represent a late-onset psychiatric disorder [3].

PhFTD is more common in the male-to-female ratio of 10:1, and typically presents between the ages of 45–65 years [1]. Neuropsychological test scores such as the Mini-Mental State Examination (MMSE) [4] show no significant differences compared to controls. However, these patients achieve higher scores in episodic memory tests than individuals with bvFTD. Some researchers suggest that emotion recognition or sarcasm detection tests help differentiate phFTD cases. Here, we report a patient with a 20-year history of frontally mediated behavioral changes and mild executive dysfunction, yet with remarkably slow progression and preserved independence in basic functioning consistent with a diagnosis of phFTD.

Case report

A 71-year-old right-handed male with 13 years of education. At age 40, he earned a law degree but never practiced it, describing the study of law as a personal interest. His medical history included colon cancer in remission, hypothyroidism, non-specified arrhythmia and past tobacco use. His mother suffered from sporadic Alzheimer's disease.

The patient developed depressive-type affective symptoms at age 53 and did not respond to two antidepressants with different mechanisms (fluoxetine and bupropion). Due to the lack of response and emerging behavioral changes, bipolar spectrum disorder was considered, leading to treatment with valproate and atypical antipsychotics (quetiapine, olanzapine, risperidone), also without improvement. The progression of apathy, disinhibition, impulsivity, and declining self-care prompted neurological evaluation to rule out other causes.

The physical examination was unremarkable. Mental status examination was notable for poor eye contact, apathy, reduced initiative, impaired self-care and hygiene. The MOCA test was 29/30 and the subsequent evaluations remained stable over time. From the onset of the disease, neuropsychological follow-up revealed a fluctuating course in cognitive performance, with persistent difficulties in attention, constructive praxis, and executive functions (Table 1). We also performed the Neuropsychiatric Inventory Questionnaire (NPI-Q), with a current score of 16, indicating adequate symptom control after 20 years of evolution.

Table 1.

Longitudinal neuropsychological evolution over two decades in a patient with phenocopy frontotemporal dementia.

Year	2005	2012	2014	2015	2016	2020	2023	2024	Reference range
Continuous visual performance test	16	16	16	16	14	16	16	13*	/1613.94–16.64
Trail making test part A (s)	55	37	42	31	78	66	42	62	51.16–120.64
Failure to maintain category	1	1	1	5*	1	4*	8*	2*	0.00–0.99
Verbal memory curve – initial recall	5	7	5	5	5	6	6	4	/103.90–6.90
Verbal memory curve – delayed recall (20′)	10	9	8	8	8	6	7	10	/106.20–9.20
Rey–Osterrieth complex figure test – copy	33	31	15*	29	35	36	25	21*	/3624.02–28.52
Rey–Osterrieth complex figure test – immediate recall	29	27	17.5	28	24	23	25	25	/366.73–17.39
Motor-free visual perception test	36	36	34	35	34	36	36	35	/36
Boston naming test	59	59	58	60	52	59	59	59	/6041.47–46.73
Semantic verbal fluency (mean)	15	12*	14*	16.5	18	12*	17	16.5	16.33–24.91
Phonemic verbal fluency (mean)	7*	6*	8*	12	8.7	8*	15	9.7	8.42–17.74
Wisconsin card sorting test – errors	41	44	45	38	42	64*	30	60	25.2–63.00
Wisconsin card sorting test – perseverative errors (%)	11	19	12.5	13	16	25	10	19	10.4–28.8
Wisconsin card sorting test – conceptual level responses (%)	60	59	34.7	60	50	32*	70	34	33–67

*

Altered scores.

The brain MRI reported a temporal and frontal atrophy. The following laboratory results were normal. A positron emission tomography fluorodeoxyglucose (FDG-PET) scan reported that cortical metabolism in the frontal, parietal, and both temporal lobes is preserved, without any metabolic pattern suggestive of Alzheimer's disease or frontotemporal dementia. No metabolic abnormalities were observed in the basal ganglia, thalamus, midbrain, or cerebellar hemispheres (Figs. 1 and 2). Cerebrospinal fluid biomarkers were not analyzed.

Fig. 1.

3T. Brain contrast enhanced magnetic resonance imaging. (A) Axial FLAIR sequence demonstrating mild temporal and frontal lobe atrophy. (B) Coronal T2-weighted sequence demonstrating adequate hippocampal visualization and mild temporal and frontal lobe atrophy.

Fig. 2.

FDG-PET acquisition without hypometabolism. (A) Qualitative analysis. (B) FDG-PET fused with head computerized tomography. (C) Quantitative Z-score analysis.

Whole exome sequencing did not identify pathogenic variants in dementia associated genes. The clinical profile and absence of cognitive progression supported the diagnosis of phFTD. Later, the patient could not find words and had fluent language problems; family members reported heteroaggressive behavior and needed adjustment medication. According to the above description, the patient meets the criteria for possible phFTD as described by Rascovsky et al. [2]. This is an unusual case because over approximately 20 years, he has preserved some aspects of functioning, memory, attention, calculation and visuospatial skills.

Discussion

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by behavioral and language disturbances, and marked atrophy of the frontal and/or temporal lobes [5]. Its behavioral variant manifests with disinhibition, apathy, inertia, and loss of empathy or sympathy. Since 2006, cases of slow progression, known as phFTD, have been described, in which patients do not progress to advanced stages of dementia and present minimal changes or normal neuroimaging [1]. PhFTD typically presents between the ages of 45–65 years, predominantly in males [1]. Our patient has the epidemiological characteristics and satisfies the diagnostic criteria of Rascovsky [2].

An alternative hypothesis proposes a neuropsychiatric syndrome associated with dysfunction of the orbitofrontal-thalamo-amygdala network in which the patients may exhibit difficulties in interpersonal relationships and prominent depressive symptoms [3]. Over the course of the illness, the patient experienced multiple major depressive episodes without satisfactory clinical response to antidepressants with different mechanisms of action.

Although many phFTD patients present with depressive symptoms, distinguishing them from a depressive disorder is essential, as both conditions share features such as apathy, loss of interest, lack of initiative and inactivity, however, sustained mood worsening is uncommon in frontotemporal degeneration (FTD), the emotional distress characteristic of most psychiatric disorders is usually absent, and patients frequently exhibit a marked lack of insight [6]. This distinction is fundamental in this case because the cardinal manifestation was the depressive-type affective symptoms without cognitive decline in two decades.

In contrast with the patient, most phFTD cases have a high frequency of extreme life events and a higher prevalence of Cluster C personalities has been observed [7]. These individuals may also show difficulties with temporal memory recall and with assessing emotion or sarcasm recognition [1]. Some authors suggest that phFTD may lie within the high-functioning autism spectrum (formerly known as Asperger's syndrome), manifesting with decompensation in mid to late adulthood. Additionally, FTD can involve impairments in executive, memory skills, phonetic fluency, behavioral changes, apathy, disinhibition, and abnormal eating patterns, typical features of the bvFTD [1].

Other authors have hypothesized that terminal bipolar affective disorder (BAD) may underlie phFTD or represent a form of late-onset atypical psychosis. Early symptom onset, a strong family history of psychiatric illness, periods of increased energy, and an episodic course with cognitive recovery would instead favor a diagnosis of BAD [3]. This is relevant to the present case, in which the patient underwent unsuccessful treatment for this presumed etiology. He also did not meet the criteria for autism spectrum disorder [8], as there was no history of developmental abnormalities or persistent patterns of atypical social communication, restricted interests, or repetitive behaviors. Taken together, the clinical course allowed psychiatric and neurodevelopmental etiologies to be excluded.

Since disease onset, multiple neuropsychological assessments have been performed. The most recent documented deficits in sustained attention, executive dysfunction and an early-stage Major Neurocognitive Disorder (MND), characterized by impairment across all frontal circuits with predominant ventromedial involvement, while the NPI-Q showed no behavioral disturbance. Interestingly, the semantic and phonological performance tasks were preserved. This profile partially overlaps with FTD; however, unlike bvFTD, patients with phFTD typically maintain functional capacity and perform normally on screening tests such as the Mini-Mental State Examination [1]. A qualitative design compared some cases and reported unclear longitudinal clinical changes, stable cognitive profiles over time and an absence of functional brain changes in phFTD [9].

Follow-up brain MRI demonstrated atrophy in the temporal and frontal lobes, but the FDG-PET scan did not reveal hypometabolism. Commonly, FTD cases showed hypometabolism in the frontal lobes, whereas in phFTD, FDG-PET findings show little hypometabolism and even metabolism preserved over time. This discrepancy has led to the hypothesis that phFTD does not follow a primary neurodegenerative pathophysiological process [10,11].

Regarding genetic testing, some studies have reported slowly progressive bvFTD in carriers of the C9orf72 expansion. The presence of a pathogenic mutation in patients with bvFTD, regardless of neuroimaging findings, constitutes a “definitive” diagnosis of bvFTD. Therefore, patients with phenocopy syndrome may have neurodegenerative pathology and a definitive diagnosis of FTD when screened for the C9orf72 mutation. Given that the R406W MAPT mutation has also been associated with slowly progressive behavioral disorder, these cases should also be investigated [12]. Our patient underwent targeted exome sequencing for dementia, which did not find clinically significant variants in the C9orf72, MAPT, GRN, APOE, and other genes.

Conclusions

The patient presents with the characteristic behavioral and executive dysfunction of FTD. Still, the preserved memory performance, stable neuroimaging, and remarkably slow, non-progressive clinical course over 20 years are the features that support the diagnosis of phFTD. This case highlights the importance of distinguishing phFTD from true bvFTD to avoid unnecessary pharmacological strategies and manage clinical care appropriately.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the author(s) did not used artificial intelligence tools. The author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the published article.

Funding

Non-financial support.

Conflict of interest

None to declare.

Acknowledgments

At Fundación Instituto Neurológico de Colombia and CES University.