When It’s Not Alzheimer’s: The Differential Diagnosis of Frontotemporal Lobar Degeneration

“When It’s Not Alzheimer’s” is an ongoing series exploring the multiple differential diagnoses of Alzheimer’s disease. Explore Part 1 of the series here. 

Frontotemporal lobar degeneration (FTLD) refers to a group of non-Alzheimer’s dementias that cause portions of the frontal and temporal lobes to atrophy, leading to impairments in behavior, personality, language, and movement. FTLD is estimated to cause up to 10% of dementia cases, and it is the most common cause of dementia in individuals younger than 60 years old, with symptoms usually appearing between the ages of 50 and 60.¹

In people under the age of 65, FTLD is believed to be as common as Alzheimer’s disease (AD), and therefore it may be mistaken for AD. “Clinicians tend not to suspect dementia in patients under age 65 – it’s often just not on their radar,” said Sharon Sha, MD, MS, a clinical assistant professor of neurology and neurological sciences at Stanford University in California. “When they do, they may assume Alzheimer’s because it is so prevalent,” she told Neurology Advisor.

Types and Diagnostic Challenges

There is a lack of absolute agreement among experts regarding which specific diseases fall under the frontotemporal dementia umbrella. However, the most prevalent type is behavioral variant frontotemporal dementia (bvFTD), formerly known as Pick’s disease, which accounts for approximately 60% of cases. Other common types are the primary progressive aphasias (PPA), including the nonfluent/agrammatic variant — also known as progressive nonfluent aphasia (PNFA) – and the semantic variant. Also known as semantic dementia, semantic variant PPA “includes a left temporal lobe variant, which has the appearance of progressive inability to name things, and a right temporal lobe variant, with progressive inability to distinguish familiar faces and to some degree places,” explained Richard J. Caselli, MD, a professor of neurology at Mayo Clinic in Phoenix, Arizona.

“The nomenclature and various acronyms are confusing, and neurologists often find daunting the overlapping features of the various disorders,” Melanie B. Shulman, MD, a clinical associate professor of neurology and psychiatry at NYU Langone Medical Center in New York, told Neurology Advisor. . The confusion can lead to misdiagnosis and under-diagnosis of FTLD. For example, bvFTD is often misdiagnosed as a psychiatric problem, AD, or Parkinson’s disease. Further complicating the clinical picture, approximately 15% of patients with FTLD will develop motor neuron disease (FTD-MND), of which the most common type is amyotrophic lateral sclerosis (ALS).

Key Clinical Differences

Clear differences between AD and FTLD typically do exist, however, especially in the early stages of the disease. “In the late stages of any dementing illness it can be difficult to tell one disease from another, but in the mild and moderate stages these differences can be quite obvious,” Dr Caselli told Neurology Advisor. “Dementia symptoms often include trouble with social skills, but this is especially the case with bvFTD, in which a loss of social skills can be the presenting feature, even before there is any significant loss of intellectual ability,” he noted. In addition, while language impairment affects most dementia patients at some point, it is especially severe and appears early in the course of the disease in patients with PPA caused by FTLD.

Though memory loss is often a prominent symptom in early AD, it may not appear until the advanced stages of FTLD. Unlike AD, changes in personality, behavior, and social cognition appear early in bvFTD, while memory and visuospatial abilities remain relatively intact, according to Dr Shulman. Additionally, motor symptoms may appear in the early stages of bvFTD but are typically absent in early AD. With the non-fluent/agrammatic variant of PPA, patients “have an expressive aphasia, often with a notable stutter, grammatical slips, and impaired retention, while word-finding difficulties are present in Alzheimer’s.” In the semantic variant of PPA, “episodic memory is relatively well-preserved, but word-finding difficulties are more profound–loss of word knowledge and object meaning, surface dyslexia, intact calculations,” she explained.

Screening and Neuroimaging to Aid Diagnosis

Recent findings published in Alzheimer’s Disease and Associated Disorders suggest that the Montreal Cognitive Assessment (MoCA) may be a valuable tool in distinguishing FTD from AD.² The results show a significant difference in overall scores between the 2 patient groups (P= .023), and the following specific MoCA items differed between AD and FTD: serial 7 subtractions (28% AD vs 54% FTD patients scored 3/3; P= .016), delayed recall (75.5% AD vs 50% FTD scored 0/5; P< .001), and orientation (50% AD vs 68% FTD scored 5 to 6/6; P= .012).

For bvFTD in particular, the criteria developed by the International Behavioural Variant FTD Criteria Consortium (FTDC), revised in 2011, have shown high diagnostic accuracy for probable bvFTD [sensitivity of 85% (95% CI, 69-95%), specificity of 82% (95% CI, 73-89%)].^3,4  

In establishing a diagnosis in suspected cases of FTLD, neuroimaging is a key component. Dr Shulman described the following defining imaging patterns of FTLD:

• The majority of patients have focal frontal or anterior temporal atrophy that is readily identifiable by visual inspection. The atrophy is often asymmetric, even in patients with bvFTD. 
• Lateralized findings are almost always present in patients with PPA, encompassing a wide network of brain regions. The whole left peri-Sylvian region, anterior temporal lobes (left > right), and basal ganglia bilaterally are all found to be atrophied in PPA patients. 
• In PNFA, the inferior frontal lobe and insula are atrophied, while in semantic dementia, the anterior temporal lobe is focally atrophied. 
• FDG-PET imaging demonstrates variable patterns of frontal and temporal hypometabolism; in contradistinction to the biparietal hypometabolism most commonly seen in AD.

Further distinguishing FTD is the absence of amyloid plaques and neurofibrillary tangles that characterize AD. Instead, FTLD pathology involves one of 2 proteins: tau or TDP-43. “The neurofibrillary tangles of AD are also a manifestation of tau, but the appearance is different than the appearance of tau pathology in FTLD cases so that a pathologist can tell them apart,” said Dr Caselli.

Finally, a small proportion of FTD and AD cases are caused by gene mutations, noted Dr Sha. The 3 main genes involved in FTD are C9orf72, progranulin, and MAPT, while those involved in AD are APP, PSEN1, and PSEN2. “If the patient has a family history of either disease and has positive genetic test results showing the relevant mutations, then that’s confirmatory,” she said.

Despite the significant overlap between many AD and FTD symptoms, clear differences are often present in the early stages of each disease. Neuroimaging and if necessary, genetic testing, can help to confirm the diagnosis.

References

1. Rosness TA, Engedal K, Chemali Z. Frontotemporal dementia: an updated clinician’s guide. J Geriatr Psychiatry Neurol. 2016; 29(5):271-80.
2. Coleman KK, Coleman BL, MacKinley JD, Pasternak SH, Finger EC. Detection and differentiation of frontotemporal dementia and related disorders from alzheimer disease using the Montreal Cognitive Assessment. Alzheimer Dis Assoc Disord. 2016; 30(3):258-63.
3. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011; 134(9):2456–2477.
4. Vijverberg EG, Dols A, Krudop WA, et al. Diagnostic accuracy of the frontotemporal dementia consensus criteria in the late-onset frontal lobe syndrome. Dement Geriatr Cogn Disord. 2016; 41(3-4):210-9.