Among the general public, the deteriorating cognitive skills associated with the dementias are typically interpreted as memory loss and labeled Alzheimer's disease. Non-Alzheimer's dementias (NADs), however, constitute a separate group of dementing illnesses that differ from Alzheimer's disease in pathogenesis and behavioral consequences.
Research over the past decade has shown that although some NADs may affect memory, memory loss is not a principal component of these diseases. Depending on the syndrome, the principal symptoms may be:
NADs are thought to be as prevalent as Alzheimer's disease in people less than 65 years of age.
Subsumed under the category called frontotemporal lobar degenerations, NADs share many histopathological characteristics and biochemical abnormalities. They also share certain clinicopathological features with some extrapyramidal syndromes and motor neuron disease. The result has been substantial category overlap and syndrome confusion.
Keith A. Josephs, M.D., a Mayo Clinic neurologist, and his colleagues are dedicated to refining and redefining these subcategories. Their work, funded by the National Institutes of Health, is based not only on behavioral symptoms, but also on imaging and newly identified protein-based mechanisms. It has already led to more precise prognosis and improved genetic counseling and is helping patients and families plan for the immediate and long-term future. Equally important, it is preparing the way for targeted molecular treatments.
At Mayo Clinic, diagnosis of NADs takes a unique approach. It is based on pattern recognition — a pattern that combines detailed behavioral, motor, and speech-language assessment with the results of MRI and PET imaging. From these results, Dr. Josephs generates probabilities about underlying protein pathology on the basis of large clinicopathological studies.
Trained in movement disorders, pathology, and behavioral neurology, Dr. Josephs is particularly well qualified to diagnose NADs. His team of collaborators includes:
Teasing apart the clinical presentation of NADs is complex. Symptoms may overlap across syndromes, and apparently unrelated symptoms may emerge within a syndrome as disease progresses. The key is determining the prominence, as opposed to the presence, of a symptom at a given stage in the disease.
For example, as Dr. Josephs and his colleagues have reported, corticobasal syndrome (CBS) often begins with a prominent and isolated apraxia of speech (a nonaphasic speech-motor-programming deficit). Several years later, as speech continues to deteriorate, patients may have dystonia of the arm and alien limb syndrome. Although the symptoms appear to affect different parts of the nervous system, they are usually caused by a single protein aberration.
Frontotemporal dementia (FTD) is an umbrella term that encompasses three major syndromes:
These syndromes are distinguished by their dominant presenting features:
PNFA, bvFTD, and SD may all have extrapyramidal symptoms, and the syndromes may overlap with progressive supranuclear palsy syndrome (PSP-S) and CBS. The dominant symptoms of PSP-S and CBS are the following:
FTDs may also include features of motor neuron disease (MND) with the bulbar symptoms of speech and swallowing difficulty, weakness, spasticity, fasciculations, hyperactive reflexes, clonus, and a Babinski sign.
Motor neuron signs are rarely associated with SD, PNFA, or PSP-S but may be found with a bvFTD-like syndrome. When motor neuron signs are involved, the syndrome is called FTD-MND.
Patterns of atrophy that appear on MRI or hypometabolism on PET scans help to distinguish affected areas in FTD syndromes and related dementias. The patterns are the following:
As Dr. Josephs points out, there appear to be associations between clinical syndromes and biochemistry, with some associations stronger than others. Several protein aberrations have been identified as the pathological mechanism for NADs. TDP-43, a protein important in DNA transcription and alternative splicing, is implicated in most FTD syndromes that previously lacked distinctive histologic features. It is associated with bvFTD, SD, PNFA, and FTD-MND, although accurate biomarkers are still being sought.
Abnormal accumulation of the microtubule-associated protein tau (MAPT) is linked with PSP-S and sometimes with CBS and bvFTD, which are called tauopathies. More than 90% of FTDs and related disorders can be classified as either a variant of TDP-43 proteinopathy or a tauopathy. Very recently, the protein FUS (fused in sarcoma) has been implicated in three additional types of NAD.
Patients with NADs may have a family history that suggests a genetic underpinning. Mutations have been identified in five genes, although most mutations that are identified have been in the progranulin (GRN) gene or the MAPT gene. These two genetic variants have been associated with specific clinical syndromes and imaging signatures:
Dr. Josephs notes a recently examined patient who had an isolated apraxic dysgraphia. She could print words but had difficulty writing in cursive. Speech pathology testing identified no speech or language impairments. Given the patient's clinical presentation and PET scan findings, she was further tested and found to have a positive result for a specific gene mutation with high penetrance that predicts she has a TDP-43 proteinopathy, a finding with implications for her and her offspring.
NADs may generate symptoms that are not as easily understood as the memory loss in Alzheimer's disease. For example, prosopagnosia may be the issue in failure to recognize family members. In some NAD syndromes, patients may believe that their spouse has been replaced by an identical-looking impostor (Capgras syndrome). Apraxia of speech, which affects speech output, can exist in the context of unimpaired language skills or can be the initial presentation of PSP-S and is highly predictive of a tauopathy.
In addition, NAD syndromes progress at different rates. Some cases, like those of SD, have a survival of approximately 10 years, compared with cases of FTD-MND, which have an average survival of 2 years — a difference with important implications for long-term care.
By drawing biochemical, imaging, and behavioral symptom associations, Dr. Josephs and his colleagues are helping patients and families understand the implications of previously poorly understood dementing illnesses. As they continue to redefine syndrome criteria, they are also setting the stage for future targeted intervention.