The Puzzle of Language

There was an unspoken script in a young girl’s life growing up in a cultured family in Brescia, Italy in the 1970s that she would go on to a university to study the humanities. But this young girl had no interest in the arts or classics – she did poorly in Latin and Greek – and she had her sights set on medicine. Her mom grew up in a transitional generation in the early 1960s but observed feminism through a telescope. She knew she wanted something different for her only daughter, but she was still trapped in the tradition that etched out life for an Italian girl.

For Maria Luisa Gorno Tempini, her trajectory was, well, to follow the words, but it wasn’t in the classical sense. She enrolled at the University of Brescia Medical School and after graduation headed south to the University of Modena for her residency. She went on for a doctoral degree in imaging and neuroscience at University College London. It was there that her colleagues developed a program called Statistical Parameter Mapping, or SPM, that allows scientists to construct and assess the data from functional imaging. She would use this analysis in her own work. Her mentors studied aphasia and language.

It was during these years that she would carve out her place in the world of language. In 2001, she followed a boyfriend, who later became her husband, to the United States and accepted a fellowship at the Memory and Aging Center. In many ways, she was already a behavioral neurologist, and the MAC was the place to put her ideas into practice.

She almost couldn’t believe her good fortune. Patients were arriving to the new research center with various language and behavior problems and the setting was a living laboratory for her questions. One of the first papers she wrote was comparing patients with semantic dementia – these were people who can no longer name and understand objects – and frontotemporal dementia. In Europe, semantic dementia was also known as primary progressive aphasia. She divided up the many different aspects of spoken and written language – phonology, motor speech, semantics – and used neuropsychological tests to identify patients with specific deficits. Her brain imaging skills came in handy.

She began taping the aphasia patients in the clinic. She was also translating some of the neuropsychological tests into English.

The young neurologist identified three very different clinical signs that she believed represented different forms of primary progressive aphasia: the semantic variant, a non-fluent/agrammatic variant (people with problems planning and articulating speech), and another condition that she called logopenic (in Greek it means less words) dementia. In time, the group would align each variant to a specific brain region.

Imaging, biomarker and autopsy studies led to a surprising finding: patients with the logopenic form of PPA have a specific set of language problems – finding the right words for objects – and they share the same pathology as Alzheimer’s patients but the plaques and tangles are accumulating in a different area of the brain. The symptoms also develop two decades before the classic amnestic form of Alzheimer’s.

“Separating semantic from non-fluent/agrammatic allowed us to identify the new logopenic variant,” she explained. “When we divided patients with apraxia of speech (problems with forming the sounds into words) with phonological problems the atrophy patterns were very different.”

The two other types of PPA are linked to the accumulation of other abnormal proteins and fall pathologically into a group of disorders triggered by frontotemporal lobar degeneration, known as FTLD. As the name implies, the damage can be found in the front and temporal regions of the brain. These language-based dementias are almost always triggered by damage to the left side of the brain, the seat of language for most people.

Before these studies, the experts believed all these mid-life language problems were triggered by the pathology of FTLD.

Ultimately, Dr. Gorno Tempini’s research would change what clinicians and scientists understand about neurodegenerative diseases that leave people in the prime of adult life unable to remember words, or understand their meaning, or others who develop problems in the brain’s motor cortex that make it hard for them to fluently express words and ideas.

She then brought together neurologists and other language experts from around the world to develop a classification system to diagnose these different forms of primary progressive aphasia. The guidelines were published in 2011 in Neurology.

Experts in aphasia are citing her work and suggesting the findings are a major step forward. They are right. She helped define a new disease. Now, patients with logopenic PPA could be enrolled in clinical trials with Alzheimer’s medicines. They might also benefit from current AD drugs.

Of course, the findings beget more questions: why does Alzheimer’s pathology show up in a different brain region? Is there something about these patients that could explain this vulnerability?

Dr. Gorno Tempini and her colleagues believe that their life histories with words may offer some clues. It seems that many of them say that they had dyslexia, or reading problems, in school. Many also report problems with numbers as well. These hints have ignited a new area of interest for the neurologist: dyslexia. Two years ago, her team opened a dyslexia research center and every Monday kids and their parents arrive for testing. They have also started a study at a school designed for children with dyslexia – the Charles Armstrong School in Belmont.

There are other people at the Memory and Aging Center who believe that problems early in life – like working with numbers and learning to read – can provide clues to diseases that occur decades later. In every assessment, patients and their family members are asked about a variety of early life events that they hope will help them figure out how the older brain becomes vulnerable to specific diseases, and how scientists (and teachers) might go about changing the trajectory for future generations.

 

Jamie Talan is an Atlantic Fellow at the Global Brain Health Institute, a collaboration between UCSF and Trinity College in Dublin. She will be spending several months at UCSF writing about the inner workings of the brain and giving voice to patients and the doctors, nurses, psychologists, geneticists and researchers involved in building the foundation for a whole body of non-Alzheimer dementias that are often missed, lost or ignored.