Post Traumatic Stress Disorder Heralding the Onset of Semantic Frontotemporal Dementia

PTSD diagnosis

PTSD was diagnosed according to DSM-IV TR criteria [23], by means of semi-structured interviews.

The Clinician-Administered PTSD Scale for DSM-IV-TR (CAPS-IV-TR) [24] was finally applied to confirm the diagnosis [25, 26].

Prospective study

Forty-six patients with PTSD were clinically and neuropsychologically followed for 6 to 10 years on a six-month basis. Probable AD diagnosis was based on NINCDS-ADRDA criteria [27]. DLB diagnosis was based on the revision of Consensus Criteria [28]. Frontotemporal dementia (FTD) diagnosis was based on standardized clinical criteria [29]. Vascular Dementia was diagnosed based on NINDS-AIREN criteria [30].

All patients underwent Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) [31], Neuropsychiatric Inventory (NPI) [32], Clinician Assessment of Fluctuations (CAF) [33], tests for language (Token Test) [34] reasoning (Raven Colored Progressive Matrices [35], letter and category fluency test, [36]), short-term verbal memory (Digit Span Forward, [6 visuo-spatial short-term memory (Corsi Test 37]), verbal long-term memory (RAVLT, delayed recall [38]), long-term visual spatial memory (Rey-Osterrieth Complex Figure recall [39]), visuoconstructive abilities (Rey-Osterrieth Complex Figure copy [39]), and attention (Attentive Matrices, [40]). Beck Depression Inventory (BDI) was also administered [41]. The presence of REM sleep Behavior Disorder (RBD) was evaluated according to minimal International Classification of Sleep Disorders (ICSD) criteria for RBD [42] and confirmed by polysomnographic recordings.

Neuroimaging studies in all patients were performed at baseline and once a year during follow-up. They included 1.5 Tesla MRI of the brain with quantitative assessment of regional brain atrophy, including hippocampal, and frontal atrophy and assessment of sub-cortical vascular burden (leukoencephalopathy) according to Hachinski [43].

Diagnosis of AD or non-AD (DLB, FTD, VaD) dementia was supported by the measurement of specific protein levels (Aβ₄₂, tau, and Ptau) in the cerebrospinal fluid (CSF) [44]. A CSF AD profile was defined as follows: Aβ level <800 pg/mL, total tau >300 pg/mL, and phosphorylated-tau protein >60 pg/mL. A CSF profile suggestive of DLB was defined as follows: Aβ level <800 pg/mL, total tau >300 pg/mL, and P-tau<60 pg/ mL [43]. A CSF profile suggestive of non-AD and non-DLB dementia was defined as follows: Aβ 1-42 level >800 pg/mL, total tau >300 pg/mL, and P-tau>60 pg/ mL [44].

Retrospective study

849 patients regularly followed in our dementia tertiary clinic (509 AD, 207 DLB, 90 VaD, 43 FTD) in the years 1999–2014 and a population of 287 patients afferent in the year 2016 to our Neurology Clinic for any neurological condition, were retrospectively evaluated for the presence in their medical history (within 10 years before the onset of dementia) of a life-threatening trauma with PTSD as for DSM-IV-TR criteria and CAPS-IV-TR. Interviews of patients, family members and General Practioners were conducted by clinicians (MDG, GM, FV, AT) unaware of the patients status and of the purpose of the study.

In particular, PTSD was investigated as reported in PTSD diagnosis paragraph and included also information from prior hospital records related to traumas or physical assaults and reports from patient’s GPs and family members.

Statistics

In the retrospective study, age and MMSE score were statistically compared across groups by means of ANOVA with Bonferroni post-hoc test, whereas the gender variable was compared by means of the non parametric Kruskal Wallis Test. The same statistical analyses were performed for the comparison of the dementia cohort of the retrospective study (cohort 1) and the demented cohort of the comparative group (cohort 2).

Comparisons between prevalences of all the categorical variables were performed by χ² test. Bilateral confidence intervals (C.I.) for normal distribution without continuity corrections were also performed with 95% confident level, taking into account the percentage and sample size.

For the retrospective study of the cohort 1, Poisson regression was performed in the dementia cohort overall, using PTSD as the dependent variable and age, gender, and MMSE as independent possible demographic and clinical confounders.

Prospectively followed PTSD patient population

None of the 46 PTSD patients were lost to follow-up. Mean follow-up duration was 7.2±1.2 years.

18 patients were followed for 6 years, 12 patients were followed for 7 years, 9 patients for 8 years, 5 patients for 9 years, 2 patients for 10 years.

Eight patients with PTSD were diagnosed with dementia within 4 years follow-up but were followed for 6 years.

CAPS-IV-TR score was 9.3±2.2. Mean age was 65±4.3 years. Male gender represented 54% of the PTSD population (Table 1).

Twelve out of the 46 patients with PTSD were survivors from the catastrophic earthquake which stroke the city of L’Aquila in 2009.

In 28 of the 46 PTSD patients, PTSD symptoms appeared 3 to 5 months after the traumatic event (15 of these patients were initially diagnosed as affected by acute stress disorder [22]). In the remaining 18 patients symptoms had a delayed onset (in 10 patients the symptoms onset dated 6 to 10 months after the trauma, in 8 patients onset occurred between 1 and 2 years after the trauma).

Twenty-two patients completely recovered after 1 to 8 months after the symptoms onset. 10 of them were diagnosed as acute PTSD, since duration of symptoms was 1 to 3 months.

While typology of the trauma greatly varied among 34 patients, going from physical assault, to rape, to armed robbery, 12 patients shared the same trauma represented by a disastrous earthquake which hit the city of L’Aquila (the main city of Abruzzo Region) in the night between the 5 and 6 April 2009, causing the destruction of large parts of the town and the death of 309 people.

Eight patients with PTSD (17.4% of the total 46 patients) matched criteria for dementia within 4 years follow-up. In particular, one patient (female, 72 years old, educational level of 8 years, CAPS-IV-TR score 10) matched the criteria for AD dementia in 4 years (MMSE 20), one (male, 75 years old, CAPS-IV-TR score 10) for DLB dementia in 3 years (MMSE 22), 6 patients developed semantic FTD (with a latency of 2.7±1.0 years from PTSD occurrence), representing 75% of the PTSD patients who developed dementia and 13% of the total PTSD observed patients.

Table 2 reports demographical, clinical and neuropsychological test scores in the 6 patients who developed semantic FTD.

Case descriptions

Patient 1 is a 69-year-old female, with 13 years of education, a retired dealer, amateur mountain climber, and participated in 2003 in a guided climbing expedition to Mount Everest. During the ascent, a sudden storm isolated her from the rest of the group and she remained alone for 10 hours in the cold until the guide rescued her. Back to Italy she returned to her routine life without any apparent consequence from the adventure. After seven months, however, she started feeling unusually generically anxious about her 20-year-old son, who was in perfect health; she abandoned her passion for climbing and she became agoraphobic. After two months of unsuccessful attempt to sedate her anxiety with benzodiazepines, she was referred by the GP to our Psychiatry Clinic where she was diagnosed as affected by PTSD (CAPS-IV-TR total score of 12). When asked about her experience on mount Everest she started sweating and asked not to talk about that event anymore. Even mentioning it caused her a sense of thoracic constriction. She reported that during the last three months she had dreamed several times about being abandoned in the cold.

An MRI scan at that time was normal. No atrophy and unspecific mild signs of leukoencephalopathy were reported. Neck vessels Doppler ultrasound gave normal results. MMSE was 30. Beck Depression Inventory rated the presence of depression (BDI = 11).

She was successfully treated with sertraline (50 mg/day) for 3 years. She went back to climbing again, but with her bewilderment she was unable to use climbing hooks. Her family members reported also that the patient’s spontaneous speech was fluent but empty. She was then referred to our dementia center to be tested for the possible onset of a cognitive disorder.

At the end of 2006 her MMSE resulted to be 24. Her naming and comprehension appeared progressively impaired, with paraphasias. An MRI scan showed the presence of initial regional left-sided atrophy in the temporal lobe and mild signs of leukoencephalopathy, unmodified as compared to first MRI scan. EEG recording at rest showed a dominant frequency stable at 8.0 Hz in posterior derivations and theta activity at 5-6 Hz in temporal derivations.

Lumbar puncture for the dosage of CSF tau and amyloid proteins showed the following pattern: increased phospho-tau with normal amyloid levels: total tau 448 pg/ml, phosphorylated-tau protein 98 pg/ml, Aβ 1-42 level 857 pg/mL).

The patient was diagnosed as affected by semantic FTD.

She was followed in our dementia center with regular clinical and neuropsychological examinations. Dysexecutive symptoms appeared with difficulties in reasoning and planning daily activities.

An attempt to treat the patient with memantine caused the appearance of aggressiveness.

The last evaluation was performed in 2011. It was not possible to perform a neuropsychological evaluation: the patient was completely aphasic and apathetic. Fecal incontinence was reported by family members. The last MRI, performed in June 2011, showed marked frontal and temporal symmetric atrophy. EEG recording at rest showed a dominant frequency in the delta-theta bands in temporal derivations.

Patient 2 is a 73-year-old man, with 13 years of education, and a retired director of post office.

Between 2003 and 2005 he underwent 3 robbery attempts. During the first of these episodes three criminals broke in the post office shooting with their guns against the ceiling. During the second and third episode the criminals ran inside the office threatening the employees with guns.

He seemed to have reacted well in the first 4 months after the last episode. He reported that the employees felt heartened by his rational and calm behavior. But after a while he started waking up at morning with a new sense of anxiety, fearing the moment to step into his work place. He was particularly anxious when people entered the office. He became sleepless at night thinking about possible ways to make his post office more secure.

He was diagnosed as PTSD (CAPS-IV-TR = 10) and treated with mirtazapine 30 mg with good efficacy.

He spent 4 years in good health, until he started having difficulties in mathematical calculations. Neuropsychological tests showed word finding and comprehension difficulties and semantic paraphasias. MMSE was 22. He underwent an MRI scan which showed bilateral temporal atrophy, more evident on the left side. CSF tau and amyloid proteins showed: total tau 455 pg/ml, phosphorylated-tau protein 89 pg/ml, Aβ 1-42 level 915 pg/mL). The patients received the diagnosis of semantic variant of primary progressive aphasia.

Patient 3 is a 69-year-old man, with 17 years of education, and a retired middle school teacher.

In 1999, he was giving his chemistry lecture at school, when a foolish ran into his class screaming and pointing a gun against the patient and his schoolchildren, claiming that he had been fired by his company and he was then able to do anything that passed into his mind.

The patient and children were forced to listen to crazy lectures by the madman for several hours, until the police came and saved them, arresting the criminal.

The patient reported to have been extremely stricken by this experience and from the very first moments after the trauma he was unable to run his normal life. He was anxious, agitated, sleepless, often compelled to cry. He came to our center where he received the diagnosis of acute PTSD (CAPS-IV-TR = 10). He was treated with benzodiazepines and sertraline 100 mg daily.

He went back to work and felt better for 3 years, after which he reported to experience episodes of “lack of words” during teaching and of forgetfulness while carrying out normal activities of daily living: he happened to lose his keys, to forget where he had parked his car. He started also experiencing difficulties in performing sequential tasks, such as preparing a meal, or driving his car. We prescribed an MRI, which showed frontal atrophy more prominent in the left hemisphere, and an EEG which showed posterior dominant frequency stable at 10 Hz, with inscription of theta sequences and sharp waves in temporal derivations. MMSE was 21.

The patient was diagnosed as affected by semantic FTD. Complete neuropsychological test scores are reported in Table 2. He underwent lumbar puncture which showed increased level of tau and phospho-tau proteins (total tau 385 pg/ml, phosphorylated-tau protein 77 pg/ml, Aβ 1-42 level 878 pg/mL).

Patient 4 is a 75-year-old man, with 5 years of education, and a dealer. In 1999 he had a car accident while he was driving along an overpass with his 5-year-old grand-child. His car remained suspended over a canyon for one hour, before the breakdown service came, secured the car and rescued the two passengers.

The patients never stopped dreaming the accident for 3 months. He became anxious and could not drive any longer.

He came to our Psychiatry Clinic where he was diagnosed as affected by PTSD (CAPS-IV-TR score = 7).

The patient symptoms, treated with antidepressants, benzodiazepines and psychotherapy subsided in one year. He returned to a normal life and started driving again.

After three years, however, the patient’s language became poor with occasional anomia. And in the following year the patient developed dyscalculia and a dysexecutive syndrome characterized by difficulties in planning the orders of foodstuffs for his grocery store.

The patient was referred to our memory clinic. An MRI scan showed the presence of initial regional left-sided atrophy in the temporal and frontal lobe. EEG recording at rest showed a dominant frequency stable at 8.0 Hz in posterior derivations and delta-theta activity at 3–6 Hz in temporal derivations. MMSE was 23, DRS-2 total score was 103.

He underwent lumbar puncture which showed increased level of tau and phospho-tau proteins (total tau 401 pg/ml, phosporylated-tau protein 98 pg/ml, Aβ 1-42 level 856 pg/mL).

The patient was diagnosed as affected by semantic FTD and treated with transdermic rivastigmine 4.6 mg daily.

Patient 5 is a 70-year-old man, with 3 years of education, and a farmer. In 2001 the patient had a quarrel with his neighbor about the boundaries of their respective adjacent properties. During the argue his neighbor, increasingly upset, repeatedly poke the patient with a pitchfork, causing severe wounds to the patient face, neck and chest.

Conspicuously bleeding, the patient was transported to the emergency room where his wounds were sutured. A brain CT scan resulted to be normal. An X ray of the chest showed no signs of pneumothorax. He recovered in one month.

After 7 months the patient started feeling anxious with inexplicable sense of fear which caused withdrawal of social activities. He had occasional nightmares about the fight with his neighbor. He was referred by his GP to our Psychiatry Clinic where he was diagnosed as affected by PTSD (CAPS-IV-TR = 8).

These symptoms lasted for 6 months. He spent one year of fairly normal life, after which, as reported by his wife, the patient started showing progressive difficulties in recognizing familiar places. Prominent language impairment with impaired word comprehension became apparent. The patient was therefore referred to our memory clinic, where he was studied with MRI scan, EEG, complete neuropsychological test battery.

MRI showed bilateral temporal atrophy. EEG recording showed a dominant frequency stable in the alpha band (9.0 Hz) in posterior derivations and slow wave activity in temporal derivations more evident in the left hemisphere characterized by delta-theta activity at 3–5 Hz with sporadic sharp waves, MMSE was 20, DRS-2 total score was 99.

He underwent lumbar puncture which showed increased level of tau and phospho-tau proteins (total tau 397 pg/ml, phosphorylated-tau protein 82 pg/ml, Aβ 1-42 level 822 pg/mL).

The patient was diagnosed as affected by semantic FTD and treated with transdermal rivastigmine 4.6 mg.

At present the patient has a MMSE of 10 and is treated with rivastigmine 9.5 mg.

Patient 6 is a 66-year-old woman, with 5 years of education, and a farmer. On April 6th, 2009, she was sleeping in her two-storey house in the city of L’Aquila when at 3.00 a.m. a violent earthquake stroke the city, causing destruction of several buildings. The patient was transported by her son outside her house, unharmed but frightened, and spent that night in the street in her pajama with an outdoor temperature of 5°C. She was compelled with many other citizens of L’Aquila to live in a tent for three weeks before being transferred to a hotel on the coast.

A few days after, the patient, unusually silent and secluded to family members, started reporting frequent intrusive recollections of destroyed buildings and falling stones and bricks. These images appeared also at night as terrifying dreams, where the patient reported to feel lonely and helpless. At day 10 from the relocation (which lasted 4 months) the patient was found by her family members in confusional state and she was admitted to our Neurology Clinic.

EKG and laboratory exams were all normal.

EEG dominant frequency was stable at 9.0 Hz. An MRI scan showed mild signs of age-related unspecific diffuse atrophy. She was treated with benzodiazepines and quetiapine, with good clinical response, with resolution of confusion. MMSE was 27. The patient was therefore diagnosed as affected by PTSD (CAPS-IV-TR score = 6).

In June 2011 the patient’s daughter-in-law contacted our Dementia Center, concerned by a change in the patient behavior, characterized by difficulty to recall names of family members, fluent but senseless speech followed by incongruous attitude, with inappropriate language and vain hilarity.

MMSE resulted to be 25. A second MRI scan showed the presence of modest signs of leukoencephalopathy, clear signs of frontal atrophy, initial signs of bilateral temporal atrophy, with increase of lateral ventricles size.

She underwent lumbar puncture which showed increased level of tau and phospho-tau proteins (total tau 401 pg/ml, phosphorylated-tau protein 91 pg/ml, Aβ 1-42 level 813 pg/mL).

The patient was diagnosed as affected by semantic FTD.

EEG dominant frequency was still characterized by alpha dominant frequency (9 Hz) in posterior derivations.

Retrospective study

PTSD in the comparative group

Demographical and clinical data of the 287 neurological patients of the comparative group admitted to our Neurology Unit in the first six months of the year 2016 are reported in Table 4. Among them, 107 patients (37%) resulted to be affected by dementia (46 AD (43%), 45 VaD (42%), 14 DLB (13%), 2 FTD (2%). A history of PTSD was present in 4 patients (3.7%, 2 AD, 2 VaD).

On the population of 180 patients without dementia (63%), a history of PTSD was present in 2 patients (1.1%, 1 patient with ischemic stroke, 1 with brain tumor).

Statistical comparison between the demented cohort of the comparative group (cohort 2) and the retrospective cohort (cohort 1) showed that age and MMSE were higher in the cohort 2 (p < 10^-5; p < 10^-6, respectively).

Study limitations

The retrospective part of the study is, undoubtedly,flawed by the typical biases of any retrospective study, including recall bias which might explain the lower incidence of PTSD among the dementia population (4%) as compared to incidence of dementia found in PTSD population evaluated in the prospective study (17%). Another possible limitation is that the prevalence of specific diagnoses is higher in a tertiary center as our University center, which is endowed with several advanced diagnostic tools ranging from SPECT, PET, MRI, fMRI 1.5–3 T, to laboratories of proteomics for assessment of CSF proteins, to genetic assessments of neurodegenerative disease to neuroimmunological essays, to complex neuropsychological evaluations [49].

Furthermore, it is also likely that our patients population was spontaneously selected because of the severity of symptoms which often lead the patients to refer to tertiary centers. Therefore further studies in different centers should be augured.

We strictly applied, however, DSM-IV-TR classification methods, and interviews were performed by clinicians unaware of diagnosis of patients and purpose of the study.

All in all,the two parts of the study suggest a significant relationship between PTSD and FTLD,an association deserving further multicenter studies.

Strengths and limitations

One strength of our study lays in the complementary approach conferred by the prospective and retrospective observation of the association between PTSD and FTD. In particular, the retrospective study was conducted in a very large population of dementia patients and could confirm the surprising association between the two conditions, observed in the prospective study.

Further prospective or retrospective studies, from multiple centers, conducted with multivariate analyses are, undoubtedly, needed in order to confirm the relevance of our observations.

Despite this major limitation our study has a strength, as it identifies the distinct FTD phenotype, with the semantic variant, as a possible negative outcome of PTSD. Preceding literature did not categorize dementia after PTSD beyond a generic definition or anecdotal reports [1–5]. A minor strength, not overcoming the limitations reported above, is also that our observations are based on a tertiary center referral, with a wide catchment area: during the study period the incidences of different dementia types were inside the variability ranges reported in prior epidemiological surveys [49] and by other centers. Thus, we believe that our observation indicates an unexpected and unprecedented possible link between PTSD and FTD phenotype, and may constitute a preliminary background for further improved studies.

We believe that it is worthy to strictly follow patients with PTSD for the possible development of signs of cognitive decline, in order to identify these signs early in the course of dementia and allocate patients to early pharmacological and non pharmacological interventions.