A case series of PLS patients with frontotemporal dementia and overview of the literature

Figures & data

Figure 1. Summary of the results from our literature search. The search was performed using MEDLINE (via PubMed) on articles in English from July 1963 to January 2017 reporting on cognition and/or behaviour in PLS. Titles and abstracts were screened and relevant full text articles were retrieved. References were screened for additional studies and publications were also identified from the authors’ literature collections. When overlap between studies was expected, corresponding authors were contacted for further details. Since the inclusion of the search term “PLS” led to a high amount of irrelevant hits (e.g. partial least squares, post ligation syndrome, parathyroid lesions, etc.) it was not included in our list of search terms. We included studies on PLS in which dementia, cognition or behaviour was mentioned.

Figure 2. The initial axial T2 weighted MRI (A) showed left temporal lobe atrophy. The second scan made 2 years later (B) demonstrated bilateral temporal lobe and hippocampus atrophy (axial and coronal T2 weighted MRI), but more severe on the left side with a knife blade aspect of the temporal gyri while the general cerebral atrophy was limited (far right: sagittal T1 weighted MRI).

Table 1. Clinical characteristics of PLS-FTD patients.

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Gender	Male	Female	Female	Female	Female	Male
Age at onset of PLS (yrs.)	53	62	67	68	57	59
Site of onset	Left Leg	Bulbar	Left leg	Left leg	Bulbar	Right Leg
Progression to other regions over time?	Bulbar	Arms & legs	Bulbar	Bulbar	No	Arms & legs
Decreased vital capacity?	No	No	No	No	No	No
Clinical or EMG evidence of LMN involvement 4 or more years from onset?	Absent	Absent	Absent	Absent	Absent	Absent
Vertical gaze palsy	No	No	No	No	No	No
Frequent falling during 1st of symptoms?	No	No	No	No	No	No
Time from PLS onset to 1st cognitive/behavioural changes (mo.)	108	72	50	60	84	60
Most prominent feature	Behavioural changes	Language deficits	Language comprehension and apathy	Behavioural changes	Behavioural changes	Behavioural changes
FTD subtype	Possible bvFTD	Semantic dementia	Probable bvFTD	Probable bvFTD	Possible bvFTD	Probable bvFTD
Behavioural changes (consensus clinical criteria bvFTD) (12)	(1) Behavioural disinhibition	(1) Apathy	(1) Apathy	(1) Apathy	(1) Apathy or inertia	(1) Behavioural disinhibition
	(2) Apathy	(2) Behavioural disinhibition	(2) Diminished social interest	(2) Behavioural disinhibition	(2) Behavioural disinhibition	(2) Diminished social interest
	(3) Hyperorality and dietary changes	(3) Perseverative, stereotyped or compulsive/ritualistic behaviour	(3) Executive dysfunction	(3) Perseverative, stereotyped or compulsive/ritualistic behaviour	(3) Loss of sympathy	(3) Altered food preferences
Neuropsychological findings	Language deficits and executive dysfunction with relative sparing of memory and visual spatial tasks	Language deficits	Language deficits, executive dysfunction and to a lesser extent memory impairment	Mild memory impairment	Executive dysfunction and language	Language, fluency and executive dysfunction with relative sparing of memory and visual spatial tasks
Atrophy on MRI imaging	NA	Bilateral frontal atrophy and more pronounced of the anterior part of the temporal lobes	Bilateral temporal atrophy	Left temporal atrophy	NA	Bilateral frontal atrophy
Time from first cognitive/behavioural changes to FTD diagnosis (mo.)	3	4	6	12	12	60
Development of parkinsonian features during follow-up	Tremor	Bilateral resting tremor	–	–	–	–
C9orf72 (wild type/expanded)	Wild type	Wild type	Unknown	Wild type	Unknown	Wild type

PLS: Primary lateral sclerosis; FTD: Frontotemporal dementia; bvFTD: Behavioural variant FTD; EMG: Electromyography; LMN: Lower motor neuron; MRI: Magnetic resonance imaging; NA: Not available.

Table 2. Studies on PLS patients that interrogated cognition and/or behaviour.

			PLS cases
No.	1st author, year (reference)	Overlapping studies*	n	FTD (n)	CI/BI (n)	Cognitive assessment	Affected cognitive domains
1	Russo, 1982 (42)		4	0	0	–	–
2	Sotaniemi, 1985 (43)		2	0	0	–	–
3	Pringle, 1992 (26)		8	0	0	–	–
4	Kiernan, 1994 (44)		8	0	0	–	–
5	Casellli, 1995 (16)		9	0	8	Full NPE	Executive function, Memory
6	De Koning, 1997 (21)		1	0	1	Full NPE	‘Mild frontal lobe deficits’
7	Sugihara, 1999 (29)		1	1	0	HDS	–
8	Engel, 2000 (22)		1	0	1	Full NPE	Executive function
9	Forestier, 2001 (20)	9&15	20	0	9	Full NPE	Executive function
10	Kosaka, 2012 (28)	10&11	1	1	0	–	–
11	Tan, 2003 (30)	10&11	1	1	0	–	–
12	Mochizuki, 2004 (31)		1	1	0	–	–
13	Yoshida, 2004 (45)		2	2	0	–	–
14	Gordon, 2006 (4)		11	1	0	–	Memory
15	Piquard, 2006 (19)	9&15	20	0	17	Full NPE	Executive function, Memory
16	Norlinah, 2007 (33)		5	0	1	–	‘Subcortical frontal systems’
17	Tartaglia, 2007 (46)	17,18&23	43	0	0	–	–
18	Murphy, 2008 (18)	17,18&23	18	0	4	Full NPE	Executive function
19	Tomik, 2008 (47)		4	0	1	–	Memory
20	Zago, 2008 (48)		16	0	0	Token test, RCPM, writing examination	Spelling impairment
21	Huey, 2010 (49)		19	0	1	MMSE + FAB	Executive function, Memory
22	Gilbert, 2010 (50)		6	0	1	–	–
23	Grace, 2011 (17)	17,18&23	18	0	7	Full NPE	Executive function, Behaviour
24	Coon, 2012 (27)		3	0	0	MMSE, FBI, FAB	–
25	Amato, 2013 (51)		10	0	0	Stroop Test	–
26	Canu, 2013 (15)	26&30	21	0	10	Full NPE	Executive function, Language
27	Kolind, 2013 (52)	27&32	7	0	0	ACE-R, TMT, VFI	–
28	Lobo, 2013 (23)		1	1	0	Full NPE	–
29	Meoded, 2013 (53)		23	0	6	DRS-2, D-KEFS	Executive function, Behaviour
30	Agosta, 2014 (14)	26&30	24	0	2	Full NPE	Executive function, Language
31	Mitsumoto, 2015 (54)		41	0	14	ALS-CBS, MMSE, FBI	Executive function, Behaviour
32	Proudfoot, 2015 (55)	27&32	7	0	0	ACE-R + TMT	Executive function
33	Wais, 2016 (56)		36	0	0	–	–

* Studies with confirmed overlap in PLS cases. The extent of overlap was mostly unknown. In order to make an estimate of the total unique cases in each of the three groups (total PLS, CI/BI and FTD), we only counted the largest number in each group of the overlapping studies. The resulting cumulative numbers were used to approximate the frequency of published PLS cases with concomitant FTD or cognitive/behavioural changes.

The number of cases with cognitive and/or behavioural deficits based on the opinion/observation of the author and/or the results of neuropsychological evaluation without fulfilling diagnostic criteria for FTD.

FTD: frontotemporal dementia; CI: cognitive impairment; BI: behavioural impairment; NPE: neuropsychological evaluation; HDS: Hasegawa dementia scale; RCPM: Raven’s Coloured Progressive Matrices; MMSE: Mini-mental state examination; FAB: Frontal assessment battery; FBI: Frontal behavioural inventory; ACE-R: Addenbrooke's Cognitive Examination Revised; TMT: trail making test; VFI: Verbal Fluency Index; DRS-2: Dementia Rating Scale-2; D-KEFS: Delis-Kaplan Executive Function System; ALS-CBS: ALS Cognitive Behavioural Screen.

Table 3. Pooled weighted effect sizes and heterogeneity statistics of cognitive domains.

Cognitive domains	Hedges' g^a	95% CI^b	Studies (n)	Total subjects (n)	Heterogeneity between studies within cognitive domain (Q)^c	p(Q)^d	I^2 (%)^e
Delayed verbal memory	1.62	(0.79, 2.45)	1	32	NA	NA	NA
Psychomotor speed	1.47	(1.06, 1.89)	1	39	NA	NA	NA
ACE-R	1.32	(0.64, 1.99)	2	64	0.97	0.32	0%
Fluency	1.24	(0.11, 2.36)	2	58	19.61	0.0002	85%
Letter fluency	1.07	(−0.40, 2.55)	2	58	5.06	0.02	80%
Category fluency	1.59	(−1.46, 4.63)	2	58	14.38	0.0001	93%
Executive functions	0.87	(−0.27, 2.02)	2	58	4.05	0.04	75%
Language	0.39	(−0.23, 1.02)	1	40	NA	NA	NA
Visuoconstructive functions	0.24	(−0.39, 0.88)	1	39	NA	NA	NA
Immediate verbal memory	−0.07	(−0.70, 0.55)	1	39	NA	NA	NA
Attention	−0.21	(−0.72, 0.24)	1	39	NA	NA	NA
Visual memory	0.24	(−0.39, 0.88)	1	39	NA	NA	NA

(a) Effect size is expressed as Hedges’ g. A larger value indicate more impairment in PLS patients compared to healthy controls. A small effect size is represented as 0–0.2, a medium effect size as 0.2–0.5 and a large effect size as >0.8. (b) The effect size is significant when zero is not in the 95% confidence interval (95% CI), with a significance level of 0.05 (or 5%). (c) Q: Cochran’s Q test is used to assess whether observed differences in results between the individual studies are compatible with chance alone. A high value corresponds with high heterogeneity. A large amount of heterogeneity means poor overlap between the results of the individual studies. (d) A low p-value (>0.05) indicate a large amount of heterogeneity. (e) I^2: Test for quantifying inconsistencies between the results of studies. The variability in effect estimates due to heterogeneity is described as a percentage. A percentage of 0–40% indicates that heterogeneity might not be of importance, 30–60%: indicates moderate heterogeneity, 50–90%: indicate substantial heterogeneity and 75–100%: indicates considerable heterogeneity (57).

Table 4. Overview of neuroimaging findings in PLS.

	PLS (n)			Other groups (n)
Study (1st author, year, reference)	Total	co-morbid FTD	CI/BI	ALS	PSP	Controls	Imaging Technique	Results
de Koning, 1997 (21)	1	0	1	–	–	–	SPECT	Bilaterally reduced activity in the motor cortex and frontal lobes.
Murphy, 2008 (18)	18	0	4	–	–	7	CT-Perfusion	Increased CBV in the grey matter of the frontal and temporal lobes, basal ganglia and thalamus in the PLS-ci group compared to controls and PLS without cognitive impairment. Increased MTT in the grey and white matter of the frontal, parietal and occipital lobes, basal ganglia and thalamus in the PLS-ci group compared to controls. Cognitive impairment in PLS is associated with haemodynamic compromise.
Pringle, 1992 (26)	8	0	0	–	–	–	MRI (1.5T); structural MRI & [18]FDG PET	Atrophy of the precentral gyrus on structural MRI and diminished glucose uptake in the pericentral cortex on [18]FDG PET.
Kiernan, 1994 (44)	8	0	0	11	–	49	MRI (1.5T); Cortical surface measurements	25% reduction in mean cortical surface area of the precentral gyrus and 15% reduction in the frontal lobes in PLS patients compared to ALS and controls (no differences seen between ALS and controls).
Coon, 2012 (27)	3	0	0	–	10	20	MRI (3T); DTI on regions of interest (CST (pons), body of the CC and superior cerebellar peduncle (decussatio)	Reduced FA in superior cerebellar peduncle and corpus callosum in PLS and PSP compared to controls. FA reduction in the corticospinal tracts only seen in PLS.
Kolind, 2013 (52)	7	0	0	23	–	7	MRI (3T); mcDESPOT protocol (in vivo myelin imaging: SPGR, bSSFP, IR-SPGR)	Cerebral myelin water fraction reductions in PLS, but not in controls and ALS.
Canu, 2013 (15)	21	0	10	–	–	35	MRI (3T); DTI	Increased MD and radD in the CST, corpus callosum, brainstem, anterior limb of internal capsule, superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes, bilaterally in PLS-ci compared to PLS without cognitive deficits and controls. Executive and language test scores correlated with extent of WM damage.
Meoded, 2013 (53)	17	0	4	13	–	17	MRI (3T); structural & DTI	Reduced grey matter volume in the right motor cortex in PLS patients. Wide spread white matter involvement in both ALS and PLS, but no correlation with cognitive performance.
Agosta, 2014 (14)	24	0	2	–	–	26	MRI (3T); resting state fMRI & DTI	Increased functional connectivity in PLS spanning sensorimotor, medial, and dorsal frontal, insular, and superior temporal regions. Level of functional connectivity within the frontal network is correlated with executive dysfunction.
Proudfoot, 2015 (55)	7	NR	NR	61		39	MRI (3T); resting state fMRI	More severe cognitive abnormalities in PLS cases, but test results did not correlate with fMRI results.

PLS: primary lateral sclerosis; FTD: frontotemporal dementia; CI: cognitive impairment; BI: behavioural impairment; ALS: amyotrophic lateral sclerosis; PSP: progressive supranuclear palsy; SPECT: single-photon emission computed tomography; CBV: cerebral blood volume; PLSci: PLS with cognitive impairment; MTT: mean transit time; MRI: magnetic resonance imaging; PET: positron emission tomography; CST: corticospinal tract; DTI: diffusion tensor imaging; CC: corpus callosum; FA: fractional anisotropy; SPGR: sagittal spoiled gradient recalled echo; bSSFP: balanced steady state free progression; IR-SPGR: inversion-recovery-prepared SPGR; MD: mean diffusivity’; radD: radial diffusivity; WM: white matter.

Table 5. Overview of neuropathological findings in PLS.

Study (1st author, year, reference)	n	Phenotype	Cognitive/behavioural changes	Gross inspection	Motor Cortex (UMN)	Spinal cord and brainstem (LMN)	Frontal and temporal cortices	Miscellaneous (cerebellum, basal ganglia, etc.)	Descending axonal pathways.
Pringle, 1992 (26)	1	PLS. Spinal onset (L leg) late fifties, progressing to the bulbar region, no LMN signs, survival 15 years.	None	Cortical atrophy, esp. central sulcus	Loss of large pyramidal cells, with complete absence of Betz cells, in the precentral gyrus.	Motor nuclei in the brainstem and anterior horn cells in the in the spinal cord were preserved and did not contain Bunina bodies or skein-like inclusions.	No abnormalities (no neurofibrillary tangles, pick bodies or Lewy bodies)	No abnormalities in basal ganglia including sustantia nigra.	Myelin pallor.
Sugihara, 1999 (29)	1	PLS with dementia. Spinal onset (legs), late thirties, progressing to the bulbar region, no LMN signs, survival 17 years.	Moderate dementia (not otherwise specified 10 yrs. after onset) progressing to severe dementia over years.	Diffuse cerebral atrophy, particularly of the frontal lobe and precentral gyrus.	Loss of large pyramidal cells, with complete absence of Betz cells, in the precentral gyrus.	Motor nuclei in the brainstem were unaffected. Anterior horn cells in the in the spinal cord were well preserved and did not contain Bunina bodies or ubiquitin positive inclusions. Unusual ballooning of dendrites of anterior horn cells.	Senile plaques and neurofibrillary tangles were absent. Tau staining was negative. Severe dissociate gliomyelinique in frontal lobes and to a lesser degree in the temporal lobe.	Atrophy striatum and thalamus. Preservation of the substantia nigra and no evidence of Lewy bodies. Unusual ballooning of dendrites of Purkinje cells.	Intense pyramidal tract degeneration extending down into the spinal cord.
Engel, 2000 (22)	1	PLS with dementia. Spinal onset (L leg) late fifties, progressing to the bulbar region, no LMN signs, survival 12 years.	Concrete thinking, perseveration, and impaired executive function (7 years after onset) without memory or visuospatial impairment.	Mild, generalised atrophy.	Mild loss of neurons in all parts of the cerebral cortex, but not more prominent in the motor cortex compared to other regions.	Spinal cord motor neurons were preserved. Midbrain, pons and medulla were normal.	Beta/A4 amyloid plaques in all layers of the cortex, but most prominent in orbitofrontal cortex.	Loss of neurons and astrocytosis parahippocampal gyri. Neurofibrillary tangles and Hirano bodies were seen in the hippocampus and parahippocampal gyrus.	Bilateral loss of myelinated axons in the corticospinal tracts in the spinal cord, but did not extend rostrally into the brain stem.
Tan, 2003 (30)	1	PLS with dementia. Bulbar onset, mid-seventies, with progression of UMN signs to the limbs, no LMN signs, survival 7,5 years.	Dementia not otherwise specified. Imaging showed bilateral frontotemporal-predominant cerebral atrophy.	Striking atrophy of the precentral gyrus with marked atrophy of the frontal and temporal lobes bilaterally.	Marked neuronal loss and gliosis, with complete absence of Betz cells. Ubiquitin-positive round- or crescent-shaped inclusions in the remaining neurons.	Lower motor neuron nuclei in the brainstem were well preserved. In the spinal cord, the anterior horn cells were well preserved at all cervical, thoracic, lumbar and sacral levels.	Pronounced decrease in neuropil area, without obvious neuronal loss and gliosis. No evidence for a tauopathy or synucleinopathy. Ammon’s horn, including the dentate granule cells, and amygdaloid nucleus were well preserved.	Mild neuronal loss and gliosis was noted in the neostriatum and thalamus.	Severe degeneration of the corticospinal tract (myelin pallor, gliosis, and scattered macrophages) at the level of the internal capsule, brain stem and spinal cord.
Mochizuki, 2004 (31)	1	PLS with FTD and Parkinsonism. Bulbar onset, late fifties, progression to limbs, rigidity and bradykinesia 5 years after onset, survival 9 years.	Apathetic and severely uncooperative. Imaging: Symmetrical and severe atrophy of frontal and temporal lobes.	Marked atrophy of the frontal and temporal lobes including the precentral and superior temporal gyri. Moderate atrophy of the neostriatum.	Marked neuronal loss in the precentral cortex with complete absence of Betz cells. Ubiquitin-positive but tau-negative intraneuronal inclusions	The hypoglossal nucleus appeared preserved. Anterior horn cells were well preserved.	Neuronal loss and gliosis in the frontal and temporal cortices, most accentuated in the superior temporal cortex. Myelin pallor and gliosis in frontotemporal cortices. The hippocampus and dentate gyrus were relatively preserved. No Lewy bodies, Pick bodies, neurofibrillary tangles, or senile plaques were present.	Moderate neuronal loss and gliosis in the neostriatum. Severe neuronal loss with gliosis of the substantia nigra.	Marked degeneration with gliosis through the internal capsule, medulla oblongata, the lateral and anterior corticospinal tracts of the spinal cord.
Kosaka, 2012 (28)	1	PLS with dementia. Bulbar onset, late seventies, with progression of UMN signs to the limbs, no LMN signs, survival 7 years.	Communication became impossible (language). Frontotemporal cerebral atrophy was evident on MRI.	Atrophy of frontal lobe, especially the precentral gyrus. Additionally there was atrophy of the anterior and medial temporal lobes .	Severe neuronal loss with a complete absence of Betz cells. Ubiquitin-positive neuronal cytoplasmic inclusions. pTDP-43 positive.	Good preservation of the lower motor neuron nuclei in the brainstem and spinal cord.	Ammon’s horn, especially the CA1-subiculum border zone, were unremarkable. No pathological features of tauopathies, including AD or a–synucleinopathies were observed. pTDP-43 positive aggregates.	Neuronal loss was also noted in the neostriatum. The substantia nigra was intact.	Degeneration of the corticospinal tracts in the medulla oblongata and spinal cord with advanced, marked atrophy with dense fibrillary gliosis.

PLS: primary lateral sclerosis; UMN: upper motor neuron; LMN: lower motor neuron; FTD: frontotemporal dementia; pTDP43: phosphorylated 43-kDa TAR DNA-binding protein; AD: Alzheimer’s disease.

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