Case Studies of Plasmalogen

The following case studies were extracted from the book entitled “Dementia is no longer a fatal disease! Plasmalogens in the brain plays a major role in neurogenesis”, co-written by Takehiko Fujino, Shiro Mawatari and Toshihiko Katafuchi (ISBGN978-4-89308-850-5), This book depicts the research findings by Dr Fujino and his team on the research of Plasmalogen and dementia.

Subject A: 80 year-old male, dementia of Alzheimer’s type for 3 years

Although the symptom of repeating activities continues, he began to actively enjoy life after consuming Scallop-derived PLASMALOGEN for 3 months. He took part in ball games at the elderly club, invited friends for a meal and grew vegetables in the garden. His MMSE score also improved by 5 points in 3 months.

Subject B: 70 year-old female, dementia of Alzheimer’s type for 11 years

She suffered from severe delusion and could not take care of herself. Changes were seen two months after she consumed scallop-derived PLASMALOGEN. She was able to apply lipstick and put on accessories without any help. This reduced the burden on her husband as her caregiver.

Subject C: 70 year-old male, dementia of Alzheimer’s type for 1 year

He became irritable due to his inability to carry out his daily tasks. His skill in “Go” (Chinese board game) slackened from level 6 to the beginner’s level. Changes were observed after he consumed Scallop-derived PLASMALOGEN. He became more cheerful and empathetic. He recovered and his skill in “Go” was reinstated to level 6. Now he volunteers and teaches “Go” at a day service facility.

Subject D: A female patient in her 80s suffering from semantic dementia; living with her husband

Summary of patient’s initial condition:
About two years ago, she became reluctant to wash her face and hair, as well as changing into her clothes. In addition, she also suffers from aphasia, apraxia and low memory retention. She could not go to the toilet independently. A year ago, she carried all her personal belongings from her home and left them in various places. Furthermore, she lashes out at others.

First visit in the clinic:
Patient refused to try Scallop-derived PLASMALOGEN when it was given to her.
Husband, “She becomes anxious when I leave her alone, and she is also verbally aggressive whenever I refuse to suit her desires. She did not want to change her clothes or take a bath. I made her call our daughter in Tokyo every night.”
Physician, “Please do not force her to do things against her wishes. Try to mix the Scallop-derived PLASMALOGEN with yogurt. Please continue with the phone calls to her daughter.”
MMSE 1 point
Blood plasmalogen concentration 7.3 (phospholipid ratio)

1 month later:
Patient, “There haven’t been any changes. I remember him (the physician). I do not remember (the taste of Scallop-derived PLASMALOGEN).”
Husband, “There wasn’t any no particular change, except that she now takes Scallop-derived PLASMALOGEN willingly. I prepare her meals every day.”
Physician, “Her MMSE results have improved. Since it is spring now, try to go outdoors and take a stroll. Let her take a bath every day.”
MMSE 5 points (immediate memory 1 -> 3 points, repetition of statements 0 -> 1 point, verbal instruction 0 -> 1 point)

2 months later:
Husband, “There haven’t been any extraordinary changes in her condition. She can now understand simple conversations. She greets me, but as usual, she cannot carry a conversation. Her verbal aggression and emotional excitement have also reduced. She refused to sit on the toilet bowl. She has picked up singing.”
Physician, “Scallop-derived PLASMALOGEN may have helped to reduce her verbally aggressive behaviour. Bathing helps to improve her autonomic nervous system. It would be good for her to enjoy the aroma of citrus as she sings along during her showers.”
MMSE 2 points (immediate memory 3 -> 2 points, repetition of statements 1 -> 0 point, verbal instruction 1 -> 0 point)

3 months later:
Patient, “(Do you remember me?) I do remember. (Do you know about Scallop-derived PLASMALOGEN?) I know it.”
Husband, “She is no longer violent and has since stopped her aggressive verbal responses. The staff at the Day Care Service Centre has informed me that her facial expressions are milder and her verbal violence was not triggered. Now, she goes to the toilet without throwing up a fuss. I followed the doctor’s recommendation to bathe her not just at the Day Care Service Centre but also at home. She avoided baths previously. Now, the hot water makes her feel good and smile. She thanked us.” (*In the past, she cannot wait when left alone. She would walk away while her husband was interviewed, staff had to be sent to accompany her.)
Improvement in MMSE score and blood plasmalogen concentration
MMSE 3 points (immediate memory 2 -> 3 points)
Blood plasmalogen concentration 7.8 (phospholipid ratio)

Dr. Fujino’s comments:
Initially, her condition was so severe that she only managed to score 1 point in the MMSE test. Her MMSE score improved to 3 points after taking Scallop-derived PLASMALOGEN for 3 months. This is a marked improvement as she is suffering from the most severe stage of Alzheimer’s. She has stopped her verbal aggressive behavior and expressing severe facial expression towards others at the Day Care Service Centre, she goes to the toilet without throwing up a fuss, she willingly showers at home and other remarkable behavioral improvement has been observed. We have also noticed improvement in her attitude towards her husband (relatives) and the doctor (others).
These are changes observed in a patient with the most severe condition. Her husband who is not accustomed to care-giving has been caring for her. The improvement seen in this serious condition gives hope to many elderly caregivers.

Subject E: A female patient in her 30s suffering from severe brain dysfunction caused by a traffic accident.

Summary of patient’s initial condition:
She worked as a nurse previously. In 2015, at the age of 25, she suffered from a brain contusion, a traumatic subarachnoid hemorrhage, when she met with a traffic accident while she was pregnant. Her consciousness was impaired; she cannot recollect any memory beyond her high school days but her condition has gradually improved. She gave birth via a Caesarean section but she cannot remember ever giving birth. She suffers from severe high functional brain disorders and exhibited symptoms such as hemiplegia, aphasia and memory impairment. She went through a prolonged period of rehabilitation, she was discharged after a span of two years. The rehabilitation continues after her discharge. She requires care from her family members and close monitoring of her movements.

At the first visit:
Patient, “I have some understanding of plasmalogen. Would it be good to give it a try? (Asked by her mother) I am convinced and I want to try it.”
Mother “She experienced severe anxiety when I was not at home, so it was best not to leave her alone. Now, she’s fine being left alone at home. At home, she bickered with her parents and child. She manifests a different personality at home and outdoors. She enforced her own rules on her daughter and raised her voice if the child did not follow her desires. On top of that, she always wanted to enjoy the same snack her child is having. She could not recall what she wore the previous day, “What clothes did I wear yesterday?” She asks me. Now she goes for rehabilitation once a week and visits a Day Care Service Centre twice a week.”
MMSE 18 points
Blood plasmalogen concentration 7.4 (phospholipid ratio)

1 month later:
Mother, “She no longer gives up quickly.”
Patient, “I have a stronger motivation to get things moving now.”
Physician, “In medicine if you remain hopeless regarding your condition, you will not get better. From now on, please be aware that your condition can be treated. Without willpower, even curable diseases cannot be treated. Now I do see more hope in your eyes.”
Patient, “But it is a necessity to give up (jokingly).” I do need to get better”
Physician, “She started to display higher emotional functions such as embarrassment and humor. Please continue with the rehabilitation treatment. Remain active physically, read a book and enjoy the beautiful scenery.”
MMSE 19 points

2 months later:
Mother “She remembered that I had bought a cake.”
Patient “I do not need to go to work if I continue to weed the garden. Reading a book is troublesome. Everything is tiresome.”
Physician “You are probably afraid to start work. You don’t need to consider returning to the society at this moment. It is important for you to enjoy the present. You can choose an interesting book to read. Your mum has become your biggest support, this will spur your desire to become better. You can pick up some interesting physical activities.”
MMSE 24 points (place orientation 4 -> 5 points, delayed recall 0 -> 3 points, calculation 2 ->4 points)

3 months later:
Mother “One evening when I met up with her at her work place, she mentioned to me that someone working at the same place has passed away”. She repeated the same thing at night. She never mentioned any happenings at her work place previously.”
Physician “There are chances of her recovering well enough to return to the society. You can expect further improvement in her condition.”
MMSE 27 points (Answers 3 questions immediately. Perfect score for computational skills). Tremendous Improvement
Blood plasmalogen concentration 6.8 (phospholipid ratio) Reduced level of blood plasmalogen

Dr. Fujino’s comments:
She met with a traffic accident 10 years ago. She worked as a young nurse before she suffered from dementia caused by the brain damage resulting from the accident. She did not expect to see any improvement. Her family placed their hopes on Scallop-derived PLASMALOGEN. Interestingly, the plasmalogen concentration in her blood has decreased but her MMSE score has improved drastically to 27 points from 18 points (initial assessment), this is close to the range of MMSE score for normal people.

Subject F: A male patient in his 80s with Alzheimer’s dementia, living with his wife

Summary of patient’s initial condition:
Two years ago, his family became aware of the changes in his behaviour when he forgot his purse while travelling overseas. Subsequently, he forgot to switch off his car’s engine after driving. He also tried to drink soy sauce, mistakenly overdosed on medicine and was subsequently sent to the hospital. It was only then that he was diagnosed with dementia. Aricept, an anti-dementia drug, was prescribed to him. However, he has stopped taking the medication as he gets overly stimulated from the use of Aricept. He requires level 3 of receiving care.

At the first visit:
Patient, “I am not forgetful.”
Wife, “He ranted when he was frustrated. He is reluctant to take all heart and blood pressure medicines. He walked alone in the park whenever he’s not in the Day Care Service Centre (We have placed a name tag on him as he might sometimes loiter to a wrong house).”
Physician, “First try to measure his blood pressure at home. Do not blame him for his behaviour and words. Do give him credit for his deeds and words.”
MMSE 15 points
Blood plasmalogen concentration 6.9 (phospholipid ratio)

1 month later:
Wife, “There is a slight improvement in his place orientation, memory retention, concentration and emotions. Initially, after taking Scallop-derived PLASMALOGEN, he rebutted me more frequently.
Daughter, “When I asked my father why he rebuked my mother, he answered me logically.”
Wife, “His tantrums have reduced and he is tamer now. When he was asked to name a flower, he answered “Tulip”. He was able to understand stories. He asked me if he could help me (with the house work) this morning. I was surprised, he has never done this before.
MMSE 12 points (place orientation 3 -> 1 point, calculation 1 -> 0 point)

2 months later:
Patient, “I want to work. I am practicing golf. I think I will ask my son-in-law to bring me to play golf.”
Wife, “He answers with better logic. He is getting lucid motivation such as he wants to work and play golf.”
MMSE 12 points

3 months later:
Patient, “I spoke to my daughter (living apart) on the phone. I was told by the doctors that I have to read the newspapers aloud, but I was scolded blatantly by my wife.”
Wife, “My husband called our daughter via phone for the very first time yesterday, and he said “I want you to wash your hair tomorrow before going to hospital”. He asked our daughter to wash her hair which he usually was reluctant to do it. I helped him in washing his hands but he thought that our daughter did it for him. The chances of him mistaking the front and back of his clothes and confusing the order of dressing have been reduced. He can change his clothes easily most of the time now.
Patient, “I always run 1600m in the park.”
Wife, “In fact we were walking rather than running. One round is 2km, he always tells us a different number.”
Adopted son-in-law, “There are markings indicating 1200 and 1600 on the outside circles in the park, and I think he is mentioning those numbers.”
Wife, “But a mistake is mistake, isn’t it? I can’t stand that he doesn’t correct it.”
Patient, “When I crushed insects, she (wife) says it’s cruel.”
Wife, “I told him not to kill spiders because they are beneficial insects.”
Physician, “Spiders are beneficial insects to you (wife) but they are pests to him (patient). There are written numbers outside the park and your husband can remember clearly. Even if he mentions the wrong numbers, please do not be troubled by this”.
MMSE 20 points (Marked Improvement)
Blood plasmalogen concentration 7.7 (phospholipid ratio) (Improvement)

Dr. Fujino’s comments:
MMSE score of this patient has increased by 5 points in three months, he displays improvement in the areas of time and place orientation, memory retention and replication of graphics. From the anecdotes told by his family, negative feelings (tantrums and anger) have also reduced. He started proactive communications, for instance, wanting to help out. Interestingly, this person remained calm when his wife described his condition to be degenerating. Based on the feedback given by his daughter during consultation he has regained his logic and has showed improvement in his responses. Another interesting thing is his opinions were not aligned with his wife’s, and she insisted that his husband was in the wrong. I think people make the egocentric mistake of considering themselves to be right and everyone else who thinks differently has a problem. It would be important to know that this kind of attitude worsens the condition of dementia patients.

Subject G: A male patient in his 80s with Alzheimer’s dementia, living with 4 other family members

Summary of patient’s initial condition:
10 years ago, the patient and his wife went on a trip to commemorate their wedding anniversary. He could not recall anything the following day. 5 to 6 years ago, he could not recognize his family members. Occasionally, he will request to go outdoors. He has been diagnosed with dementia but he has not been prescribed as he did not visit the hospital.

At the first visit:
Wife, “He lives in the past. He said he has to return to our old house, he also said that someone has free access to the house. He went to his workplace with his son in the morning. He got angry when he thought his son was someone else. He experiences mood swings. At times he will be sad and cries out loud. On other occasions, he will be sharp like a hawk.”
(Doctor pointed to his son and asked, “Who is he:?”) (Doctor pointed to his wife and asked the same question) Patient responded, “They are my neighbours.”
MMSE 14 points
Blood plasmalogen concentration 8.5 (phospholipid ratio)

After 1 month:
Patient, “I do thank my wife occasionally but I also use harsh words on her. Doctor pointed to his wife and asked him, “Who is she?” He responded, “She is my sibling. I do not think I have a disease.”
Wife, “There is no improvement in his symptoms. He still experiences delusion and he still wanders away. He went out alone and came back alone. At night, he went to our old house and he came back after he recognized his mistake. He walks 1.5km to reach his workplace.”
Physician, “He knows how to go home, this cannot be considered wandering. (He smiled when his wife spoke about his story) It is a good sign that he laughs.”
MMSE 10 points

After 2 months:
Wife “He went to the old house in the day. He told me that he had not taken his lunch although he had already eaten. I feel that his condition has deteriorated.”
Son “These are existing symptoms. Nothing has changed. At midnight, he said he would go to the house of a friend, who has died 20 years ago. Many years ago, my father had dozens of employees. However, we only have two employees now and he says he needs to go to work as everyone is waiting for him.”
(Listening to his son) Patient, “What he said has nothing to do with me. I was told by the doctor that there’s nothing wrong with me. These people (wife and son) are my neighbours. We met together today by chance.”
Physician, “He recalls the old days vividly and he smiles from time to time. There is a possibility that he could revive some of his old memory. Please note down what he says. You can also work on this with him (son).”
Patient “They are neighbours and it is difficult to work together because the work is different.”
MMSE 11 points

After 3 months:
Looking at the doctor. Patient, “Have I met you before? I cannot remember. The condition of my brain will not improve, but it’s fine I will not live for long.
Physician,” Are you a little forgetful?
Patient, “Yes”.
Doctor pointed at his wife and asked, “Who is she?” Patient answered, “She is my colleague.”
Wife “His condition is fluctuating. The frequency of the trips to the old house has reduced. He told me that old friend has passed on … the frequency of him mentioning that he had gone somewhere has also reduced. He looked at the number plate of cars and sometimes he can recall it even after 2, 3 minutes. I sense that his memory has improved. Recently, he said ‘Thank you’ after meal.”
MMSE 17 points (Improvement in time orientation, place orientation, calculation)
Blood plasmalogen concentration 8.6 (phospholipid ratio) Blood plasmalogen level remains unchanged

Dr. Fujino’s comments:
The patient suffers from dementia for 10 years. He scored 14 points (moderate dementia) in his MMSE test during the first visit. His behaviour was normal but he could not even recognise his family members, this is very painful for his family. However, we can still see the warmth from the eyes of this sad family and they have accepted his condition. The strong ties between the family members will alleviate the sadness.
The MMSE score of this patient has increased significantly from 14 to 17 points after three-month intake of Scallop-derived PLASMALOGEN. His family noticed an improvement in his memory retention. He also visits the old house less frequently, this is evidence of his ability in recognising the current moment. This patient does not recognise anyone in family, but as long as they continue to accept him warmly, his condition will improve. Therefore, I am positive that his condition will improve gradually.

Subject H: A female patient in her 70s living alone suffering from Alzheimer’s dementia

Summary of patient’s initial condition:
About one and half year ago, she began suspecting that her things have been stolen even when she had put them aside. She visited a hospital nearby and was diagnosed with dementia. Her constant worries at night and led to insomnia. She requires level 1 care in the Day Care Service Centre.
At the first visit
MMSE 17 points
Blood plasmalogen concentration 6.4 (phospholipid ratio)

After 1 month:
Patient, “It’s fun to go to the Day Care Service Centre.”
Daughter, “She goes to the Day Care Service Centre on weekdays. I talk to her on the phone every morning and evening. She was in good condition for the first half of the month. She laughs heartily and frequently. She also says positive words. However, she does not sleep well when she has a concern.
MMSE 22 points (Orientation 4 -> 6 points, calculation 1 -> 4 points)

After 2 months:
Patient, “Previously, I always forgot things. Now, I remember where I have placed my things and I no longer need to go on a rampage.”
Daughter, “Her MMSE score has improved. However, she still has a sulky mood when we converse on the phone ….”
Patient, “This is due to the unhappy events at the Day Care Service Centre. I tolerated the stress from facing others while I helped out. I am agitated, I was more carefree previously.”
Daughter, “She can sleep better now as she gets exhausted after her day at the Day Care Service Centre.”
MMSE 24 points

After 3 months:
Patient, “I am mentally drained at the Day Care Service Centre, I think this is because I think too much. I was frequently told to help others now that I have recovered. I am an optimist and I prefer not to think too deeply.
Daughter, “I think she’s tired as she cares too much for others. At night, she would tell me about her daily frustrations on the telephone. She also informed me about missing items.”
Patient, “I regret venting my frustrations at my daughter.
Daughter, “She would usually forget that she had phoned me. Now she can remember better and knows that she had called.”
MMSE 22 points. Marked improvement in MMSE score
Blood plasmalogen concentration 7.2 (phospholipid ratio) Marked improvement in blood plasmalogen level

Dr. Fujino’s comments:
This is a very interesting case study. The patient was receiving care from the Day Care Service Centre but her role has reversed and she became a caregiver after seeing an improvement in her condition. As a caregiver, she will experience more stress and this can cause frustrations. For this reason, her daughter (the caregiver) gave a poorer evaluation as she felt that her conditions have worsened, this is in contrast with her increase in her MMSE scores.
When she came back to the hospital 2 months later, she said that she was troubled by the events at the Day Care Service Centre, she dealt with the stress from caring for other people. For her, this was not a concern previously. She expressed her reasons with clarity. There are many patients who are anxious because they cannot comprehend their situation. Now that she has improved, she can consider the events objectively. However, once she gets better, she always complains to her family members who are closest to her. Her increased capability to complain causes her family to mistake her condition to be worsening.

Subject I: A male patient in his 70s suffering from Lewy body dementia; living with his wife and daughter

Summary of patient’s initial condition:
He first started his checkups in a hospital near his place 4 years ago when he was found to be facing problems with memory retention. He has been prescribed one tablet of Aricept daily. His condition was good for the next 3 years but he later started having hallucinations when the dosage was increased to 2 tablets daily, he has stopped taking Aricept. He has tried other drugs but his hallucinations continue to haunt him. This patient was then transferred to another hospital.

At the first visit:
Wife, “One Saturday morning, he suddenly disappeared. We found him at a bus stop. He then told us that he went to resident’s association. Since then, we have made multiple attempts to stop him from wandering away. He likes to make a clicking sound with his ballpoint pen.”
Physician, “You should not blame him for his forgetfulness. We should always thank each other to recognize the efforts made. When he is at the Day Care Service Centre, you should take a break from caring for your husband. Do not warn, order or discipline him. Family members can take turns to show him care and concern.”
MMSE 11 points
Blood plasmalogen concentration 8.0 (phospholipid ratio)

After 1 month:
Patient, “Hallucinations have become less frequent. Now, I can strike up conversations with acquaintances. My wife reassured me that I am in a good condition and I sense that I am getting better. I met you (doctor) and this spurs me to do my best.”
Wife, “After taking Scallop-derived plasmalogen for a week, he told all his children to come home. The next day, he repeatedly instructs me to prepare the meals as all our children are coming home. The following day, he informed me of 500,000 yen credited to our account. His hallucinations and delusions lasted for 3 days. He seems to be suffering from hallucination occasionally but it has diminished since then. He also experiences urinary incontinence less frequently. Now, he can confidently go around without diapers. He now keeps his dentures and folds his futon. He couldn’t use the TV remote control. I have taught him to press the red button several times and he was able to turn on the TV after 2 – 3 days. He previously always forgot the location of the altar in our house, but now he knows where he can find it and prays daily. I can sense his gradual improvement. His facial expressions have improved, some of our children noticed them. The children have been working hard. (To her husband) He can soon bathe on his own.”
Patient has tears in his eyes as his family speaks about him.
Wife, “I think he is happy.”
MMSE 11 points

After 2 months:
Patient, “This month, I experience the greatest change in my life. I cannot really express this in words, but I can feel the difference. I also think that the flowers in the garden are beautiful.”
Wife “When I greet him, most of the time, his response is lukewarm but he talks a lot in front of the doctor. Now, he goes to the Day Care Service Centre twice a week. He seems to enjoy gymnastic and favourite karaoke there. His laughter has returned and he is facially expressive once again. I sense that the improvement was not as great as what we have experienced in the previous assessment, so I told him that he is not trying his best. He thanked me once. However, he does not express gratitude with words of appreciations most of the time. He started to put his hands together for prayers in front of the altar recently, he didn’t do that previously. He said the food there was delicious and eats more than before. He made ticking sound with ball pen a little less frequent now.
MMSE 15 points (place orientation 3 -> 4 points, naming objects 1 -> 2 points, verbal instruction 1 -> 3 points, spontaneous writing 0 -> 1 point, written instruction 1 -> 0 point)

After 3 months:
Patient, “The hallucinations have almost stopped entirely.”
Wife “He started to question me about where we will be going today. He seems to be anticipating a trip. He was disappointed when I told him there aren’t any plans today. He was happy when his daughter brought him out for a walk on Saturday. Now, he can express himself more freely. I have tested the temperature of the tea. He could tell me that the water for making tea was not right, he could recall my dislike for cold tea. There was a karaoke held by the OB Association and I refused to let him go, but he insisted. After that, he hummed to the tunes. He did not notice his incontinence. At night, he requested for diapers and since then he has been in his diapers once again. He had excreted in his diapers thrice. During the day, he uses the toilet and remembers to flush it but he tends to forget at night. I ordered him to go for a bath. He can now shampoo his hair. Today, he is able to walk as quickly as he used to. He went to the bathroom before the consultation and it seemed he couldn’t figure out how to open the door. His condition is inconsistent.”
MMSE 18 points (time orientation 1 -> 2 points, place orientation 3 -> 5 points, delayed recall 1 -> 3 points, written instruction 0 -> 1 point, naming objects 2 -> 1 point, spontaneous writing 1 -> 0 point) Marked Improvement in his MMSE score
Blood plasmalogen concentration 8.3 (phospholipid ratio) Blood plasmalogen level remains unchanged

Dr. Fujino’s comments:
This is a rare case in which the MMSE score of this patient improved 7 points in 3 months. “This month, I experience the greatest change in my life” “I think that the flowers in the garden are beautiful.” These phrases show the revival of ultra-high-order brain function of the patient. After 3 months, hallucination has almost disappeared. In other words, the scariest symptom of Lewy body dementia has disappeared. However, sometimes it seems that he does not know how to open the door when he goes to toilet. This shows that he will not recover immediately as he is still in the midst of recovery. There is clear evidence that the patient improves towards normal condition since he has the desire to go outside. Thus, it is very important to allow him to go out, even though caregivers are a bit anxious about him.

Other Successful Case Studies of Plasmalogen

In the video below, we examine case studies of patients who have consumed Scallop-derived PLASMALOGEN.

Subject J (88), dementia of Alzheimer’s type

She experienced changes to her condition just one month after consuming Scallop-derived PLASMALOGEN. According to her family members “She reads more books than before and she is a tidier person now.”

Subject K (81), dementia with Lewy bodies

She used to experience hallucinations, which is one of the symptoms of Lewy body dementia. Amazing changes were observed 2 weeks after the intake of Scallop-derived PLASMALOGEN. She showed drastic improvement in her condition and she stopped having hallucinations.

Pls refers to Scallop-derived PLASMALOGEN

Follow the footsteps of Mr. Fuji to explore the benefits of Scallop-derived PLASMALOGEN on patients with Alzheimer’s and dementia. This Thai documentary was broadcasted on Thailand’s National TV. The Scallop-derived PLASMALOGEN featured in this trial is in the jelly form, while the commercial version is in a capsule form (for better protection of the integrity of the substance).